Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats

Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats Mohamed Fouad, Hekma A. Abd El Latif, May Galal, Mohammed El Yamani, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-44926/v2 This work is licensed under a CC BY 4.0 License Status: Under Review Version 2 posted 11 You are reading this latest preprint version Show more versions Abstract Background : The investigation aims to represent the activity of sarpogrelate, a particular 5-HT (2A) receptor blocker, in reducing myocardial injury prompted by extended haul utilization of D 2 agonist drugs in diabetic rats. Dopamine D2 agonists are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation showed between the enlistment of myocardial injury ailment and long term treatment with dopamine D 2 agonist drugs identified with the partial initiation of 5-HT 2a receptors. Methods : Both bromocriptine and cabergoline were managed independently and combined with sarpogelate for about a month to diabetic nephropathy rats. Both tail-cuff blood pressure and BGL were recorded weekly. For all animals, kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of LDH-1, cardiac troponin I, and TNFα. Triphenyl tetrazolium chloride staining method used to determine experimental myocardial infarction (MI) size. Results : Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine, cabergoline, alone, or in combination with sarbogrelate fundamentally diminished blood concentrations of ALP, AST, urea, and creatinine. Bromocriptine and cabergoline alone showed noteworthy ascending of LDH-1, Troponin I, and TNFα1 levels in the serum (p<0.05). Paradoxically, utilizing bromocriptine and cabergoline with sarpogrelate treatment altogether diminished the degree of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed utilizing the TTC staining method. Conclusions : The examination exhibited that both bromocriptine and cabergoline could be utilized safely in blend with sarpogrelate for a long duration of treatment for diseases like hypertension and diabetes. Pharmacodynamics Cardiovascular diabetic nephropathy myocardial injury TNFα1 Dopamine receptors Figures Figure 1 Background Regarding various diabetes progress complications, diabetic nephropathy is the foremost well-known renal difficulty and the ultimate source of end-stage renal disease. The later phases of diabetic nephropathy define glomerulosclerosis. It was represented by transforming growth factor-ß1 overexpression, extracellular matrix deposition, and glomerular structure loss [1]. Hyperglycemia is the primary factor for the progress of diabetic nephropathy [2]. It has been demonstrated in several in vitro studies of STZ-induced diabetic nephropathy where serious glucose-induced renal damage is claimed to excessive production of reactive oxygen species (ROS) under hyperglycemic conditions [3, 4, 5]. Bromocriptine is a sympatholytic dopamine D2 agonist that has been approved for treating type 2 diabetes without risk of hypoglycemia because there is no insulin secretion. Supported previous studies stated bromocriptine administration believed to strengthen low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the central system, leading to a reduction in post-meal plasma glucose levels because of enhanced suppression of hepatic glucose production [6, 7]. Agonists working on dopamine D2 receptors can lower hypertension sign by inhibition of Na/k ATPase activity, vasodilation, and sympathetic nerve activity inhibition. Bromocriptine may secure against I/R injury of the kidney utilizing p44/42 mitogen-initiated protein kinase actuation [8] and preventing chronic nephropathy [9]. Conversely, the bromocriptine-actuated hypotension was wholly nullified by pretreatment with metoclopramide, a dopamine D2 receptor antagonist that crosses the barrier [10, 11]. However, D2 agonists' use is often related to cardiovascular complications, including hypotension and myocardial disorder. There is an identified relationship between the utilization of D2-like R agonists in patients with Parkinson's disease and cardiopathy, especially in the early phase of therapy [12]. D2 receptors are pleiotropic receptors having multiple effects in that activating them inhibits adenylyl cyclase, resulting in inhibition of voltage-gated calcium ions and activation of potassium conductance [13]. Early studies suggested that the use of D2 receptor agonists resulted in a reduction in pituitary tumor mass [14]. It was demonstrated that long term use of bromocriptine therapy was associated with an increased risk of developing heart disease, which occurred in a cumulative dose-dependent treatment [15]. Dopamine D2 receptor agonists are classified as ergot dopamine D2 agonists and non-ergot D2 agonists. Bromocriptine and cabergoline (ergot derivative) are related to valvular cardiopathy since the two drugs have both dopamine D2 and serotonin 5-HT (2A) receptors agonistic activities. Pramipexole (non-ergot derivative) shows few incidences of heart disease onset since it does not affect 5-HT (2B) receptors [16, 17, 18]. Both sarpogrelate and ketanserin (selective 5HT2a/2b antagonists) constrict cardiac brokenness, infarct size, and changes within the electrocardiogram because of myocardial injury. Likewise, these outcomes bolster the view that serotonin and 5-HT (2A) may augment the harmful impacts of ischemic injury within the heart [19, 20]. Sarpogrelate found to possess beneficial impacts in peripheral vascular sickness, restenosis after coronary stenting, pneumonic hypertension, intense and relentless myocardial localized necrosis [21]. The current study aims to identify the possible protective effect of sarpogrelate, a 5-HT (2A) receptor blocker, associated with cumulative use of D2 agonist drugs therapy on cardiac and renal functions in the diabetic nephropathy model of rats. Materials And Methods Materials Sarpogrelate was obtained from Shanghai Linebon Ltd. Shanghai, China. Bromocriptine was from Novartis, Italy. Cabergoline was purchased from Pfizer, Italy. Domperidone was purchased from Jamjoom pharmaceutical company, KSA. Alloxan was obtained from Sigma‐Aldrich (St Louis, MO, USA). Urea; Creatinine; Alkaline Phosphatase; Aspartate Aminotransferase Activity; LDH-1 assay kits; and TNF alpha ELISA Kit were obtained from Abcam company. Troponin I test kit was obtained from Encode Medical Engineering Company, Jeddah, KSA. 2,3,5-Triphenyltetrazolium chloride was obtained from Gold Biotechnology, USA. Animals Forty-two Wister albino male rats 5–7 weeks of age weighing 150 –200 g were obtained from the animal house of Batterjee medical college, Jeddah, KSA. The animals were housed three per cage under controlled standard laboratory conditions in monitored ventilated cages and spontaneously given food and water. The ethical committee of research of Batterjee medical college approved the steps of the investigation. Tutelage was taken, particularly with relevant housing conditions, to avoid or minimize the animals' discomfort. The animals were kept on solid floored cages with a deep layer of sawdust, and the cages were changed daily. Data were coded prior to analysis so that the treatment group cannot be identified before analysis is completed. At the end of the study, all animals were euthanized by thiopental (intravenous injection, 150 mg/kg) for tissue collection. Induction of diabetes by alloxan Alloxan monohydrate was dissolved in sterile normal saline. Diabetes was induced in 30 rats (150-200 g) by a single intraperitoneal injection of alloxan (5%) 150 mg/kg b.w. The rats kept fasting for 12 h before the injection of alloxan. Fasting plasma glucose was measured in blood samples collected from the tail vein. The rats which showed a plasma glucose level of 200 mg/dl or more were considered diabetic and taken in the study [22]. Experimental design Tests took place four weeks after the induction of diabetes. The diabetic rats divided randomly into six diabetic groups and one healthy control group, each group of 6 rats. The sampling calculation was done based on the resource equation method [23]. Once there was a stable rising in the urea and creatinine levels in the blood, drugs were injected once daily for one month. The normal control group (Saline, IP) Diabetic control group (Saline, IP) Diabetic group treated with bromocriptine (4 mg/kg b.w, IP) [24] Diabetic group treated with cabergoline (0.6 mg/kg b.w ,IP) [25] Diabetic group treated with sarpogrelate (50 mg/kg b.w, IP) [26] Diabetic group treated with a combination between bromocriptine and sarpogrelate at the same doses. Diabetic group treated with a combination between cabergoline and sarpogrelate at the same doses. Determination of blood glucose level Blood glucose levels were tested on the 7 th , 14 th , 21 th , and 28 th days from the beginning of the treatment. One millimeter of its end cut and a drop of blood was used for blood glucose tests using an advanced glucometer (Roche, USA). The accuracy of glucometer was checked with the O-toluidine method [27]. Blood Pressure Recording Basal blood pressure was measured employing tail-cuff non-invasive blood pressure recorder apparatus (Ugobasile instruments, Italy). The measurement of the mean systolic blood pressure for each group of rats was done once time weekly for one month. Each rat was placed in an exceeding restrainer, and an appropriate cuff sensor mounted on its tail and warmed to about 33- 35 °C. The tail cuff was inflated to a pressure above 200 mmHg, systolic blood pressure; diastolic blood pressure was measured directly by the tail-cuff and pulse sensor two hours after treatment of drugs [28]. Estimation of liver & kidney functions At the end of the study, the blood sample was withdrawn through the retro-orbital venous plexus method, kept at 37°C for 30 min, and centrifuged at 4°C, 3000 rpm for 10 min. Then the separated serum was stored at -20°C for various biochemical analyses. Alkaline phosphatase and aspartate aminotransferase activities were determined using the method described by King and King (1954) [29]. The procedure of Tietz et al. (1994) [30] was used to determine serum creatinine concentration, while the serum urea concentration was determined by the method of Kaplan (1965) [31]. After the end of the study, all of the rats were sacrificed. The kidneys samples were collected, washed with normal saline, and weighed. The kidney hypertrophy index was calculated by determining the kidney weight and body weight ratio (g/g) x10 3 . Estimation of serum biomarkers of myocardial injury The severity of the cardiac injury was assessed by estimating lactate dehydrogenase (LDH-1) and cardiac troponin I (cTnI) in serum. LDH-1 and troponin levels were analyzed by spectrophotometric methods using commercially available diagnostic kits consistent with the methods of Nieland [32]. Serum TNF-α concentration Serum TNF-alpha cytokines level was identified by the ELISA technique using a quantitative sandwich enzyme immunoassay technique (Abcam Company). The test was done according to the company's instructions. The ELISA reader's optical density at 405nm was immediately calculated and applied on a standard curve to sort out the cytokines' concentration. Evaluation of Myocardial Infarct Size by TTC For assessment of the myocardial infarcted area, the hearts were removed, washed in phosphate-buffered saline, frozen, and stored at −20°C. The frozen hearts were sliced into 1 mm sections along the long axis from apex to base. Triphenyl tetrazolium chloride (TTC) staining is accustomed to assess myocardial tissue viability and determine myocardial infarction size. The tissue slices were incubated in 1% TTC PBS solution, pH 7.4, at 37°C for 20 min. Tissues were fixed in 10% PBS-buffered formalin overnight at 2°C–8°C. Either side of every TTC-stained tissue slice was photographed with the photographic camera to differentiate the red-stained viable and white-unstained necrotic tissues [33]. Digital photographs are downloaded to a computer. Areas stained in white and red were measured using SigmaScan software (SPSS Science) in trace-measurement mode. That mode was wont to measure either the ischemic or the infarcted areas, which may be a sum of calibrated pixels during a defined region. This was done manually by drawing an image layer on the photograph [34]. The infarction size percentage was calculated using the following equation: The percentage of Infarct volume = Infarct volume / Total volume of slice X 100 Statistical analysis The data and statistical analysis done comply with the recommendations on experimental design and analysis in pharmacology [35]. The results expressed as mean± SE. The significance of the differences between the values were performed by a one-way ANOVA test and Dunnett's Multiple Comparison Test using GraphPad Prism software. P < 0.05 was considered to be a significant difference. Results Estimation of blood glucose levels The diabetic control group showed a significant increase in BGL compared to the healthy control group. On repeated administration of the bromocriptine (4 mg/kg), cabergoline (0.6 mg/kg) individually or in combination with sarbogrelate, a significant (p < 0.05) decrease in blood glucose by time was observed compared to the diabetic control group throughout the four weeks of treatment (Table 1). Kidney hypertrophy index The results showed that the kidney hypertrophy index significantly increased in the diabetic group of rats compared with the normal control rats. However, the index was markedly reduced by both bromocriptine and cabergoline treatment, even individually or mixed with sarpogrelate (as seen in Table 2). There is no effect of using sarpogrelate on the diabetic kidney index. Hemodynamic Parameter (Antihypertensive activity) Alloxan-induced diabetes in rats showed a significant rise in blood pressure after three weeks from the induction of diabetes. Daily oral administration of bromocriptine and cabergoline individually or in combination with sarpogrelate showed a significant decrease in the systolic blood pressure in third week and fourth week of treatment (Table 3). There is no effect of sarpogrelate on BP in diabetic rats. Estimation of Liver and kidney Functions: The serum levels of AST, ALP, urea, and creatinine as an indicator of liver and kidney functions are recorded in table 4. Data revealed that the diabetic control group had a significant increase in the previous biomarkers' serum concentrations compared to the healthy control rats. Daily administration of bromocriptine, cabergoline even alone, or in combination with sarbogrelate significantly decreased serum concentrations of the previous biomarkers compared to the positive control of diabetic rats. There is no marked effect of sarpogrelate treatment on the previous biochemical indicators in the diabetic rats. Myocardial biomarkers Animals treated with bromocriptine and cabergoline for one month in doses 10 mg/kg and 0.6 mg/kg respectively displayed significant elevation of LDH-1 activity in the serum. By contrast, using a combination of bromocriptine and cabergoline with sarpogrelate treatment significantly decreases the level of the biomarkers in the serum were observed. The results in table 5 indicated that the qualitative test of the troponin I reagent kit showed only positive results with bromocriptine and cabergoline treated groups. The results of the ELISA test indicate that the expression levels of TNF-alpha 1 in the diabetic rats' groups treated with bromocriptine or cabergoline individually were significantly higher comparing to the diabetic control rats. The groups of combinations between bromocriptine and cabergoline with sarbogrelate showed lower TNF-alpha 1 expression levels than the groups treated with bromocriptine or cabergoline individually (Table 5). Evaluation of myocardial injury Myocardial infarction size was used as an indicator of the progress of the myocardial injury. The hearts of rats treated with bromocriptine 4 mg/kg, and cabergoline 0.6 mg/kg showed a significant increase in risk area infarction. By contrast, the combination of bromocriptine or cabergoline with sarpogrelate (50 mg/kg) reduced the percentage of the myocardial infarct size (Figures 1A, 1B). Discussion Both bromocriptine and cabergoline induced hypoglycemic activity may be due to enhanced suppressive hepatic glucose production [36]. The exact mechanism of action as antidiabetic is not entirely identified; bromocriptine decrease hepatic production of glucose, increase glucose transporter production, or increase or mimic glucagon-like peptide-1 activity [37]. Its contribution to hypoglycemia may be due to adjustments in the neural control of seasonal and patterns of food intake and nutrient storage [38]. Bromocriptine was approved by the Food and Drug Administration (FDA) in May 2009 for the treatment of type 2 diabetes. In the present study, diabetic nephropathy is the most common cause of renal complication and the leading of hypertension. Both bromocriptine and cabergoline showed a marked antihypertensive activity, which agrees with some previous reports [39, 40]. This action is related to dopamine D2 receptors acting drugs can lower the blood pressure by inhibition of Na/k ATPase activity, vasodilation, and inhibition of sympathetic nerve activity. Both bromocriptine and cabergoline induced a marked improvement in the kidney function by decreasing urea and creatinine serum levels. The pharmacological pathways that explain this effect have not been sufficiently determined. The result agrees with some of the previous studies suggesting that the development of therapies directed to increase renal D2 receptor expression/function may provide novel and practical approaches to treating renal injury [41]. The high noted adverse effect of bromocriptine and cabergoline on the heart is represented in myocardial injury and infarction approved in the present study by using relative overdoses for a month of treatment manner. The action may be related to dopamine D2 and serotonin 5-HT (2A) receptors agonistic properties, increasing the heart pumping rate. It has been reported that both bromocriptine and cabergoline (ergot derivative) have been associated with heart disease since the two drugs have both dopamine D2 and serotonin 5-HT (2A) receptors agonistic properties [17, 18]. It is hypothesized that the 5-HT2A receptor is a common contributing factor underlying aspects of vasoconstriction and cardiovascular disorders [42] and vasodilation through activating nitric oxide (NO) synthase (NOS) via serotonin 5-HT (1B) receptors in endothelial cells, possess different effects on regulating vascular tone. These facts lead to consider that sarpogrelate, a 5-HT (2A) receptor blocker, may increase coronary blood flow via either attenuation of vasoconstriction through 5HT(2A) receptor blockade or of vasodilation by relative stimulation of NOS through 5-HT1B receptor [43]. According to the current observed data, the combination of bromocriptine and cabergoline with the new chemical agent sarpogrelate (selective 5HT2a/2b antagonists) decreases the adverse effects of these two drugs on the heart. The protective effects of sarpogrelate on myocardial tissue were approved by its ability to decrease the secretion of myocardial biomarkers. As shown by decreasing LDH-1, Troponin I, and TNF alpha 1 during the treatment of bromocriptine and cabergoline. Sarpogrelate attenuates cardiac dysfunction, infarct size; these results support the view said that serotonin and 5-HT (2A) might contribute to the harmful effects of ischemic injury in the heart. Regarding the biochemical study, sarpogrelate drug can be considered a safe drug on liver and kidney functions. Conclusions According to the given study, both bromocriptine and cabergoline can be used safely in combination with sarpogrelate for the treatment of many diseases like hypertension, diabetes, and Parkinsonism. Thus, we hypothesize that sarpogrelate deserves additional experimental and clinical research related to cardiovascular diseases. Abbreviations ALT: Alanine Aminotransferase AST: Aspartate Aminotransferase TNF: Tumor necrosis factor TTC: Triphenyl tetrazolium chloride LDH: Lactate dehydrogenase TTC: Triphenyl tetrazolium chloride 5HT: 5- hydroxytryptamine ELISA: Enzyme-linked immunosorbent assay Declarations Ethics approval and consent to participate: The study was approved in December 2019 by the ethical committee of research of Batterjee medical college. The committee consists of four people. The research protocol and the study plan were submitted. The committee held a comprehensive discussion of risks and benefits before reaching the approval conclusion. During the study, the research coordinator of the ethics committee updated the progress of the research. In addition, the research experiments on animals followed the guidelines of the experimental animals’ research and ethics committee "EAREC", King Abdulaziz University. Consent for publication Not applicable Availability of data and materials Not applicable Competing interests No competing interests Funding There was no funding available for the current manuscript submitted. Authors' contributions All authors conceived and planned the experiments. MF carried out the implementation of the experiments. RM planned and carried out the statistical analyses and contributed to sample preparation. MF took the lead in writing the manuscript. HA, MY, MG, and SK contributed to the interpretation of the results, provided critical feedback, supervision and helped shape the research, analysis, and manuscript. Acknowledgments I would like to express my sincere gratitude to my advisor Prof. Hekma Abdul Latif, for her continuous support of my researches, for her patience, motivation, and immense knowledge. I would like to thank the rest of my thesis committee: Assistant Prof. May Galal, Assistant Prof. Mohamed El yammany, for their, insightful comments. 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D., Zhang, Y., Yang, Y., Drachenberg, C., Zheng, X., Han, F., Jose, P. A., & Armando, I. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight. 2016; 1:e85888. doi:10.1172/jci.insight.85888 Nichols CD. Serotonin 5-HT(2A) Receptor Function as a Contributing Factor to Both Neuropsychiatric and Cardiovascular Diseases. Cardiovasc Psychiatry Neurol. 2009; 2009:475108. doi:10.1155/2009/475108 Fujita, M., Minamino, T., Sanada, S., Asanuma, H., Hirata, A., Ogita, H., Okada, K., Tsukamoto, O., Takashima, S., Tomoike, H., Node, K., Hori, M., & Kitakaze, M.Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts. J Mol Cell Cardiol. 2004; 37:1219-1223. doi:10.1016/j.yjmcc.2004.09.016 Tables Table 1: Effect of the tested drugs on BGL in alloxan-induced diabetic rats. BGL mg/dL Groups week 1 week 2 week 3 week 4 Normal control group 136.5 ± 18.52 121.33 ± 12.08 119.25 ± 11.35 109 ± 10.92 Diabetic control group 359.75 ± 45.13* 328 ± 141.34* 428.5 ± 121.17* 396.5 ± 80.60* Diabetic group treated with Bromocriptine 191 ± 16.89 # 199.25 ± 65.05 # 238.25 ± 56.88 # 284.25 ± 148.00 # Diabetic group treated with Cabergoline 213.75 ± 37.74 # 211.75 ± 38.62 # 293 ± 213.15 # 280.25 ± 220.48 # Diabetic group treated with Sarpogrelate 326.25 ± 93.45 298.25 ± 122.37 393.75 ± 118.77 369.75 ± 43.15 Diabetic group treated with Bromocriptine +sarpogrelate 247.75 ± 50.35 # 215.5 ± 33.20 # 310.25 ± 70.59 # 288.25 ± 109.41 # Diabetic group treated with cabergoline + sarpogrelate 196 ± 54.20 # 158.75 ± 35.01 # 235.5 ± 182.22 # 215.75 ± 141.46 # Values shown are means ± SEM; n = 6 rats per group. * P < 0.05, significantly different from normal control group; # P < 0.05, significantly different from diabetic control group. Table 2: Effect of the tested drugs on Kidney Hypertrophic Index in alloxan-induced diabetic rats. Kidney Hypertrophic Index Groups KHI ( g/g * 1000 ) Normal control group 4.555 ± 0.423 Diabetic control group 6.6125 ± 0.57* Diabetic group treated with Bromocriptine 4.7475 ± 0.33 # Diabetic group treated with Cabergoline 4.81 ± 0.49 # Diabetic group treated with Sarpogrelate 5.90 ± 0.27 Diabetic group treated with Bromocriptine +sarpogrelate 4.715 ± 0.61 # Diabetic group treated with cabergoline + sarpogrelate 4.46 ± 0.48 # Values shown are means ± SEM; n = 6 rats per group. * P < 0.05, significantly different from normal control group; # P < 0.05, significantly different from diabetic control group. Table 3: Effect of the tested drugs on mean systolic blood pressure in alloxan-induced diabetic rats. Mean Systolic Blood Pressure MSBP (mmHg) Groups week 1 week 2 week 3 week 4 Normal control group 110 ± 4.01 118.25 ± 8.99 108.75 ± 4.57 111.5 ± 4.20 Diabetic control group 112.5 ± 9.14 121.75 ± 11.35 150.75 ± 5.25* 151.25 ± 5.12* Diabetic group treated with Bromocriptine 115 ± 9.12 102.75 ± 6.8 109 ± 10.23 # 121.75 ± 15.26 # Diabetic group treated with Cabergoline 103.75 ± 7.0 105.5 ± 9.14 123 ± 7.87 # 107.75 ± 107.75 # Diabetic group treated with Sarpogrelate 118.75 ± 10.87 114.75 ± 8.53 137.75 ± 8.53 139 ± 18.56 Diabetic group treated with Bromocriptine +sarpogrelate 104.5 ± 7.59 104.75 ± 4.99 106.25 ± 11.08 # 118 ± 13.03 # Diabetic group treated with cabergoline + sarpogrelate 109.25 ± 11.58 105 ± 9.05 106 ± 18.3 # 104.25 ± 5.5 # Values shown are means ± SEM; n = 6 rats per group. * P < 0.05, significantly different from normal control group; # P < 0.05, significantly different from diabetic control group. Table 4: Effect of the tested drugs on liver and kidney functions in alloxan-induced diabetic rats after 4 weeks. BIOCHEMICALS Group ALP(IU/L) AST(IU/L) Urea (mmol/L) Creatinine (mmol/L) Normal control group 60.85±8.77 25.04±4.96 43.38±4.77 0.46 ± 0.07 Diabetic control group 89.05±10.44* 45.86±7.57* 75.81±18.85* 1.89 ± 0.19* Diabetic group treated with Bromocriptine 68.83±7.27 # 34.18±5.78 # 60.41±6.22 # 1.04 ± 0.26 # Diabetic group treated with Cabergoline 73.27±7.93 # 21.37±10.05 # 52.09±2.23 # 0.79 ± 0.11 # Diabetic group treated with Sarpogrelate 82.16±23.83 41.47±10.02 69.41±7.65 1.68 ± 0.25 Diabetic group treated with Bromocriptine +sarpogrelate 64.8±7.21 # 31.03±6.44 # 44.4±8.23 # 1.26 ±0.25 # Diabetic group treated with cabergoline + sarpogrelate 73.44±6.68 # 33.79±11.18 # 51.16±10.43 # 1.33 ± 0.21 # Values shown are means ± SEM; n = 6 rats per group. * P < 0.05, significantly different from normal control group; # P < 0.05, significantly different from diabetic control group. Table 5: Effect of the tested drugs on Lactate dehydrogenase-1 and TNFα1 in alloxan-induced diabetic rats. BIOCHEMICALS Group LDH (IU/L) TNFα1 (pg/mL) Normal control group 17.42± 0.69 06.12±0.45 Diabetic control group 18.50 ± 1.53 08.32 ±0.56 Diabetic group treated with Bromocriptine 40.50 ± 10.69 # 36.56 ±2.32# Diabetic group treated with Cabergoline 36.86 ±12.47 # 31.20 ±4.23# Diabetic group treated with Sarpogrelate 19.55 ± 2.20 09.74 ±0.98 Diabetic group treated with Bromocriptine +sarpogrelate 27.75 ± 3.91 a 14.84 ±1.23 a Diabetic group treated with cabergoline + sarpogrelate 34.57 ±6.60 b 08.59 ±0.76 b Values shown are means ± SEM; n = 6 rats per group. # P < 0.05, significantly different from diabetic control group. a P < 0.05, significantly different from diabetic group treated with bromocriptine. b P < 0.05, significantly different from diabetic group treated with cabergoline. Cite Share Download PDF Status: Under Review Version 2 posted Editorial decision: Major revision 31 Jan, 2021 Review # 3 received at journal 24 Jan, 2021 Reviewer # 3 agreed at journal 14 Jan, 2021 Review # 2 received at journal 10 Jan, 2021 Review # 1 received at journal 12 Nov, 2020 Reviewer # 2 agreed at journal 28 Oct, 2020 Reviewer # 1 agreed at journal 26 Oct, 2020 Reviewers invited by journal 26 Oct, 2020 Editor assigned by journal 10 Sep, 2020 Submission checks completed at journal 09 Sep, 2020 Editor invited by journal 09 Sep, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-44926","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":2268580,"identity":"529544a3-0f84-44f9-894b-75be9118ac62","order_by":0,"name":"Mohamed Fouad","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBACgwOMD4CUBA8/AwMbcVosDzAbACkLOckGYrXYQ7RUGBscIFaL2fHDbB8+1Egkbr6R/OzBhwoGeX6xAwS0nElmnjnjmETithtp5oYzzjAYzpydQEDLgfzDzLwNIC0JZtK8bQwJBrcJaDE4/5iZ+S9Qy+YZ6d+I1HIjmZmZsUHC2EAih1hbbjxmZuw5JiEnceZNmeSMMxKE/WJwPpmZ4UdNHQ9/e/o2iQ8VNvL80gS0IIAAWKUEscpBgP8AKapHwSgYBaNgJAEAoWpDbTKo8FQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-6291-6784","institution":"Batterjee Medical College for Sciences and Technology","correspondingAuthor":true,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Fouad","suffix":""},{"id":2268581,"identity":"2a616fcd-6435-47e5-9970-f22943e6d051","order_by":1,"name":"Hekma A. Abd El Latif","email":"","orcid":"","institution":"Cairo University Faculty of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Hekma","middleName":"A. Abd El","lastName":"Latif","suffix":""},{"id":2268582,"identity":"2bdc6eb1-442e-4f81-9f8d-ea1e26856010","order_by":2,"name":"May Galal","email":"","orcid":"","institution":"Cairo University Faculty of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"May","middleName":"","lastName":"Galal","suffix":""},{"id":2268583,"identity":"da8435d7-e8c2-4c76-a508-ef0325ee32b0","order_by":3,"name":"Mohammed El Yamani","email":"","orcid":"","institution":"Cairo University Faculty of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Mohammed","middleName":"El","lastName":"Yamani","suffix":""},{"id":2268584,"identity":"ba549621-4b05-472e-a828-ee0647ba5cd0","order_by":4,"name":"Sherifa Hassaneen","email":"","orcid":"","institution":"National Organization for Drug Control and Research","correspondingAuthor":false,"prefix":"","firstName":"Sherifa","middleName":"","lastName":"Hassaneen","suffix":""},{"id":2268585,"identity":"b0208d34-f776-40c8-8803-dbc9bfe2ce29","order_by":5,"name":"Raneem Masoaad","email":"","orcid":"","institution":"Batterjee Medical College for Sciences and Technology","correspondingAuthor":false,"prefix":"","firstName":"Raneem","middleName":"","lastName":"Masoaad","suffix":""}],"badges":[],"createdAt":"2020-07-17 11:23:17","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-44926/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-44926/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":2399442,"identity":"9c51bf88-8a51-49ec-b7a5-dc1b263d18f8","added_by":"auto","created_at":"2020-09-14 18:37:39","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113841,"visible":true,"origin":"","legend":"A: Effect of the tested drugs on the hearts in alloxan-induced diabetic mice after 4 weeks of treatment. Triphenyl Tetrazolium Chloride stained cross-section of the heart of (A) diabetic control rat showing uniform staining pattern. Both (B) Bromocriptine treated group, and (C) Cabergoline treated group showing a relative large pale, TTC negative area of infarct. Both (D) Bromocriptine+ Sarbogrelate treated group, and (E) Cabergoline+ Sarbogrelate treated group showing a relative small pale, TTC negative area of infarct. \n\nB: Effect of the tested drugs on percentage of myocardial infarct size in alloxan-induced diabetic rats. Values shown are means ± SEM; n = 6 rats per group. # P \u003c 0.05, significantly different from diabetic control group. a P \u003c 0.05, significantly different from diabetic group treated with bromocriptine. b P \u003c 0.05, significantly different from diabetic group treated with cabergoline","description":"","filename":"Fig1final.jpg","url":"https://assets-eu.researchsquare.com/files/rs-44926/v2/Fig1final.jpg"},{"id":13590798,"identity":"0d1e8b8c-5ca1-40af-9bd1-8e03a85fdbb2","added_by":"auto","created_at":"2021-09-17 05:06:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":625948,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-44926/v2/474f283d-e393-4bd4-903a-369d69789df0.pdf"}],"financialInterests":"","formattedTitle":"Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats","fulltext":[{"header":"Background","content":"\u003cp\u003eRegarding various diabetes progress complications, diabetic nephropathy is the foremost well-known renal difficulty and the ultimate source of end-stage renal disease. The later phases of diabetic nephropathy define glomerulosclerosis. It was represented by transforming growth factor-\u0026szlig;1 overexpression, extracellular matrix deposition, and glomerular structure loss [1]. Hyperglycemia is the primary factor for the progress of diabetic nephropathy [2]. It has been demonstrated in several in vitro studies of STZ-induced diabetic nephropathy where serious glucose-induced renal damage is claimed to excessive production of reactive oxygen species (ROS) under hyperglycemic conditions [3, 4, 5]. Bromocriptine is a sympatholytic dopamine D2 agonist that has been approved for treating type 2 diabetes without risk of hypoglycemia because there is no insulin secretion. Supported previous studies stated bromocriptine administration believed to strengthen low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the central system, leading to a reduction in post-meal plasma glucose levels because of enhanced suppression of hepatic glucose production [6, 7]. Agonists working on dopamine D2 receptors can lower hypertension sign by inhibition of Na/k ATPase activity, vasodilation, and sympathetic nerve activity inhibition. Bromocriptine may secure against I/R injury of the kidney utilizing p44/42 mitogen-initiated protein kinase actuation [8] and preventing chronic nephropathy [9].\u003c/p\u003e\n\u003cp\u003eConversely, the bromocriptine-actuated hypotension was wholly nullified by pretreatment with metoclopramide, a dopamine D2 receptor antagonist that crosses the barrier [10, 11]. However, D2 agonists' use is often related to cardiovascular complications, including hypotension and myocardial disorder. There is an identified relationship between the utilization of D2-like R agonists in patients with Parkinson's disease and cardiopathy, especially in the early phase of therapy [12]. D2 receptors are pleiotropic receptors having multiple effects in that activating them inhibits adenylyl cyclase, resulting in inhibition of voltage-gated calcium ions and activation of potassium conductance [13]. Early studies suggested that the use of D2 receptor agonists resulted in a reduction in pituitary tumor mass [14].\u003c/p\u003e\n\u003cp\u003eIt was demonstrated that long term use of bromocriptine therapy was associated with an increased risk of developing heart disease, which occurred in a cumulative dose-dependent treatment [15]. Dopamine D2 receptor agonists are classified as ergot dopamine D2 agonists and non-ergot D2 agonists. Bromocriptine and cabergoline (ergot derivative) are related to valvular cardiopathy since the two drugs have both dopamine D2 and serotonin 5-HT (2A) receptors agonistic activities. Pramipexole (non-ergot derivative) shows few incidences of heart disease onset since it does not affect 5-HT (2B) receptors [16, 17, 18]. Both sarpogrelate and ketanserin (selective 5HT2a/2b antagonists) constrict cardiac brokenness, infarct size, and changes within the electrocardiogram because of myocardial injury. Likewise, these outcomes bolster the view that serotonin and 5-HT (2A) may augment the harmful impacts of ischemic injury within the heart [19, 20]. Sarpogrelate found to possess beneficial impacts in peripheral vascular sickness, restenosis after coronary stenting, pneumonic hypertension, intense and relentless myocardial localized necrosis [21]. The current study aims to identify the possible protective effect of sarpogrelate, a 5-HT (2A) receptor blocker, associated with cumulative use of D2 agonist drugs therapy on cardiac and renal functions in the diabetic nephropathy model of rats.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003eMaterials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSarpogrelate was obtained from Shanghai Linebon Ltd. Shanghai, China. Bromocriptine was from Novartis, Italy. Cabergoline was purchased from Pfizer, Italy. Domperidone was purchased from Jamjoom pharmaceutical company, KSA. Alloxan was obtained from Sigma‐Aldrich (St Louis, MO, USA). Urea; Creatinine; Alkaline Phosphatase; Aspartate Aminotransferase Activity; LDH-1 assay kits; and TNF alpha ELISA Kit were obtained from Abcam company. Troponin I test kit was obtained from Encode Medical Engineering Company, Jeddah, KSA. 2,3,5-Triphenyltetrazolium chloride was obtained from Gold Biotechnology, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnimals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForty-two Wister albino male rats 5\u0026ndash;7 weeks of\u0026nbsp;\u003cem\u003eage weighing 150\u003c/em\u003e\u0026ndash;200 g were obtained from the animal house of Batterjee medical college, Jeddah, KSA. The animals were housed three per cage under controlled standard laboratory conditions in monitored ventilated cages and spontaneously given food and water. The ethical committee of research of Batterjee medical college approved the steps of the investigation. Tutelage was taken, particularly with relevant housing conditions, to avoid or minimize the animals' discomfort. The animals were kept on solid floored cages with a deep layer of sawdust, and the cages were changed daily. Data were coded prior to analysis so that the treatment group cannot be identified before analysis is completed. At the end of the study, all animals were euthanized by thiopental (intravenous injection, 150 mg/kg) for tissue collection.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInduction of diabetes by alloxan\u0026nbsp; \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlloxan monohydrate was dissolved in sterile normal saline. Diabetes was induced in 30 rats (150-200 g) by a single intraperitoneal injection of alloxan (5%) 150 mg/kg b.w. The rats kept fasting for 12 h before the injection of alloxan. Fasting plasma glucose was measured in blood samples collected from the tail vein. The rats which showed a plasma glucose level of 200 mg/dl or more were considered diabetic and taken in the study [22].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTests took place four weeks after the induction of diabetes. The diabetic rats divided randomly into six diabetic groups and one healthy control group, each group of 6 rats. The sampling calculation was done based on the resource equation method [23]. \u0026nbsp;Once there was a stable rising in the urea and creatinine levels in the blood, drugs were injected once daily for one month.\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eThe normal control group (Saline, IP)\u003c/li\u003e\n\u003cli\u003eDiabetic control group (Saline, IP)\u003c/li\u003e\n\u003cli\u003eDiabetic group treated with bromocriptine (4 mg/kg b.w, IP) [24]\u003c/li\u003e\n\u003cli\u003eDiabetic group treated with cabergoline (0.6 mg/kg b.w ,IP) [25]\u003c/li\u003e\n\u003cli\u003eDiabetic group treated with sarpogrelate (50 mg/kg b.w, IP) [26]\u003c/li\u003e\n\u003cli\u003eDiabetic group treated with a combination between bromocriptine and sarpogrelate at the same doses.\u003c/li\u003e\n\u003cli\u003eDiabetic group treated with a combination between cabergoline and sarpogrelate at the same doses.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eDetermination of blood glucose level \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood glucose levels were tested on the 7\u003csup\u003eth\u003c/sup\u003e, 14\u003csup\u003eth\u003c/sup\u003e, 21\u003csup\u003eth\u003c/sup\u003e, and 28\u003csup\u003eth\u003c/sup\u003e days from the beginning of the treatment. One millimeter of its end cut and a drop of blood was used for blood glucose tests using an advanced glucometer (Roche, USA). The accuracy of glucometer was checked with the O-toluidine method [27].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlood Pressure Recording\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBasal blood pressure was measured employing tail-cuff non-invasive blood pressure recorder apparatus (Ugobasile instruments, Italy). The measurement of the mean systolic blood pressure for each group of rats was done once time weekly for one month.\u003c/p\u003e\n\u003cp\u003eEach rat was placed in an exceeding restrainer, and an appropriate cuff sensor mounted on its tail and warmed to about 33- 35 \u0026deg;C. The tail cuff was inflated to a pressure above 200 mmHg, systolic blood pressure; diastolic blood pressure was measured directly by the tail-cuff and pulse sensor two hours after treatment of drugs [28].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEstimation of liver \u0026amp; kidney functions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the end of the study, the blood sample was withdrawn through the retro-orbital venous plexus method, kept at 37\u0026deg;C for 30 min, and centrifuged at 4\u0026deg;C, 3000 rpm for 10 min. Then the separated serum was stored at -20\u0026deg;C for various biochemical analyses. Alkaline phosphatase and aspartate aminotransferase activities were determined using the method described by King and King (1954) [29]. The procedure of Tietz et al. (1994) [30] was used to determine serum creatinine concentration, while the serum urea concentration was determined by the method of Kaplan (1965) [31]. After the end of the study, all of the rats were sacrificed. The kidneys samples were collected, washed with normal saline, and weighed. The kidney hypertrophy index was calculated by determining the kidney weight and body weight ratio (g/g) x10\u003csup\u003e3\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEstimation of serum biomarkers of myocardial injury\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe severity of the cardiac injury was assessed by estimating lactate dehydrogenase (LDH-1) and cardiac troponin I (cTnI) in serum. LDH-1 and troponin levels were analyzed by spectrophotometric methods using commercially available diagnostic kits consistent with the methods of Nieland [32].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum TNF-\u0026alpha; concentration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum TNF-alpha cytokines level was identified by the ELISA technique using a quantitative sandwich enzyme immunoassay technique (Abcam Company). The test was done according to the company's instructions. The ELISA reader's optical density at 405nm was immediately calculated and applied on a standard curve to sort out the cytokines' concentration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of Myocardial Infarct Size by TTC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor assessment of the myocardial infarcted area, the hearts were removed, washed in phosphate-buffered saline, frozen, and stored at \u0026minus;20\u0026deg;C. The frozen hearts were sliced into 1 mm sections along the long axis from apex to base. Triphenyl tetrazolium chloride (TTC) staining is accustomed to assess myocardial tissue viability and determine myocardial infarction size. The tissue slices were incubated in 1% TTC PBS solution, pH 7.4, at 37\u0026deg;C for 20 min. Tissues were fixed in 10% PBS-buffered formalin overnight at 2\u0026deg;C\u0026ndash;8\u0026deg;C. Either side of every TTC-stained tissue slice was photographed with the photographic camera to differentiate the red-stained viable and white-unstained necrotic tissues [33]. Digital photographs are downloaded to a computer. Areas stained in white and red were measured using SigmaScan software (SPSS Science) in trace-measurement mode. That mode was wont to measure either the ischemic or the infarcted areas, which may be a sum of calibrated pixels during a defined region. This was done manually by drawing an image layer on the photograph [34]. The infarction size percentage was calculated using the following equation:\u003c/p\u003e\n\u003cp\u003eThe percentage of Infarct volume = Infarct volume / Total volume of slice X 100\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data and statistical analysis done comply with the recommendations on experimental design and analysis in pharmacology [35]. The results expressed as mean\u0026plusmn; SE. The significance of the differences between the values were performed by a one-way ANOVA test and Dunnett's Multiple Comparison Test using GraphPad Prism software. P \u0026lt; 0.05 was considered to be a significant difference.\u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eEstimation of blood glucose levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diabetic control group showed a significant increase in BGL compared to the healthy control group. On repeated administration of the bromocriptine (4 mg/kg), cabergoline (0.6 mg/kg) individually or in combination with sarbogrelate, a significant (p \u0026lt; 0.05) decrease in blood glucose by time was observed compared to the diabetic control group throughout the four weeks of treatment (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKidney hypertrophy index\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results showed that the kidney hypertrophy index significantly increased in the diabetic group of rats compared with the normal control rats. However, the index was markedly reduced by both bromocriptine and cabergoline treatment, even individually or mixed with sarpogrelate (as seen in Table 2). There is no effect of using sarpogrelate on the diabetic kidney index.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHemodynamic Parameter (Antihypertensive activity)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlloxan-induced diabetes in rats showed a significant rise in blood pressure after three weeks from the induction of diabetes. Daily oral administration of bromocriptine and cabergoline individually or in combination with sarpogrelate showed a significant decrease in the systolic blood pressure in third week and fourth week of treatment (Table 3). There is no effect of sarpogrelate on BP in diabetic rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEstimation of Liver and kidney Functions: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe serum levels of AST, ALP, urea, and creatinine as an indicator of liver and kidney functions are recorded in table 4. Data revealed that the diabetic control group had a significant increase in the previous biomarkers' serum concentrations compared to the healthy control rats. Daily administration of bromocriptine, cabergoline even alone, or in combination with sarbogrelate significantly decreased serum concentrations of the previous biomarkers compared to the positive control of diabetic rats. There is no marked effect of sarpogrelate treatment on the previous biochemical indicators in the diabetic rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMyocardial biomarkers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnimals treated with bromocriptine and cabergoline for one month in doses 10 mg/kg and 0.6 mg/kg respectively displayed significant elevation of LDH-1 activity in the serum. By contrast, using a combination of bromocriptine and cabergoline with sarpogrelate treatment significantly decreases the level of the biomarkers in the serum were observed. The results in table 5 indicated that the qualitative test of the troponin I reagent kit showed only positive results with bromocriptine and cabergoline treated groups. The results of the ELISA test indicate that the expression levels of TNF-alpha 1 in the diabetic rats' groups treated with bromocriptine or cabergoline individually were significantly higher comparing to the diabetic control rats. The groups of combinations between bromocriptine and cabergoline with sarbogrelate showed lower TNF-alpha 1 expression levels than the groups treated with bromocriptine or cabergoline individually (Table 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of myocardial injury\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMyocardial infarction size was used as an indicator of the progress of the myocardial injury. The hearts of rats treated with bromocriptine 4 mg/kg, and cabergoline 0.6 mg/kg showed a significant increase in risk area infarction. By contrast, the combination of bromocriptine or cabergoline with sarpogrelate (50 mg/kg) reduced the percentage of the myocardial infarct size (Figures 1A, 1B).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBoth bromocriptine and cabergoline induced hypoglycemic activity may be due to enhanced suppressive hepatic glucose production [36]. The exact mechanism of action as antidiabetic is not entirely identified; bromocriptine decrease hepatic production of glucose, increase glucose transporter production, or increase or mimic glucagon-like peptide-1 activity [37].\u0026nbsp;Its contribution to hypoglycemia may be due to adjustments in the neural control of seasonal and patterns of food intake and nutrient storage [38]. Bromocriptine was approved by the Food and Drug Administration (FDA) in May 2009 for the treatment of type 2 diabetes.\u003c/p\u003e\n\u003cp\u003eIn the present study, diabetic nephropathy is the most common cause of renal complication and the leading of hypertension. Both bromocriptine and cabergoline showed a marked antihypertensive activity, which agrees with some previous reports [39, 40]. This action is related to dopamine D2 receptors acting drugs can lower the blood pressure by inhibition of Na/k ATPase activity, vasodilation, and inhibition of sympathetic nerve activity. Both bromocriptine and cabergoline induced a marked improvement in the kidney function by decreasing urea and creatinine serum levels. The pharmacological pathways that explain this effect have not been sufficiently determined. The result agrees with some of the previous studies suggesting that the development of therapies directed to increase renal D2 receptor expression/function may provide novel and practical approaches to treating renal injury [41].\u003c/p\u003e\n\u003cp\u003eThe high noted adverse effect of bromocriptine and cabergoline on the heart is represented in myocardial injury and infarction approved in the present study by using relative overdoses for a month of treatment manner. The action may be related to dopamine D2 and serotonin 5-HT (2A) receptors agonistic properties, increasing the heart pumping rate. It has been reported that both bromocriptine and cabergoline (ergot derivative) have been associated with heart disease since the two drugs have both dopamine D2 and serotonin 5-HT (2A) receptors agonistic properties [17, 18]. It is hypothesized that the 5-HT2A receptor is a common contributing factor underlying aspects of vasoconstriction and cardiovascular disorders [42] and vasodilation through activating nitric oxide (NO) synthase (NOS) via serotonin 5-HT (1B) receptors in endothelial cells, possess different effects on regulating vascular tone. These\u0026nbsp;facts lead to consider that sarpogrelate,\u0026nbsp;a\u0026nbsp;5-HT (2A) receptor blocker, may increase coronary blood flow\u0026nbsp;via\u0026nbsp;either\u0026nbsp;attenuation\u0026nbsp;of\u0026nbsp;vasoconstriction\u0026nbsp;through\u0026nbsp;5HT(2A)\u0026nbsp;receptor\u0026nbsp;blockade\u0026nbsp;or\u0026nbsp;of\u0026nbsp;vasodilation\u0026nbsp;by\u0026nbsp;relative\u0026nbsp;stimulation\u0026nbsp;of\u0026nbsp;NOS\u0026nbsp;through\u0026nbsp;5-HT1B\u0026nbsp;receptor [43].\u003c/p\u003e\n\u003cp\u003eAccording to the current observed data, the combination of bromocriptine and cabergoline with the new chemical agent sarpogrelate (selective 5HT2a/2b antagonists) decreases the adverse effects of these two drugs on the heart. The protective effects of sarpogrelate on myocardial tissue were approved by its ability to decrease the secretion of myocardial biomarkers. As shown by decreasing LDH-1, Troponin I, and TNF alpha 1 during the treatment of bromocriptine and cabergoline. Sarpogrelate attenuates cardiac dysfunction, infarct size; these results support the view said that serotonin and 5-HT (2A) might contribute to the harmful effects of ischemic injury in the heart. Regarding the biochemical study, sarpogrelate drug can be considered a safe drug on liver and kidney functions.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAccording to the given study, both bromocriptine and cabergoline can be used safely in combination with sarpogrelate for the treatment of many diseases like hypertension, diabetes, and Parkinsonism. Thus, we hypothesize that sarpogrelate deserves additional experimental and clinical research related to cardiovascular diseases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALT: Alanine Aminotransferase\u003c/p\u003e\n\u003cp\u003eAST: Aspartate Aminotransferase\u003c/p\u003e\n\u003cp\u003eTNF: \u003cem\u003eTumor necrosis factor\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTTC: Triphenyl tetrazolium chloride\u003c/p\u003e\n\u003cp\u003eLDH: \u003cem\u003eLactate dehydrogenase\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTTC: Triphenyl tetrazolium chloride\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e5HT: 5- hydroxytryptamine\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eELISA: Enzyme-linked immunosorbent assay\u003c/em\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved in December 2019 by the ethical committee of research of Batterjee medical college. The committee consists of four people. The research protocol and the study plan were submitted. The committee held a comprehensive discussion of risks and benefits before reaching the approval conclusion. During the study, the research coordinator of the ethics committee updated the progress of the research. In addition, the research experiments on animals followed the guidelines of the experimental animals\u0026rsquo; research and ethics committee \"EAREC\", King Abdulaziz University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding available for the current manuscript submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors conceived and planned the experiments. MF carried out the implementation of the experiments. RM planned and carried out the statistical analyses and contributed to sample preparation. MF took the lead in writing the manuscript. HA, MY, MG, and SK contributed to the interpretation of the results, provided critical feedback, supervision and helped shape the research, analysis, and manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI would like to express my sincere gratitude to my advisor Prof. Hekma Abdul Latif, for her continuous support of my researches, for her patience, motivation, and immense knowledge.\u0026nbsp; I would like to thank the rest of my thesis committee: Assistant Prof. May Galal, Assistant Prof. Mohamed El yammany, for their, insightful comments. My sincere thanks also go to Dr. Iklas Sindi, Batterjee medical college, Jeddah, KSA for offering me the opportunities to work on this project in the college laboratories.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKoya D, Hayashi K, Kitada M, Kashiwagi A, Kikkawa R, Haneda M. Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats. J Am Soc Nephrol. 2003; 14:S250-S253.\u003c/li\u003e\n\u003cli\u003eDebnam ES and Unwin RJ. ''Hyperglycemia and intestinal and renal glucose transport: implications for diabetic renal injury''. Kidney Int 1996; 50:1101\u0026ndash; 1109\u003c/li\u003e\n\u003cli\u003eFridlyand LE and Philipson LH. ''Oxidative reactive species in cell injury: mechanisms in diabetes mellitus and therapeutic approaches''. Ann N Y Acad Sci 2005; 1066:136\u0026ndash;15\u003c/li\u003e\n\u003cli\u003eSevindik M. 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Am.J.Pathol 1963; 42:379-406\u003c/li\u003e\n\u003cli\u003eCurtis, M. J., Bond, R. A., Spina, D., Ahluwalia, A., Alexander, S. P., Giembycz, M. A., Gilchrist, A., Hoyer, D., Insel, P. A., Izzo, A. A., Lawrence, A. J., MacEwan, D. J., Moon, L. D., Wonnacott, S., Weston, A. H., \u0026amp; McGrath, J. C.. Experimental design and analysis and their reporting: new guidance for publication in BJP [published correction appears in Br J Pharmacol. 2015 Sep;172(18):4600]. Br J Pharmacol. 2015; 172(14):3461-3471. doi:10.1111/bph.12856\u003c/li\u003e\n\u003cli\u003eDefronzo RA. Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care. 2011; 34:789-794. doi:10.2337/dc11-0064\u003c/li\u003e\n\u003cli\u003eScranton R, Cincotta A. Bromocriptine--unique formulation of a dopamine agonist for the treatment of type 2 diabetes.\u0026nbsp;Expert Opin Pharmaco. 2010; 11:269-279. doi:10.1517/14656560903501544\u003c/li\u003e\n\u003cli\u003eAminorroaya A, Janghorbani M, Ramezani M, Haghighi S, Amini M. Does bromocriptine improve glycemic control of obese type-2 diabetics?.\u0026nbsp;Horm Res. 2004; 62:55-59. doi:10.1159/000078932\u003c/li\u003e\n\u003cli\u003eZeng C, Zhang M, Asico LD, Eisner GM, Jose PA. The dopaminergic system in hypertension. Clin Sci (Lond). 2007; 112(12):583-597. doi:10.1042/CS20070018\u003c/li\u003e\n\u003cli\u003eMcCoy CE, Douglas FL, Goldberg LI. Selective antagonism of the hypotensive effects of dopamine agonists in spontaneously hypertensive rats. Hypertension. 1986; 8(4):298-302. doi:10.1161/01.hyp.8.4.298\u003c/li\u003e\n\u003cli\u003eKonkalmatt, P. R., Asico, L. D., Zhang, Y., Yang, Y., Drachenberg, C., Zheng, X., Han, F., Jose, P. A., \u0026amp; Armando, I. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure.\u0026nbsp;JCI Insight. 2016; 1:e85888. doi:10.1172/jci.insight.85888\u003c/li\u003e\n\u003cli\u003eNichols CD. Serotonin 5-HT(2A) Receptor Function as a Contributing Factor to Both Neuropsychiatric and Cardiovascular Diseases.\u0026nbsp;Cardiovasc Psychiatry Neurol. 2009; 2009:475108. doi:10.1155/2009/475108\u003c/li\u003e\n\u003cli\u003eFujita, M., Minamino, T., Sanada, S., Asanuma, H., Hirata, A., Ogita, H., Okada, K., Tsukamoto, O., Takashima, S., Tomoike, H., Node, K., Hori, M., \u0026amp; Kitakaze, M.Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts.\u0026nbsp;J Mol Cell Cardiol. 2004; 37:1219-1223. doi:10.1016/j.yjmcc.2004.09.016\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-left:-4.5pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eTable 1: Effect of the tested drugs on BGL in alloxan-induced diabetic rats.\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 5.1e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 510.35pt;border-width: 1pt;border-style: solid;border-color: windowtext black windowtext windowtext;border-image: initial;padding: 0in 5.4pt;height: 25.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;margin-right:8.1pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eBGL mg/dL\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003eGroups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003eweek 1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003eweek 2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003eweek 3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003eweek 4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 35.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eNormal control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:35.95pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e136.5 \u0026plusmn; 18.52\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:35.95pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e121.33 \u0026plusmn; 12.08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:35.95pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e119.25 \u0026plusmn; 11.35\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:35.95pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e109 \u0026plusmn; 10.92\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eDiabetic control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e359.75 \u0026plusmn; 45.13*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e328 \u0026plusmn; 141.34*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e428.5 \u0026plusmn; 121.17*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e396.5 \u0026plusmn; 80.60*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 13pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e191 \u0026plusmn; 16.89\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e199.25 \u0026plusmn; 65.05\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e238.25 \u0026plusmn; \u0026nbsp;56.88\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e284.25 \u0026plusmn; 148.00\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 13.45pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Cabergoline\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.45pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e213.75 \u0026plusmn; 37.74\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.45pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e211.75 \u0026plusmn; 38.62\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.45pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e293 \u0026plusmn; 213.15\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:13.45pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e280.25 \u0026nbsp;\u0026plusmn; 220.48\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e326.25 \u0026plusmn; 93.45\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e298.25 \u0026plusmn; \u0026nbsp;122.37\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e393.75 \u0026plusmn; 118.77\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.55pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e369.75 \u0026plusmn; 43.15\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 73.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine +sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:73.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e247.75 \u0026plusmn; \u0026nbsp;50.35\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:73.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e215.5 \u0026plusmn; 33.20\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:73.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e310.25 \u0026plusmn; 70.59\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:73.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e288.25 \u0026plusmn; 109.41\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 120.55pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 14.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with cabergoline + sarpogrelate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.35pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e196 \u0026plusmn; 54.20\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.35pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e158.75 \u0026plusmn; 35.01\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.35pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e235.5 \u0026plusmn; 182.22\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.2pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:14.35pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:16px;line-height:115%;font-family:\"Times New Roman\",serif;color:black;'\u003e215.75 \u0026plusmn; 141.46\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-left:-4.5pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eValues shown are means \u0026plusmn; SEM; n = 6 rats per group. \u0026nbsp;* P \u0026lt; 0.05, significantly different from normal control group; # P \u0026lt; 0.05, significantly different from diabetic control group.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eTable 2: Effect of the tested drugs on Kidney Hypertrophic Index in alloxan-induced diabetic rats.\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 3.4e+2pt;border: none;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 342.9pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.25in;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;margin-bottom:10.0pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eKidney Hypertrophic Index\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eGroups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eKHI ( g/g * 1000 )\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eNormal control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e4.555 \u0026plusmn; 0.423\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDiabetic control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e6.6125 \u0026plusmn; 0.57*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDiabetic group treated with Bromocriptine\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;4.7475 \u0026plusmn; 0.33\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDiabetic group treated with Cabergoline\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;4.81 \u0026plusmn; 0.49\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDiabetic group treated with Sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e5.90 \u0026plusmn; 0.27\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDiabetic group treated with Bromocriptine +sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;4.715 \u0026plusmn; 0.61\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 3.2in;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDiabetic group treated with cabergoline + sarpogrelate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 18.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e4.46 \u0026plusmn; 0.48\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-right:61.4pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eValues shown are means \u0026plusmn; SEM; n = 6 rats per group. \u0026nbsp;* P \u0026lt; 0.05, significantly different from normal control group; \u0026nbsp; \u0026nbsp;# P \u0026lt; 0.05, significantly different from diabetic control group.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-left:-9.0pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eTable 3: Effect of the tested drugs on mean systolic blood pressure in alloxan-induced diabetic rats.\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 5.0e+2pt;border: none;margin-left:-15.9pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 496.2pt;border-width: 1pt;border-style: solid;border-color: windowtext black windowtext windowtext;border-image: initial;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eMean Systolic Blood Pressure MSBP (mmHg)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eGroups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 91.65pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eweek 1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eweek 2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eweek 3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99.25pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eweek 4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eNormal control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e110 \u0026plusmn; 4.01\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e118.25 \u0026plusmn; 8.99\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e108.75 \u0026plusmn; 4.57\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e111.5 \u0026plusmn; 4.20\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e112.5 \u0026plusmn; 9.14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e121.75 \u0026plusmn; 11.35\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e150.75 \u0026plusmn; 5.25*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e151.25 \u0026plusmn; 5.12*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e115 \u0026plusmn; 9.12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e102.75 \u0026plusmn; \u0026nbsp;6.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e109 \u0026plusmn; 10.23\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e121.75 \u0026plusmn; 15.26\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Cabergoline\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e103.75 \u0026plusmn; 7.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e105.5 \u0026plusmn; 9.14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e123 \u0026plusmn; 7.87\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e107.75 \u0026plusmn; 107.75\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e118.75 \u0026plusmn; 10.87\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e114.75 \u0026plusmn; 8.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e137.75 \u0026plusmn; 8.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e139 \u0026plusmn; 18.56\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine +sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e104.5 \u0026plusmn; 7.59\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e104.75 \u0026plusmn; 4.99\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e106.25 \u0026plusmn; 11.08\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.0pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e118 \u0026plusmn; 13.03\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 127.65pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with cabergoline + sarpogrelate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:91.65pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e109.25 \u0026plusmn; 11.58\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:85.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e105 \u0026plusmn; 9.05\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e106 \u0026plusmn; 18.3\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e104.25 \u0026plusmn; 5.5\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-top:0in;margin-right:13.5pt;margin-bottom:.0001pt;margin-left:-9.0pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eValues shown are means \u0026plusmn; SEM; n = 6 rats per group. \u0026nbsp;* P \u0026lt; 0.05, significantly different from normal control group; \u0026nbsp; \u0026nbsp;# P \u0026lt; 0.05, significantly different from diabetic control group.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-left:-4.5pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eTable 4: Effect of the tested drugs on liver and kidney functions in alloxan-induced diabetic rats after 4 weeks.\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.8e+2pt;border: none;margin-left:-15.9pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 480.3pt;border-width: 1pt;border-style: solid;border-color: windowtext black windowtext windowtext;border-image: initial;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eBIOCHEMICALS\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eGroup\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80.85pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eALP(IU/L)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 82.15pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eAST(IU/L)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77.95pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eUrea (mmol/L)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90.45pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eCreatinine (mmol/L)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eNormal control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e60.85\u0026plusmn;8.77\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e25.04\u0026plusmn;4.96\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e43.38\u0026plusmn;4.77\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:white;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.46 \u0026plusmn; 0.07\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e89.05\u0026plusmn;10.44*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e45.86\u0026plusmn;7.57*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e75.81\u0026plusmn;18.85*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e1.89 \u0026plusmn; 0.19*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e68.83\u0026plusmn;7.27\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e34.18\u0026plusmn;5.78\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e60.41\u0026plusmn;6.22\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e1.04 \u0026plusmn; 0.26\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Cabergoline\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e73.27\u0026plusmn;7.93\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e21.37\u0026plusmn;10.05\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e52.09\u0026plusmn;2.23\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e0.79 \u0026plusmn; 0.11\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e82.16\u0026plusmn;23.83\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e41.47\u0026plusmn;10.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e69.41\u0026plusmn;7.65\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e1.68 \u0026plusmn; 0.25\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine +sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e64.8\u0026plusmn;7.21\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e31.03\u0026plusmn;6.44\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e44.4\u0026plusmn;8.23\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e1.26 \u0026plusmn;0.25\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 148.9pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with cabergoline + sarpogrelate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:80.85pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e73.44\u0026plusmn;6.68\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:82.15pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e33.79\u0026plusmn;11.18\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:77.95pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e51.16\u0026plusmn;10.43\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:90.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:150%;'\u003e\u003cspan style='font-size:16px;line-height:150%;font-family:\"Times New Roman\",serif;'\u003e1.33 \u0026plusmn; 0.21\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-top:0in;margin-right:31.5pt;margin-bottom:.0001pt;margin-left:-9.0pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eValues shown are means \u0026plusmn; SEM; n = 6 rats per group. \u0026nbsp;* P \u0026lt; 0.05, significantly different from normal control group; \u0026nbsp; \u0026nbsp;# P \u0026lt; 0.05, significantly different from diabetic control group.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-top:0in;margin-right:25.95pt;margin-bottom:.0001pt;margin-left:-7.1pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eTable 5: Effect of the tested drugs on Lactate dehydrogenase-1 and TNF\u0026alpha;1 in alloxan-induced diabetic rats.\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 4.1e+2pt;border: none;margin-left:33.75pt;border-collapse:collapse;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 411.1pt;border-width: 1pt;border-style: solid;border-color: windowtext black windowtext windowtext;border-image: initial;padding: 0in 5.4pt;height: 12.75pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;margin-bottom:10.0pt;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eBIOCHEMICALS\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:219.75pt;border:solid windowtext 1.0pt;border-top: none;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eGroup\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eLDH (IU/L)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eTNF\u0026alpha;1 (pg/mL)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 17.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eNormal control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.95pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e17.42\u0026plusmn; 0.69\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.95pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e06.12\u0026plusmn;0.45\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eDiabetic control group\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e18.50 \u0026plusmn; 1.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e08.32 \u0026plusmn;0.56\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e40.50 \u0026plusmn; 10.69\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e36.56 \u0026plusmn;2.32#\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Cabergoline\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e36.86 \u0026plusmn;12.47\u003csup\u003e#\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e31.20 \u0026plusmn;4.23#\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e19.55 \u0026plusmn; 2.20\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e09.74 \u0026plusmn;0.98\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with Bromocriptine +sarpogrelate\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e27.75 \u0026plusmn; 3.91 \u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e14.84 \u0026plusmn;1.23 \u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219.75pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eDiabetic group treated with cabergoline + sarpogrelate\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.1pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e34.57 \u0026plusmn;6.60 \u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.25pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:12.75pt;\"\u003e\n \u003cp style='margin:0in;text-align:center;font-size:14px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e08.59 \u0026plusmn;0.76 \u003csup\u003eb\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:justify;font-size:14px;font-family:\"Calibri\",sans-serif;margin-top:0in;margin-right:49.5pt;margin-bottom:.0001pt;margin-left:.5in;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eValues shown are means \u0026plusmn; SEM; n = 6 rats per group. \u0026nbsp; # \u0026nbsp;P \u0026lt; 0.05, significantly different from diabetic control group. a \u0026nbsp;P \u0026lt; 0.05, significantly different from diabetic group treated with bromocriptine. b \u0026nbsp; P \u0026lt; 0.05, significantly different from diabetic group treated with cabergoline.\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cardiovascular, diabetic nephropathy, myocardial injury, TNFα1, Dopamine receptors","lastPublishedDoi":"10.21203/rs.3.rs-44926/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-44926/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The investigation aims to represent the activity of sarpogrelate, a particular 5-HT (2A) receptor blocker, in reducing myocardial injury prompted by extended haul utilization of D\u003csub\u003e2\u003c/sub\u003e agonist drugs in diabetic rats. Dopamine D2 agonists are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation showed between the enlistment of myocardial injury ailment and long term treatment with dopamine D\u003csub\u003e2\u003c/sub\u003e agonist drugs identified with the partial initiation of 5-HT 2a receptors. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Both bromocriptine and cabergoline were managed independently and combined with sarpogelate for about a month to diabetic nephropathy rats. Both tail-cuff blood pressure and BGL were recorded weekly. For all animals, kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of LDH-1, cardiac troponin I, and TNFα. Triphenyl tetrazolium chloride staining method used to determine experimental myocardial infarction (MI) size. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine, cabergoline, alone, or in combination with sarbogrelate fundamentally diminished blood concentrations of ALP, AST, urea, and creatinine. Bromocriptine and cabergoline alone showed noteworthy ascending of LDH-1, Troponin I, and TNFα1 levels in the serum (p\u0026lt;0.05). Paradoxically, utilizing bromocriptine and cabergoline with sarpogrelate treatment altogether diminished the degree of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed utilizing the TTC staining method. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: The examination exhibited that both bromocriptine and cabergoline could be utilized safely in blend with sarpogrelate for a long duration of treatment for diseases like hypertension and diabetes.\u003c/p\u003e","manuscriptTitle":"Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-09-14 18:37:32","doi":"10.21203/rs.3.rs-44926/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-02-01T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-01-25T00:00:00+00:00","index":3,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nPEER REVIEWER ASSESSMENTS:\n\nOBJECTIVE - Full research articles: is there a clear objective that addresses a testable research question(s) (brief or other article types: is there a clear objective)?\nYes - there is a clear objective\n\nDESIGN - Is the current approach (including controls and analysis protocols) appropriate for the objective?\nNot sure - key details are missing from the manuscript\n\nEXECUTION - Are the experiments and analyses performed with technical rigor to allow confidence in the results?\nNot sure - key details are missing from the manuscript\n\nSTATISTICS - Is the use of statistics in the manuscript appropriate?\nNo - there are issues with the statistics in the study\n\nINTERPRETATION - Is the current interpretation/discussion of the results reasonable and not overstated?\nNo - there are major issues\n\nOVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically sound? If not, can revisions be made to make the work technically sound?\nMaybe - with major revisions\n\nPEER REVIEWER COMMENTS:\n\nGENERAL COMMENTS:\nThe study provides some new information. However, the manuscript was not well written, especially for the abstract, the experimental procedure, and the conclusion.\n\nREQUESTED REVISIONS:\nThe title of the abstract can be changed as \"Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in rats with alloxan-induced diabetes\n\nThe abstract was not well written. Usually, the background is placed before the purpose of the study. The nature of bromocriptine and cabergoline (D2 agonists) should be mentioned to facilitate reading. The conclusions in the abstract do not correspond to the purpose of the study and the title of the manuscript, although these sentences may be the part of your conclusions. Thus, you need to change conclusions by emphasizing the effect of the combination of sarpogrelate with bromocriptine or cabergoline (for example, the combined use of sarpogrelate with bromocriptine or cabergoline decreased the adverse effects of these two drugs on the heart and kidney). Nevertheless, the sentence \"The investigation aims to represent the activity of sarpogrelate, a particular 5-HT (2A) receptor blocker, in reducing myocardial injury prompted by extended haul utilization of D 2 agonist drugs in diabetic rats\" may be changed as \"The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilization of D2 receptor agonists in rats with alloxan-induced diabetes\". In addition, in the abstract, some sentences were not well structured or had redundant components (lines 13-17, lines 39-42).\n\nHow did you induce myocardial infarction in rats in your study? There was no description of the method of induction of myocardial infarction in the manuscript.\n\nTukey test or Tukey-Kramer test may be more appropriate when comparing every mean with every other mean.\n\nThe conclusion of the study should also be modified to answer the purpose and the title of the study.\nADDITIONAL REQUESTS/SUGGESTIONS:\nIt would be preferable to use 5-HT2A or 5-HT2B instead of 5-HT (2A) or 5-HT (2B). Similarly, D2 receptor agonist can be used instead of D 2 agonist.\nPage 3, lines 18-25, the meaning of the sentence is not clear, so, the sentence needs to be modified.\nPage 4, lines 30-35, did you mean \"Both sarpogrelate and ketanserin (selective 5HT2A/2B antagonists) reduce heart fracture, infarct size, and changes in the EKG due to myocardial injury\"? If so, you may change the sentence.\nPage 4, lines 49-51, \"in the diabetic nephropathy model of rats\" can be changed as \"in a rat model of diabetic nephropathy\".\n\nPage 8, lines 26-29, the sentence \"Triphenyl tetrazolium chloride (TTC) staining is accustomed to assess myocardial tissue viability and determine myocardial infarction size\" can be changed as \"Triphenyl tetrazolium chloride (TTC) staining was used to assess myocardial tissue viability and determine myocardial infarction size\".\n\nPage 11, lines 40-50, the sentences need to be corrected for grammatical error.\n\nPage12, lines 22-30, \",\" is not needed.\n\nPage 21, line 46, \"mice\" should be rats.\n\nThe manuscript should be thoroughly checked for grammatical errors.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **This reviewer has been recruited by a partner organization, Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer has agreed to publication of their comments online under a Creative Commons Attribution License attributed to Research Square and was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2021-01-15T00:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-01-11T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reject\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nyoyr respon are unsastified* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **No**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2020-11-13T00:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThe manuscript is interesting and the results are promising; however, there are several comments in the PDF file and should be addressed before final decision * Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **None of this**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-10-29T00:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-27T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-10-26T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-09-10T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-09-09T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-09-09T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-07-30 20:08:46","doi":"10.21203/rs.3.rs-44926/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-09-04T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-08-06T12:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nPlease overwrite this text when adding your comments to the authors.\n\nthis work needed to answer the main questions\nTherapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats\n\ncomment :What do you mean as therapeutic effect (specifically )\nComment : against on : what do you mean ?\nComment : your works is survey about all D2 agonist effect?\nComment : in animal study how to get diabetic complication ?\nComment : induced diabetic rats or in rats ??\nThese major questions related to title of manuscript ??\nAbstract :\nComment :needed to rephrase according to priority in the title\nComment: the method doesn't contain method ?????\nComment : this work was badly described and written\nComment @ can you described the mortality rate ? survival rate for each week?\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n \n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests'**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2020-08-06T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThis manuscript described the therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats. Although the results are informative, the manuscript needs extensive revision since there are a lot of grammatical and structural defects. The materials and methods are vague and need to rewritten. I have made several corrections in the PDF file and all these comments should be addressed before the final decision of the editor. * Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **None of all**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. 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