The Effect of Losartan Versus Telmisartan on Renal Hemodynamics Responses to Angiotensin II administration in Male and Female Rats

The Effect of Losartan Versus Telmisartan on Renal Hemodynamics Responses to Angiotensin II administration in Male and Female 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 The Effect of Losartan Versus Telmisartan on Renal Hemodynamics Responses to Angiotensin II administration in Male and Female Rats Samira Choopani, Hajaralsadat Hosseini-Dastgerdi, Zahra Pezeshki, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7563367/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background. The renin–angiotensin system (RAS) is crucial in regulating blood pressure, fluid volume, and sodium balance in the body. Overactivation of this system can lead to the development of several medical conditions, such as kidney, and cardiovascular disorders. Losartan and telmisartan are two common angiotensin II (Ang II) receptor blockers (ARBs) which used for hypertension therapy. Both of these blockers affect renal blood flow (RBF), and this study aimed to compare the effects of losartan and telmisartan on the (RBF) and renal vascular resistance (RVR) responses to Ang II infusion in male and female rats. Methods. Three groups of males and three groups of females Wistar rats were assigned, and they randomized in vehicle, losartan (10 mg/kg), and telmisartan (10 mg/kg) treated groups. Subsequently, under anesthesia, mean arterial pressure (MAP), RBF and RVR responses to graded doses of Ang II administration under controlled renal perfusion pressure (RPP) were determined. Results. Infusion of Ang II resulted in dose-dependent increases in MAP that were similar in both male (P treat < 0.0001) and female (P treat < 0.002) rats. However, in females, the losartan group showed significantly lower MAP (P group = 0.018) and RPP (P group = 0.019) compared to the other groups. Ang II infusion led to a dose-dependent percentage change of RBF decreasing and RVR increasing in the vehicle group for both genders, and these changes were significantly different from others group ((P < 0.05). Additionally, urine flow was increased significantly in telmisartan group when compared with others groups (P < 0.05). Conclusion. Losartan in female rats is more effective in reducing MAP than telmisartan, while similar RBF and RVR responses to Ang II infusion were conducted in losartan and telmisartan groups. Losartan Telmisartan Gender Differences Renal Blood Flow Renal Vascular Resistance Figures Figure 1 Figure 2 Figure 3 Introduction The renin–angiotensin system (RAS) is crucial in regulating blood pressure, fluid volume, and sodium balance. Overactivation of this system can lead to the development of several medical disorders such as hypertension and heart failure (1). The main two important of RAS receptors includes angiotensin II (Ang II) type 1 receptor (AT1R) and type 2 receptor (AT2R). The angiotensinogen (AGT)/renin/angiotensin-converting enzyme (ACE)/Ang II /AT1R (AGT/renin/ACE/Ang II/AT1R) axis is the main pathway for the production of Ang II and is accountable for nearly all the traditional effects of Ang II in the progression of hypertension as well as cardiovascular and kidney diseases (2). Consequently, targeting the RAS is a sensible approach for hypertension, kidney disorders, and cardiovascular disease (CVD) treatments. At present, three categories of drugs modulate the RAS including: 1) angiotensin-converting enzyme (ACE) inhibitors (ACEIs), which prevent the production of Ang II; 2) angiotensin receptor blockers (ARBs), which obstruct the harmful effects of Ang II at the AT1R; and 3) aliskiren, which acts as a renin inhibitor. ACEIs and ARBs help lower the risk of kidney disease and decrease cardiovascular mortality and morbidity (1,3–5). Losartan, a first-generation AT1R antagonist, effectively counters the metabolic changes caused by Ang II and elevated oxygen radicals (6). Moreover, it functions as a partial agonist on the bradykinin receptor B2, and in addition to the classical action of ARBs, it can provide additional cardioprotective benefits (7). Losartan is well-tolerated, highly effective at lowering blood pressure, and provides beneficial uricosuric and kidney-protective effects. Therefore, it can be considered a first choice drug for elderly patients with hypertension and hyperuricemia undergoing chemotherapy (8). Telmisartan, an ARBs received Food and Drug Administration (FDA) approval in November 1998 for managing high blood pressure. The ONTARGET trial's findings prompted the FDA to authorize telmisartan as the first ARB to lower cardiovascular risk in patients unable to take ACE inhibitors (9). Telmisartan is a commonly prescribed medication for hypertension, known for its excellent safety and tolerability, both alone and in combination therapies. It has several pharmacological characteristics that distinguish it from other ARBs, including the longest plasma half-life, the highest lipophilicity, and the strongest receptor binding affinity in its class. Telmisartan is therefore widely indicated for lowering cardiovascular risk in individuals with atherothrombotic disease or diabetes mellitus associated with end-organ damage (10). Its additional p eroxisome proliferator-activated receptor gamma (PPARγ) agonistic effect also alleviates vascular inflammation, reduces visceral fat, and increases serum adiponectin levels while simultaneously lowering high blood pressure in patients with essential hypertension (11). A meta-analysis revealed that telmisartan treatment may reduce the left ventricular mass index more effectively than other antihypertensive medications in individuals with hypertension, and this effect was largely independent of its capacity to lower blood pressure (12). Awareness is growing about the differences between genders in various systems that govern blood pressure and chronic kidney disease. It is believed that the protection women experience against cardiovascular disease during their reproductive years is partly attributed to 17β-estradiol (E2), as the natural levels of E2 and the expression of estrogen receptors differ significantly between men and women (13). Sex differences in the expression of RAS components have also been identified (14–16). Despite the increase in RAS substrates, E2 has a downregulatory effect on AT1R expression while simultaneously enhancing AT2R expression (17). Experimental studies indicated that estrogen may shift the vasoconstrictor–vasodilator balance of the RAS (18–20). Numerous studies have demonstrated variations in the renal vascular response to Ang II infusion across different normotensive (21–25), renal ischemia-reperfusion (26,27), and hypertensive conditions (28,29), particularly with the blockade of various RAS receptors in both sexes. Now, losartan and telmisartan are two common medications used to manage hypertension and cardiovascular and renal diseases. However, it remains unclear which of these two drugs enhances renal blood flow (RBF) more effectively, and the gender differences effect. Accordingly, this study was designed to compare the effects of losartan and telmisartan on the hemodynamics responses to Ang II administration in male and female rats. Material and Methods Study population. Male and female rats were obtained from Royan Biotechnology Research Institute, Isfahan, Iran. They were initially brought to the laboratory to acclimate to their environment. Consequently, the temperature was maintained at 22–25°C, and they had unrestricted access to food and water. The study protocol was first submitted to the Ethics Committee of Isfahan University of Medical Sciences and received approval under code number IR.MUI.AEC.1403.012. The study design adheres to the principles of the Helsinki Declaration, version 2013, regarding animal rights. Study groups. This experimental animal study involved 36 Wistar rats (7-9 weeks), comprising 20 males and 16 females, randomized into six groups (3 groups of males and 3 groups of females): Groups 1,2 (named Vehicle group): Male (n=7), and female (n=5) rats receiving saline 0.9%. Groups 3,4 (named Losartan group): Male (n=5), and female (n=6) rats receiving losartan (10 mg/kg) (30). Groups 5,6 (named Telmisartan group): Male (n=8), and female (n=5) rats receiving telmisartan (10 mg/kg) (31). All the groups were subjected to graded doses of Ang II administration. Losartan was dissolved in saline 0.9%, and telmisartan dissolved in polyethylene glycol, and all drugs were freshly prepared before each administration. Experimental Procedure . The rats were anesthetized with urethane at a dose of 1.7 g/kg−1 intraperitoneal (Merck, Germany). To facilitate breathing, the trachea was cannulated, and polyethylene catheters were inserted into the carotid and femoral arteries, as well as the jugular vein, to monitor mean arterial pressure (MAP), renal perfusion pressure (RPP), and to infuse drugs, respectively. The carotid and femoral catheters were linked to a Power Lab System (AD Instrument, Australia). In addition, polyethylene catheter was also inserted in the bladder to collect the urine volume during the test. To maintain RPP at the baseline level during Ang II infusion, an adjustable clamp was placed around the abdominal aorta above the left renal artery (30). In a lateral position, the rats had their left kidney exposed, and the renal artery was isolated. An ultrasound flow probe (TRANSONIC MA0.7PSB, Flow Probe, USA) was then placed around the artery to directly measure RBF. Throughout the experiment, the MAP, RPP, and RBF were continuously monitored. After a 30-minute period and once the animal reached a stable condition, either saline, losartan, or telmisartan was administered through the vein catheter. Losartan or telmisartan was given as an initial bolus dose of 10 mg/kg, followed by a continuous infusion at a rate of 10 mg/kg/h. In the control groups, an equivalent volume of saline was infused. Thirty minutes after administering the antagonist, the required data were collected and considered as antagonists’ effects. Then along with the continuation of the antagonist injection, Ang II was infused intravenously in incremental doses of 30, 100, 300, and 1000 ng/kg/min using a micro syringe pump (New Era Pump System Inc., Farmingdale, NY, USA). Each dose was given until the MAP, RPP, and RBF responses stabilized, which took about 15 minutes. During the final 3-5 minutes of each phase, measurements were taken for MAP, RPP, and RBF. To express renal vascular resistance (RVR), the RPP/RBF ratio was calculated. Subsequently, the rats were euthanized by rapid intra venous administration of potassium chloride (75 to 150 mg /kg of body weight) (32), which induces cardiac arrest. Then kidneys were then removed and promptly weighed. Statistical Analysis. The data were presented as mean ± SEM and analyzed with SPSS 24 statistical software. A one-way analysis of variance (ANOVA) was applied on the baseline data, kidney weight (KW) and urine flow (UF). Repeated measures ANOVA was utilized to compare the effects of antagonist or vehicle treatments on baseline variables. The effects of Ang II administration on MAP, RPP, RBF, and RVR were analyzed using ANOVA for repeated measures. To identify specific effects within each group, a post hoc Tukey analysis was performed. The significance level was set at P ≤ 0.05. Results Baseline Measurements. In the equilibrium phase and before administration of vehicle or antagonists (losartan or telmisartan), no significant differences were observed in basal values for MAP, RPP and RBF between the groups of different genders (Table 1). Effect of Antagonist. Before infusion of Ang II, it is essential to assess the antagonist's effect on MAP, RPP, and RBF. Therefore, 30 minutes after administering the antagonist was selected as the time to evaluate theses effects. After administering the vehicle, losartan, or telmisartan, no significant differences were found in MAP, RPP, and RBF between the groups. However, losartan and telmisartan infusion resulted in a significant decrease in MAP and RPP (P dose < 0.0001) for both males and females, while a notable increase in RBF (P dose < 0.0001) was observed only in the female group when compared with the baseline data (Fig. 1). Responses to Ang II Infusion. Infusion of Ang II resulted in dose-dependent increases in MAP that were similar in both male (P treat < 0.0001) and female (P trea t < 0.002) rats (Fig. 2). The losartan group showed significantly lower MAP (P group = 0.018) and RPP (P group = 0.019) compared to the other groups, while in males’ groups, no significant differences were noted between the groups. Additionally, Ang II infusion led to a dose-dependent percentage change decrease in RBF and an increase in RVR in the vehicle group for both males and females. For example, at the dose of 1000 ng/kg/min of Ang II, the percentage change of RBF was -47.72 ± 4.91%, -11.14 ± 12.01%, and -7.25 ± 5.29% ml/min and RVR was 99.82 ± 20.4%, 23.66 ± 25.01%, and 9.84 ± 6.17% mmHg·min/ml in the male groups of vehicle, losartan, and telmisartan respectively. As well as, in female groups RBF was -58.08 ± 4.17%, -6.58 ± 11.97%, and -16.76 ± 3.81% ml/min and RVR was 140.93 ± 17.72%, 10.27 ± 12.72%, and 21.72 ± 5.12% mmHg·min/ml in vehicle, losartan, and telmisartan group respectively (Fig. 2). Table 1: Baseline data for mean arterial pressure (MAP), renal perfusion pressure (RPP) and renal blood flow (RBF) in male and female rats. No significant difference was obtained between the groups in both genders. Gender Group MAP (mmHg) RPP (mmHg) RBF (ml/min) Male Vehicle 103.4±6.3 97.2±7.0 1.6±0.2 Losartan 103.1±9.4 99.5±9.8 2.02±0.4 Telmisartan 95.5±4.7 90.4±4.9 1.58±0.1 P (ANOVA) 0.60 0.62 0.47 Female Vehicle 98.7±2.5 95.4±4.1 1.14±0.1 Losartan 103.3±7.5 100.1±8.9 1.36±0.2 Telmisartan 103.5±8.2 100.1±7.8 1.24±0.1 P (ANOVA) 0.86 0.88 0.61 Kidneys weight and urine flow in both genders No significant differences were observed in kidney weight (g) per 100 g body weight among male groups (P=0.12) or female groups (P=0.38). Nevertheless, urine flow was elevated in the telmisartan-treated group compared to the saline and losartan groups, with this increase being notably more pronounced in males (P=0.015). The urine flow in the saline, losartan, and telmisartan groups were 0.78 ± 0.4, 1.63 ± 0.6, and 6.58 ± 1.4 for males, respectively, and 1.15 ± 0.5, 0.94 ± 0.3, and 5.33 ± 1.8 for females (Fig. 3). Discussion The study’s main objective was comparison of losartan and telmisartan effects on hemodynamics responses to Ang II in male and female rats. The MAP response to Ang II administration was not similar between male and female. However, the RBF and RVR responses to Ang II were almost similar between genders. This study had three main findings: First, in females, losartan caused a significant reduction in MAP and RPP compared to the vehicle and telmisartan groups, whereas in males, no significant difference was observed between the groups. The NIH Policies for Biomedical Research have even required the consideration of gender- and/or sex-related factors as biological variables (33,34). As expected, gender difference have been noted in blood pressure, proinflammatory responses, and renal excretory or transport reactions to Ang II or RAS blockers (35–40), and it was initially accepted that gender differences were influenced by AT1R expression and Ang II production. Research on AT2R knockout mice indicates that AT2R independently triggers responses and acts as a functional counterbalance to the responses mediated by AT1R (36,41). In these researches, AT2R decreased the constrictor effect of Ang II in wild-type female mice, while female AT2R knockout mice exhibited responses similar to those of male wild-type and male AT2R knockout mice (36,41). In animal studies, estrogen increases the activation of the counterregulatory RAS by lowering circulating Ang II levels and enhancing AT2R expression (17,18,41). The female normotensive mice and rats exhibit a lower AT1R/AT2R ratio compared to their male counterparts (42), a pattern also observed in hypertensive rodents (36,43). In contrast, testosterone shifts the balance towards the vasoconstrictive RAS by enhancing sensitivity to Ang II and activating AT1R (44). Rodrigues et al. investigated the effect of losartan on AT2R expression and observed that administering losartan (acute or chronically), increased the expression of the AT2R gene in female spontaneously hypertensive rat, but this effect was not seen in males (45). Schwartz et.al discovered that administering losartan locally enhanced AT2R-mediated vasorelaxation in men, but it did not produce any effect in women (46). TJ et al. demonstrated that at the lowest dose of systemic Ang II, women exhibit a significant reduction in MAP, a response not seen in men (47). Comparable findings in rodent studies suggest that low doses of Ang II cause a reduction in MAP in normotensive females (48), whereas AT2R activation leads to enhanced RBF in hypertensive females (42), a mechanism demonstrated to depend on estrogens (49). In summary, it can be concluded that the use of losartan in female rats has a greater effect on reducing MAP and RPP than telmisartan possibly due to increased expression of the AT2R. Second: There was no difference in the RBF and RVR response to Ang II between the telmisartan and losartan groups in both genders. Acute vasoconstrictor response to Ang II in the renal circulation was almost completely extinguished (50,51). Therefore, administering an ARB causes dilation of both the afferent and efferent arterioles under normal circumstances (52). When ARBs cause renal vasodilation, it leads to enhanced RBF, which helps relieve renal ischemia and hypoxia (53). Sparks et al. demonstrated that the elimination of AT1aR from vascular smooth muscle cells results in increased RBF and differing vascular responses to Ang II in both the systemic and renal circulations (54). Toering et al. studied sex differences in Ang II response during acute (humans) and chronic (rats) administration. Baseline glomerular filtration rate (GFR) showed no sex difference, but males had significantly higher effective renal plasma flow than females (47). Miller et al. have indicated that administering ARB treatment (irbesartan at a dosage of 75 mg/day for 4 weeks) to healthy individuals resulted in a comparable reduction in MAP, RVR, RBF, GFR, effective renal plasma flow, and filtration fraction in both men and women (55). Pezeshki et al. demonstrated that in the two kidney- one clip (2K1C) model, vehicle-treated rats exhibited a more renal vasoconstriction response to Ang II infusion in males compared to females, confirming sex differences. However, losartan eliminated this response in both sexes (29). In males, the distribution and function of renal AT1R are greater than in females (56). Therefore, the absence of sex differences in the vasoconstriction response to Ang II might be attributed to the removal of the greater AT1R response to Ang II in male rats. Therefore, despite the typical gender differences in the response of renal vessels to Ang II, administration of losartan and telmisartan increases RBF to the same extent in both sexes. Third: Urine flow was significantly higher in the groups receiving telmisartan than in the groups receiving saline and losartan, and this increase was significant in the male group. Ang II predominantly influences on the AT1 subtype (95%), in the proximal convoluted tubule to regulate the excretion of water and electrolytes (57) . Accordingly, Ang II antagonists that selectively target AT1Rs resulting in vasodilation, increased urine production, and sodium excretion. Indeed, studies have shown that losartan has beneficial effects on kidney function in dogs with hypertension (58) and salt depletion (59). In isolated rat kidneys, telmisartan increased furosemide-induced enhancements in kidney perfusion, GFR, and UF in a dose-dependent manner (60). Telmisartan also promoted the excretion of water, sodium, and chloride without changing potassium excretion in anesthetized rats with normal blood pressure (60). Another study demonstrated that telmisartan influences kidney function in awake female dogs by increasing the excretion of water, sodium, and chloride, while not affecting the elimination of potassium or creatinine. These effects were observed within 6 hours after telmisartan was given either intravenously or orally (61). Conclusion We concluded that in females, losartan caused a significant reduction in MAP and RPP compared to the vehicle and telmisartan groups, whereas there was no difference in the RBF and RVR response to Ang II between the telmisartan and losartan groups in both genders. However, the effect of telmisartan on increasing UF was significantly greater. This observation indicates that telmisartan influence kidney function and promote diuresis through additional mechanisms. These effects on water and electrolyte balance, beyond its blood pressure-lowering action, potentially distinguish telmisartan from losartan in clinical management of hypertension. Abbreviations Renin–angiotensin system (RAS); Angiotensin II (Ang II); Angiotensin II receptor blockers (ARBs); Rrenal blood flow (RBF); Renal vascular resistance (RVR); Mean arterial pressure (MAP); Rrenal perfusion pressure (RPP); Angiotensin II type 1 receptor (AT1R); Angiotensin II type 2 receptor (AT2R); angiotensinogen (AGT); Angiotensin-converting enzyme (ACE); Cardiovascular disease (CVD); Angiotensin-converting enzyme inhibitors (ACEIs); Angiotensin receptor blockers (ARBs); Food and Drug Administration (FDA); Peroxisome proliferator-activated receptor gamma (PPARγ); 17β-estradiol (E2); Kidney weight (KW); and urine flow (UF). Declarations ● Ethics approval and consent to participate: Ethics Committee code number IR.MUI.AEC.1403.012. ● Consent for publication All authors have read and approved the final manuscript and agree to its submission and publication in this journal. ● Availability of data and materials: The authors confirm that all data supporting the findings of this study are included within the article. Additional detailed data and results can be made available from the corresponding author upon reasonable request. ● Competing Interests: The authors declare that they have no competing interests. ● Funding: This study was supported by Isfahan University of Medical Sciences under grant number 1402379. ● Authors' contributions: Author 1: Study design, Data collection, Data analysis, Manuscript writing. Author 2: Data collection. Author 3: Data collection. Corresponding author: Study design, Data analysis, Manuscript writing . ● Acknowledgements: Not applicable. References Ferrario CM, Strawn WB. 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effect of vehicle/antagonists on mean arterial pressure (MAP), renal perfusion pressure (RPP) and renal blood flow (RBF) in male (left), and female (right) rats. No significant difference was obtained between the groups in both genders.\u003c/p\u003e","description":"","filename":"Fig1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7563367/v1/fbe52f229a2ca545c02692de.jpg"},{"id":93005752,"identity":"ffb4603f-f98f-46b0-baae-702f40bb7550","added_by":"auto","created_at":"2025-10-08 06:38:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":355070,"visible":true,"origin":"","legend":"\u003cp\u003eMean arterial pressure (MAP), renal perfusion pressure (RPP), renal blood flow (RBF), and renal vascular (RVR) response responses to graded angiotensin II (Ang II) infusion in male (left), and female (right) rats. The star (*) indicates significant difference from vehicle group (P \u0026lt; 0.05), and the symbol (#) indicates significant difference from others group (P \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"Fig2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7563367/v1/f78d460b48f97c2ff246b959.jpg"},{"id":93005137,"identity":"a53a3160-ebe0-4347-a3ee-bf729a21110c","added_by":"auto","created_at":"2025-10-08 06:30:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":232198,"visible":true,"origin":"","legend":"\u003cp\u003eTotal kidney weight per 100-gram body weight (KW(g)/100g BW), urine flow per g kidney weight (UF). Data are presented as mean±SEM and were analyzed using Student’s t-test. The star (*) indicates significant difference from vehicle and losartan group (P \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"Fig3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7563367/v1/3c90037827b60b395f77d02f.jpg"},{"id":100942560,"identity":"234197e6-9a5e-4cbc-bb88-5ac024124e3c","added_by":"auto","created_at":"2026-01-23 05:10:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1285826,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7563367/v1/9a402b70-41fb-49c3-81d7-61faeb936015.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of Losartan Versus Telmisartan on Renal Hemodynamics Responses to Angiotensin II administration in Male and Female Rats","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe renin\u0026ndash;angiotensin system (RAS) is crucial in regulating blood pressure, fluid volume, and sodium balance. Overactivation of this system can lead to the development of several medical disorders such as hypertension and heart failure (1). The main two important of RAS receptors includes angiotensin II (Ang II) type 1 receptor (AT1R) and type 2 receptor (AT2R). The angiotensinogen (AGT)/renin/angiotensin-converting enzyme (ACE)/Ang II /AT1R (AGT/renin/ACE/Ang II/AT1R) axis is the main pathway for the production of Ang II and is accountable for nearly all the traditional effects of Ang II in the progression of hypertension as well as cardiovascular and kidney diseases (2). Consequently, targeting the RAS is a sensible approach for hypertension, kidney disorders, and cardiovascular disease (CVD) treatments. At present, three categories of drugs modulate the RAS including: 1) angiotensin-converting enzyme (ACE) inhibitors (ACEIs), which prevent the production of Ang II; 2) angiotensin receptor blockers (ARBs), which obstruct the harmful effects of Ang II at the AT1R; and 3) aliskiren, which acts as a renin inhibitor. ACEIs and ARBs help lower the risk of kidney disease and decrease cardiovascular mortality and morbidity (1,3\u0026ndash;5).\u003c/p\u003e\n\u003cp\u003eLosartan, a first-generation AT1R antagonist, effectively counters the metabolic changes caused by Ang II and elevated oxygen radicals (6). Moreover, it functions as a partial agonist on the bradykinin receptor B2, and in addition to the classical action of ARBs, it can provide additional cardioprotective benefits (7). Losartan is well-tolerated, highly effective at lowering blood pressure, and provides beneficial uricosuric and kidney-protective effects. Therefore, it can be considered a first choice drug for elderly patients with hypertension and hyperuricemia undergoing chemotherapy (8).\u003c/p\u003e\n\u003cp\u003eTelmisartan, an ARBs received Food and Drug Administration (FDA) approval in November 1998 for managing high blood pressure. The ONTARGET trial\u0026apos;s findings prompted the FDA to authorize telmisartan as the first ARB to lower cardiovascular risk in patients unable to take ACE inhibitors (9). Telmisartan is a commonly prescribed medication for hypertension, known for its excellent safety and tolerability, both alone and in combination therapies. It has several pharmacological characteristics that distinguish it from other ARBs, including the longest plasma half-life, the highest lipophilicity, and the strongest receptor binding affinity in its class. Telmisartan is therefore widely indicated for lowering cardiovascular risk in individuals with atherothrombotic disease or diabetes mellitus associated with end-organ damage (10). Its additional p\u003cem\u003eeroxisome proliferator-activated receptor gamma\u003c/em\u003e (PPAR\u0026gamma;) agonistic effect also alleviates vascular inflammation, reduces visceral fat, and increases serum adiponectin levels while simultaneously lowering high blood pressure in patients with essential hypertension (11). A meta-analysis revealed that telmisartan treatment may reduce the left ventricular mass index more effectively than other antihypertensive medications in individuals with hypertension, and this effect was largely independent of its capacity to lower blood pressure (12). \u003c/p\u003e\n\u003cp\u003eAwareness is growing about the differences between genders in various systems that govern blood pressure and chronic kidney disease. It is believed that the protection women experience against cardiovascular disease during their reproductive years is partly attributed to 17\u0026beta;-estradiol (E2), as the natural levels of E2 and the expression of estrogen receptors differ significantly between men and women (13). Sex differences in the expression of RAS components have also been identified (14\u0026ndash;16). Despite the increase in RAS substrates, E2 has a downregulatory effect on AT1R expression while simultaneously enhancing AT2R expression (17). Experimental studies indicated that estrogen may shift the vasoconstrictor\u0026ndash;vasodilator balance of the RAS (18\u0026ndash;20). Numerous studies have demonstrated variations in the renal vascular response to Ang II infusion across different normotensive (21\u0026ndash;25), renal ischemia-reperfusion (26,27), and hypertensive conditions (28,29), particularly with the blockade of various RAS receptors in both sexes.\u003c/p\u003e\n\u003cp\u003eNow, losartan and telmisartan are two common medications used to manage hypertension and cardiovascular and renal diseases. However, it remains unclear which of these two drugs enhances renal blood flow (RBF) more effectively, and the gender differences effect. Accordingly, this study was designed to compare the effects of losartan and telmisartan on the hemodynamics responses to Ang II administration in male and female rats.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cem\u003eStudy population.\u003c/em\u003e Male and female rats were obtained from Royan Biotechnology Research Institute, Isfahan, Iran. They were initially brought to the laboratory to acclimate to their environment. Consequently, the temperature was maintained at 22–25°C, and they had unrestricted access to food and water. The study protocol was first submitted to the Ethics Committee of Isfahan University of Medical Sciences and received approval under code number IR.MUI.AEC.1403.012. The study design adheres to the principles of the Helsinki Declaration, version 2013, regarding animal rights.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy groups.\u003c/em\u003e This experimental animal study involved 36 Wistar rats (7-9 weeks), comprising 20 males and 16 females, randomized into six groups (3 groups of males and 3 groups of females):\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroups 1,2 (named Vehicle group): Male (n=7), and female (n=5) rats receiving saline 0.9%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGroups 3,4 (named Losartan group): Male (n=5), and female (n=6) rats receiving losartan (10 mg/kg) (30).\u003c/p\u003e\n\u003cp\u003eGroups 5,6 (named Telmisartan group): Male (n=8), and female (n=5) rats receiving telmisartan (10 mg/kg) (31). All the groups were subjected to graded doses of Ang II administration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLosartan was dissolved in saline 0.9%, and telmisartan dissolved in polyethylene glycol, and all drugs were freshly prepared before each administration.\u003c/p\u003e\n\u003cp skip=\"true\"\u003e\u003cem\u003eExperimental Procedure\u003c/em\u003e. The rats were anesthetized with urethane at a dose of 1.7 g/kg−1 intraperitoneal (Merck, Germany). To facilitate breathing, the trachea was cannulated, and polyethylene catheters were inserted into the carotid and femoral arteries, as well as the jugular vein, to monitor mean arterial pressure (MAP), renal perfusion pressure (RPP), and to infuse drugs, respectively. The carotid and femoral catheters were linked to a Power Lab System (AD Instrument, Australia). In addition, polyethylene catheter was also inserted in the bladder to collect the urine volume during the test. To maintain RPP at the baseline level during Ang II infusion, an adjustable clamp was placed around the abdominal aorta above the left renal artery (30). In a lateral position, the rats had their left kidney exposed, and the renal artery was isolated. An ultrasound flow probe (TRANSONIC MA0.7PSB, Flow Probe, USA) was then placed around the artery to directly measure RBF. Throughout the experiment, the MAP, RPP, and RBF were continuously monitored. After a 30-minute period and once the animal reached a stable condition, either saline, losartan, or telmisartan was administered through the vein catheter. Losartan or telmisartan was given as an initial bolus dose of 10 mg/kg, followed by a continuous infusion at a rate of 10 mg/kg/h. In the control groups, an equivalent volume of saline was infused. Thirty minutes after administering the antagonist, the required data were collected and considered as antagonists’ effects. Then along with the continuation of the antagonist injection,\u003c/p\u003e\n\u003cp\u003eAng II was infused intravenously in incremental doses of 30, 100, 300, and 1000 ng/kg/min using a micro syringe pump (New Era Pump System Inc., Farmingdale, NY, USA). Each dose was given until the MAP, RPP, and RBF responses stabilized, which took about 15 minutes. During the final 3-5 minutes of each phase, measurements were taken for MAP, RPP, and RBF. To express renal vascular resistance (RVR), the RPP/RBF ratio was calculated. Subsequently, the rats were euthanized by rapid intra venous administration of potassium chloride (75 to 150 mg /kg of body weight) (32), which induces cardiac arrest. Then kidneys were then removed and promptly weighed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Analysis.\u003c/em\u003e The data were presented as mean ± SEM and analyzed with SPSS 24 statistical software. A one-way analysis of variance (ANOVA) was applied on the baseline data, kidney weight (KW) and urine flow (UF). Repeated measures ANOVA was utilized to compare the effects of antagonist or vehicle treatments on baseline variables. The effects of Ang II administration on MAP, RPP, RBF, and RVR were analyzed using ANOVA for repeated measures. To identify specific effects within each group, a post hoc Tukey analysis was performed. The significance level was set at P ≤ 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eBaseline Measurements.\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the equilibrium phase and before administration of vehicle or antagonists (losartan or telmisartan), no significant differences were observed in basal values for MAP, RPP and RBF between the groups of different genders (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEffect of Antagonist.\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBefore infusion of Ang II, it is essential to assess the antagonist\u0026apos;s effect on MAP, RPP, and RBF. Therefore, 30 minutes after administering the antagonist was selected as the time to evaluate theses effects. After administering the vehicle, losartan, or telmisartan, no significant differences were found in MAP, RPP, and RBF between the groups. However, losartan and telmisartan infusion resulted in a significant decrease in MAP and RPP (P\u003csub\u003edose\u003c/sub\u003e \u0026lt; 0.0001) for both males and females, while a notable increase in RBF (P\u003csub\u003edose\u003c/sub\u003e \u0026lt; 0.0001) was observed only in the female group when compared with the baseline data (Fig. 1).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResponses to Ang II Infusion.\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInfusion of Ang II resulted in dose-dependent increases in MAP that were similar in both male (P\u003csub\u003etreat\u003c/sub\u003e \u0026lt; 0.0001) and female (P\u003csub\u003etrea\u003c/sub\u003et \u0026lt; 0.002) rats (Fig. 2). The losartan group showed significantly lower MAP (P\u003csub\u003egroup\u003c/sub\u003e = 0.018) and RPP (P\u003csub\u003egroup\u003c/sub\u003e = 0.019) compared to the other groups, while in males\u0026rsquo; groups, no significant differences were noted between the groups. Additionally, Ang II infusion led to a dose-dependent percentage change decrease in RBF and an increase in RVR in the vehicle group for both males and females. For example, at the dose of 1000 ng/kg/min of Ang II, the percentage change of RBF was -47.72 \u0026plusmn; 4.91%, -11.14 \u0026plusmn; 12.01%, and -7.25 \u0026plusmn; 5.29% ml/min and RVR was 99.82 \u0026plusmn; 20.4%, 23.66 \u0026plusmn; 25.01%, and 9.84 \u0026plusmn; 6.17% mmHg\u0026middot;min/ml in the male groups of vehicle, losartan, and telmisartan respectively. As well as, in female groups RBF was -58.08 \u0026plusmn; 4.17%, -6.58 \u0026plusmn; 11.97%, and -16.76 \u0026plusmn; 3.81% ml/min and RVR was 140.93 \u0026plusmn; 17.72%, 10.27 \u0026plusmn; 12.72%, and 21.72 \u0026plusmn; 5.12% mmHg\u0026middot;min/ml in vehicle, losartan, and telmisartan group respectively (Fig. 2).\u003c/p\u003e\n\u003cp\u003eTable 1: Baseline data for mean arterial pressure (MAP), renal perfusion pressure (RPP) and renal blood flow (RBF) in male and female rats. No significant difference was obtained between the groups in both genders.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cdel cite=\"mailto:drnematbakhsh.m\" datetime=\"2025-09-07T08:32\"\u003e\u0026nbsp;\u003c/del\u003e\u003c/p\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003eMAP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eRPP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eRBF (ml/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eVehicle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e103.4\u0026plusmn;6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e97.2\u0026plusmn;7.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e1.6\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eLosartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e103.1\u0026plusmn;9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e99.5\u0026plusmn;9.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e2.02\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eTelmisartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e95.5\u0026plusmn;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e90.4\u0026plusmn;4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e1.58\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003eP\u003csub\u003e(ANOVA)\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eVehicle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e98.7\u0026plusmn;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e95.4\u0026plusmn;4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e1.14\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eLosartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e103.3\u0026plusmn;7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e100.1\u0026plusmn;8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e1.36\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eTelmisartan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e103.5\u0026plusmn;8.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e100.1\u0026plusmn;7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e1.24\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 279px;\"\u003e\n \u003cp\u003eP\u003csub\u003e(ANOVA)\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 231px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eKidneys weight and urine flow in both genders\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo significant differences were observed in kidney weight (g) per 100 g body weight among male groups (P=0.12) or female groups (P=0.38). Nevertheless, urine flow was elevated in the telmisartan-treated group compared to the saline and losartan groups, with this increase being notably more pronounced in males (P=0.015). The urine flow in the saline, losartan, and telmisartan groups were 0.78 \u0026plusmn; 0.4, 1.63 \u0026plusmn; 0.6, and 6.58 \u0026plusmn; 1.4 for males, respectively, and 1.15 \u0026plusmn; 0.5, 0.94 \u0026plusmn; 0.3, and 5.33 \u0026plusmn; 1.8 for females (Fig. 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study\u0026rsquo;s main objective was comparison of losartan and telmisartan effects on hemodynamics responses to Ang II in male and female rats. The MAP response to Ang II administration was not similar between male and female. However, the RBF and RVR responses to Ang II were almost similar between genders. This study had three main findings:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFirst, in females, losartan caused a significant reduction in MAP and RPP compared to the vehicle and telmisartan groups, whereas in males, no significant difference was observed between the groups. The NIH Policies for Biomedical Research have even required the consideration of gender- and/or sex-related factors as biological variables (33,34). As expected, gender difference have been noted in blood pressure, proinflammatory responses, and renal excretory or transport reactions to Ang II or RAS blockers (35\u0026ndash;40), and it was initially accepted that \u0026nbsp;gender differences were influenced by AT1R expression and Ang II production. \u0026nbsp;Research on AT2R knockout mice indicates that AT2R independently triggers responses and acts as a functional counterbalance to the responses mediated by AT1R (36,41). In these researches, AT2R decreased the constrictor effect of Ang II in wild-type female mice, while female AT2R knockout mice exhibited responses similar to those of male wild-type and male AT2R knockout mice (36,41). In animal studies, estrogen increases the activation of the counterregulatory RAS by lowering circulating Ang II levels and enhancing AT2R expression (17,18,41). The female normotensive mice and rats exhibit a lower AT1R/AT2R ratio compared to their male counterparts (42), a pattern also observed in hypertensive rodents (36,43). In contrast, testosterone shifts the balance towards the vasoconstrictive RAS by enhancing sensitivity to Ang II and activating AT1R (44).\u0026nbsp;Rodrigues et al. investigated the effect of losartan on AT2R expression and observed that administering losartan (acute or chronically), increased the expression of the AT2R gene in female\u0026nbsp;spontaneously hypertensive\u0026nbsp;rat, but this effect was not seen in males\u0026nbsp;(45).\u0026nbsp;Schwartz et.al discovered that administering losartan locally enhanced AT2R-mediated vasorelaxation in men, but it did not produce any effect in women\u0026nbsp;(46).\u0026nbsp;TJ\u0026nbsp;et al. demonstrated that at the lowest dose of systemic Ang II, women exhibit a significant reduction in MAP, a response not seen in men\u0026nbsp;(47).\u0026nbsp;Comparable findings in rodent studies suggest that low doses of Ang II cause a reduction in MAP in normotensive females\u0026nbsp;(48), whereas AT2R activation leads to enhanced RBF in hypertensive females\u0026nbsp;(42), a mechanism demonstrated to depend on estrogens\u0026nbsp;(49).\u0026nbsp;In summary, it can be concluded that the use of losartan in female rats has a greater effect on reducing MAP and RPP than telmisartan possibly due to increased expression of the AT2R.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecond: There was no difference in the RBF and RVR response to Ang II between the telmisartan and losartan groups in both genders. Acute vasoconstrictor response to Ang II in the renal circulation was almost completely extinguished (50,51). Therefore, administering an ARB causes dilation of both the afferent and efferent arterioles under normal circumstances (52). When ARBs cause renal vasodilation, it leads to enhanced RBF, which helps relieve renal ischemia and hypoxia\u0026nbsp;(53).\u0026nbsp;Sparks et al. demonstrated that the elimination of AT1aR from\u0026nbsp;vascular smooth muscle cells\u0026nbsp;results in increased RBF and differing vascular responses to Ang II in both the systemic and renal circulations\u0026nbsp;(54). Toering et al. studied sex differences in Ang II response during acute (humans) and chronic (rats) administration. Baseline\u0026nbsp;glomerular filtration rate (GFR) showed no sex difference, but males had significantly higher effective renal plasma flow than females\u0026nbsp;(47).\u0026nbsp;Miller et al. have indicated that administering ARB treatment (irbesartan at a dosage of 75 mg/day for 4 weeks) to healthy individuals resulted in a comparable reduction in MAP, RVR, RBF, GFR, effective renal plasma flow, and filtration fraction in both men and women\u0026nbsp;(55). Pezeshki et al. demonstrated that in the two kidney- one clip (2K1C) model, vehicle-treated rats exhibited a more renal vasoconstriction response to Ang II infusion in males compared to females, confirming sex differences. However, losartan eliminated this response in both sexes\u0026nbsp;(29). In males, the distribution and function of renal AT1R are greater than in females\u0026nbsp;(56). Therefore, the absence of sex differences in the vasoconstriction response to Ang II might be attributed to the removal of the greater AT1R response to Ang II in male rats. Therefore, despite\u0026nbsp;the typical\u0026nbsp;gender differences in the response of renal vessels to Ang II, administration of losartan and telmisartan increases RBF to the same extent in both sexes.\u003c/p\u003e\n\u003cp\u003eThird:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eUrine flow was significantly higher in the groups receiving telmisartan than in the groups receiving saline and losartan, and this increase was significant in the male group. Ang II predominantly influences on the AT1 subtype (95%), in the proximal convoluted tubule to regulate the excretion of water and electrolytes (57) . Accordingly, Ang II antagonists that selectively target AT1Rs resulting in vasodilation, increased urine production, and sodium excretion. Indeed, studies have shown that losartan has beneficial effects on kidney function in dogs with hypertension (58) \u0026nbsp;and salt depletion (59). In isolated rat kidneys, telmisartan increased furosemide-induced enhancements in kidney perfusion, GFR, and UF in a dose-dependent manner (60). Telmisartan also promoted the excretion of water, sodium, and chloride without changing potassium excretion in anesthetized rats with normal blood pressure (60). Another study demonstrated that telmisartan influences kidney function in awake female dogs by increasing the excretion of water, sodium, and chloride, while not affecting the elimination of potassium or creatinine. These effects were observed within 6 hours after telmisartan was given either intravenously or orally (61).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe concluded that in females, losartan caused a significant reduction in MAP and RPP compared to the vehicle and telmisartan groups, whereas there was no difference in the RBF and RVR response to Ang II between the telmisartan and losartan groups in both genders. However, the effect of telmisartan on increasing UF was significantly greater. This observation indicates that telmisartan influence kidney function and promote diuresis through additional mechanisms. These effects on water and electrolyte balance, beyond its blood pressure-lowering action, potentially distinguish telmisartan from losartan in clinical management of hypertension.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRenin\u0026ndash;angiotensin system (RAS); Angiotensin II (Ang II); Angiotensin II receptor blockers (ARBs); Rrenal blood flow (RBF); Renal vascular resistance (RVR); Mean arterial pressure (MAP); Rrenal perfusion pressure (RPP); Angiotensin II type 1 receptor (AT1R); Angiotensin II type 2 receptor (AT2R); angiotensinogen (AGT); Angiotensin-converting enzyme (ACE); Cardiovascular disease (CVD); Angiotensin-converting enzyme inhibitors (ACEIs); Angiotensin receptor blockers (ARBs); Food and Drug Administration (FDA); Peroxisome proliferator-activated receptor gamma (PPAR\u0026gamma;); 17\u0026beta;-estradiol (E2); Kidney weight (KW); and urine flow (UF).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e● Ethics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eEthics Committee code number IR.MUI.AEC.1403.012.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;● Consent for publication \u0026nbsp;\u003c/strong\u003eAll authors have read and approved the final manuscript and agree to its submission and publication in this journal.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003e● Availability of data and materials:\u0026nbsp;\u003c/strong\u003eThe authors confirm that all data supporting the findings of this study are included within the article. Additional detailed data and results can be made available from the corresponding author upon reasonable request.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003e● Competing Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003cbr\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;● Funding:\u0026nbsp;\u003c/strong\u003eThis study was supported by Isfahan University of Medical Sciences under grant number 1402379.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e● Authors\u0026apos; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthor 1: Study design, Data collection, Data analysis, Manuscript writing.\u003c/p\u003e\n\u003cp\u003eAuthor 2: Data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor 3: Data collection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCorresponding author: Study design, Data analysis, Manuscript writing .\u003cbr\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;● Acknowledgements:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFerrario CM, Strawn WB. 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AVMA guidelines for the euthanasia of animals: 2020 edition. Retrieved on March. 2020;2013(30):2020\u0026ndash;1. \u003c/li\u003e\n\u003cli\u003eClayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509(7500):282\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eGalea LAM, Choleris E, Albert AYK, McCarthy MM, Sohrabji F. The promises and pitfalls of sex difference research. Front Neuroendocrinol. 2020;56:100817. \u003c/li\u003e\n\u003cli\u003eVeiras LC, McFarlin BE, Ralph DL, Buncha V, Prescott J, Shirvani BS, et al. Electrolyte and transporter responses to angiotensin II induced hypertension in female and male rats and mice. Acta Physiol. 2020;229(1):e13448. \u003c/li\u003e\n\u003cli\u003eBrown RD, Hilliard LM, Head GA, Jones ES, Widdop RE, Denton KM. Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II. 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Hypertension. 2014;64(2):384\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eMirabito KM, Hilliard LM, Head GA, Widdop RE, Denton KM. Pressor responsiveness to angiotensin II in female mice is enhanced with age: role of the angiotensin type 2 receptor. Biol Sex Differ. 2014;5(1):1\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eHilliard LM, Chow CLE, Mirabito KM, Steckelings UM, Unger T, Widdop RE, et al. Angiotensin type 2 receptor stimulation increases renal function in female, but not male, spontaneously hypertensive rats. Hypertension. 2014;64(2):378\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eLee SH, Lee YH, Jung SW, Kim DJ, Park SH, Song SJ, et al. Sex-related differences in the intratubular renin-angiotensin system in two-kidney, one-clip hypertensive rats. Am J Physiol Physiol. 2019;317(3):F670\u0026ndash;82. \u003c/li\u003e\n\u003cli\u003eChinnathambi V, More AS, Hankins GD, Yallampalli C, Sathishkumar K. 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Physiol Rep. 2015;3(7):e12434. \u003c/li\u003e\n\u003cli\u003eSampson AK, Moritz KM, Jones ES, Flower RL, Widdop RE, Denton KM. Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats. Hypertension. 2008;52(4):666\u0026ndash;71. \u003c/li\u003e\n\u003cli\u003eSampson AK, Hilliard LM, Moritz KM, Thomas MC, Tikellis C, Widdop RE, et al. The arterial depressor response to chronic low-dose angiotensin II infusion in female rats is estrogen dependent. Am J Physiol Integr Comp Physiol. 2012;302(1):R159\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eStevenson MD, Vendrov AE, Yang X, Chen Y, Navarro HA, Moss N, et al. Reactivity of renal and mesenteric resistance vessels to angiotensin II is mediated by NOXA1/NOX1 and superoxide signaling. Am J Physiol Physiol. 2023;324(4):F335\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eJust A, Olson AJM, Whitten CL, Arendshorst WJ. 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Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs. Eur J Pharmacol. 1991;202(3):323\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eWienen W, Entzeroth M. Effects on binding characteristics and renal function of the novel, non-peptide angiotensin II antagonist BIBR 277 in the rat. J Hypertens. 1994;12(2):119\u0026ndash;28. \u003c/li\u003e\n\u003cli\u003eSchierok H, Pairet M, Hauel N, Wienen W. Effects of telmisartan on renal excretory function in conscious dogs. J Int Med Res. 2001;29(2):131\u0026ndash;9. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Losartan, Telmisartan, Gender Differences, Renal Blood Flow, Renal Vascular Resistance","lastPublishedDoi":"10.21203/rs.3.rs-7563367/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7563367/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground.\u003c/strong\u003e The renin–angiotensin system (RAS) is crucial in regulating blood pressure, fluid volume, and sodium balance in the body. Overactivation of this system can lead to the development of several medical conditions, such as kidney, and cardiovascular disorders. Losartan and telmisartan are two common angiotensin II (Ang II) receptor blockers (ARBs) which used for hypertension therapy. Both of these blockers affect renal blood flow (RBF), and this study aimed to compare the effects of losartan and telmisartan on the (RBF) and renal vascular resistance (RVR) responses to Ang II infusion in male and female rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods. \u003c/strong\u003eThree groups of males and three groups of females Wistar rats were assigned, and they randomized in vehicle, losartan (10 mg/kg), and telmisartan (10 mg/kg) treated groups. Subsequently, under anesthesia, mean arterial pressure (MAP), RBF and RVR responses to graded doses of Ang II administration under controlled renal perfusion pressure (RPP) were determined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults. \u003c/strong\u003eInfusion of Ang II resulted in dose-dependent increases in MAP that were similar in both male (P\u003csub\u003etreat\u003c/sub\u003e \u0026lt; 0.0001) and female (P\u003csub\u003etreat\u003c/sub\u003e \u0026lt; 0.002) rats. However, in females, the losartan group showed significantly lower MAP (P\u003csub\u003egroup\u003c/sub\u003e = 0.018) and RPP (P\u003csub\u003egroup\u003c/sub\u003e = 0.019) compared to the other groups. Ang II infusion led to a dose-dependent percentage change of RBF decreasing and RVR increasing in the vehicle group for both genders, and these changes were significantly different from others group ((P \u0026lt; 0.05). Additionally, urine flow was increased significantly in telmisartan group when compared with others groups (P \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion.\u003c/strong\u003e Losartan in female rats is more effective in reducing MAP than telmisartan, while similar RBF and RVR responses to Ang II infusion were conducted in losartan and telmisartan groups.\u003c/p\u003e","manuscriptTitle":"The Effect of Losartan Versus Telmisartan on Renal Hemodynamics Responses to Angiotensin II administration in Male and Female Rats","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 06:30:41","doi":"10.21203/rs.3.rs-7563367/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0df0524-3480-44f0-ab92-ca7dfcfcbf63","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-23T05:10:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-08 06:30:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7563367","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7563367","identity":"rs-7563367","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}