{"paper_id":"42c2563f-9ec2-461c-98c3-5d28745b80b0","body_text":"Diagnostic Value of Hypoxia-Inducible Factor 1 Alpha and Adrenomedullin in Acute Mesenteric Ischemia | 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 Article Diagnostic Value of Hypoxia-Inducible Factor 1 Alpha and Adrenomedullin in Acute Mesenteric Ischemia Enes BAYINDIR, Kadir KÜÇÜKCERAN, Muhammet Raşit ÖZER, Mustafa Kürşat AYRANCI, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7397493/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 INTRODUCTION This study aims to evaluate the diagnostic significance of adrenomedullin and hypoxia-inducible factor 1 alpha (HIF1-alpha) levels in an animal model of acute mesenteric ischemia. MATERIALS AND METHODS In our study, a total of 21 male New Zealand rabbits were used, and the animals were divided into three groups for the study. Blood samples were taken for adrenomedullin and HIF1-alpha levels at 0, 1, 3, and 6 hours from the control, sham, ischemia groups. RESULTS HIF levels of the ischemia group at the 3rd and 6th hours were statistically significantly higher than those in the sham (p = 0.002, p < 0.001, respectively) and control groups (p = 0.002, p < 0.001, respectively). Adrenomedullin levels of the ischemia group at the 1st, 3rd, and 6th hours were statistically significantly higher than those in the sham (p = 0.004, p < 0.001, p < 0.001, respectively) and control groups (p < 0.001, p < 0.001, p < 0.001 respectively). CONCLUSION HIF1-alpha and adrenomedullin have significant potential in the early diagnosis of acute mesenteric ischemia. In the emergency department setting, consideration of these markers and the patient's symptoms and signs may facilitate the diagnostic process. Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Biological sciences/Physiology Acute mesenteric ischemia Hypoxia inducible factor 1 alpha Adrenomedullin Animal model Figures Figure 1 Figure 2 Figure 3 Figure 4 1. INTRODUCTION Although acute mesenteric ischemia is relatively rare, it is a disease with high mortality that may require emergency surgery. Although its incidence is reported as 0.63–12.9/100,000, it is among the most common causes of death among surgical diseases worldwide[ 1 , 2 ]. Early diagnosis and treatment are the main factors determining the prognosis of acute mesenteric ischemia. Objective findings are needed for correct diagnosis and differential diagnosis in the emergency department [ 1 ] Hypoxia Inducible Factor-1 (HIF-1) alpha is a major regulator of tissue hypoxia resulting from low oxygen levels. Although HIF1-alpha has been studied in many diseases associated with hypoxic pathophysiology, there are not enough studies on its diagnostic importance in acute mesenteric ischemia, where intestinal hypoxia is the primary mechanism [ 3 , 4 ]. Adrenomedullin, a member of the calcitonin gene-related peptide family (CGRP), has vasodilator potential [ 5 ]. In acute mesenteric ischemia, vasodilation mechanisms are activated to relieve hypoxia in the intestines and ensure adequate perfusion [ 6 ]. In our study, we aimed to examine the levels of adrenomedullin and HIF1-alpha, which we think may help in the early diagnosis of acute mesenteric ischemia in the emergency department, in an animal model in which we created experimental acute mesenteric ischemia. 2. MATERIALS AND METHODS Our study was approved by the Local Ethics Committee for Animal Experiments of Necmettin Erbakan University Hospital and conducted in accordance with the ARRIVE guidelines for animal experiments. The number of animals required for our study was calculated using G.Power. Twenty-one male New Zealand rabbits, 14–18 weeks old and weighing 2.5-3.0 kg, were used in the experiment. The New Zealand rabbits were obtained from the Experimental Medicine Application and Research Center (KONÜDAM) of Necmettin Erbakan University. All animals were given 50 mg/kg of Ketamine and 15 mg/kg of Xylazine intramuscularly in their hind legs. After anesthesia, a 26 G intravenous catheter was used to obtain blood and administer fluids to the rabbits' dorsal ear veins. Control Group No other procedure was performed on the control group except for establishing vascular access. Samples were taken to evaluate HIF1-alpha and adrenomedullin levels at 0, 1, 3, and 6 hours. A gel and clot activator (Vacusera ®) tube (2 ml) was used to collect the samples. Sham Group After the 0th-hour sample was taken, 2 ml of 0.9% NaCl was administered intravenously for irrigation. Following blood collection, the subjects' abdominal area was shaved and cleaned with 10% povidone-iodine. A laparotomy was performed with a standard midline incision. After the peritoneum was passed, the abdominal wall and peritoneum were resutured with 2/0 silk. 2 ml samples were retaken at 1, 3, and 6 hours after the operation. Following each blood collection, 2 ml of 0.9% NaCl was administered intravenously for irrigation. No tissue samples were taken from this group. Ischemia group After the zero-hour sample was taken, 2 ml of 0.9% NaCl was administered intravenously for irrigation. After blood was drawn, the abdominal area was shaved and cleaned with 10% povidone-iodine. A laparotomy was performed with a midline incision. After the small intestine and cecum were identified, the superior mesenteric artery was isolated and carefully ligated. After ligation, acute mesenteric ischemia was confirmed by the pallor of the intestines. Afterward, the abdominal contents were placed again, and the peritoneum and abdominal wall were closed by suturing with 2/0 silk. 2 ml samples were retaken at 1, 3, and 6 hours after the operation. Following each blood draw, 2 ml of 0.9% NaCl was administered intravenously for irrigation. After 6 hours of ischemia, the rabbits were sacrificed with high-dose Ketamine. After sacrificing the subjects, a 10 cm ileal loop was excised for histopathological examination, and samples were taken. STORAGE OF THE SAMPLES Each 2 ml blood sample taken into the Gel & Clot Activator (Vacusera ®) tube was centrifuged for 10 minutes at 4500 rpm at a temperature setting of + 4–8 degrees Celsius after waiting for a maximum of 30 minutes. The samples were stored at -20°C until biochemical evaluation. The 10 cm ileal loop samples taken for histopathological examination were stored in 10% formaldehyde solution after being washed with sterile saline solution. BIOCHEMICAL EVALUATION HIF-1 alpha and adrenomedullin levels were studied by Enzyme-linked immunosorbent assay (ELISA) kits. This ELISA kit uses the quantitative ELISA technique. HISTOPATHOLOGICAL EVALUATION For histopathological examination, 10 cm long ileal loop materials were excised and fixed in 10% formaldehyde solution for 24 hours, and then 0.5 cm long samples were taken. Standard Hematoxylin/Eosin staining was applied to the sections. The sections were examined by a single pathologist. The degree of morphological damage in tissues due to ischemia was classified according to the Chiu score [ 7 ]. Chiu Scoring Stage 0: Normal-appearing mucosal villi Stage 1: Low-level hydropic degeneration of the surface epithelium Stage 2: Low-level necrosis at the superficial villus epithelium apex Stage 3: Severe epithelial shedding of the villi, exposure of the villus tips Stage 4: Severe degeneration of the villi, mucosal necrosis in all layers Stage 5: Transmural necrosis STATISTICAL ANALYSIS Statistical analyses were performed using the SPSS version 22.0 package program. Normally distributed continuous variables were compared within the group using the \"Dependent groups t-test,\" and non-normally distributed continuous variables were compared within the group using the \"Wilcoxon signed rank test.\" One Way ANOVA and Kruskal Wallis test were used to compare HIF1-alpha and adrenomedullin levels between groups. In the statistical analyses of the study, comparisons with a p-value below 0.05 were considered statistically significant. 3. RESULTS Histological examination in the ischemia group showed that stage 4 ischemia occurred in 2 subjects, and stage 5 ischemia occurred in 5 subjects. In the intragroup analysis of the change in HIF1-alpha levels, no statistically significant difference was observed in HIF1-alpha levels in the control and sham groups during the study period. No statistically significant difference was observed between the 0-1st hour in the ischemia group. In contrast, the 3rd hour HIF1-alpha level was higher than the 0th hour (p = 0.018), and the 6th hour HIF1-alpha level was higher than the 0th hour (p = 0.018) (Fig. 1 , Table 1 ). Table 1 Intra-group Analysis of HIF1-alpha and Adrenomedullin Levels in the Control, Sham, and Ischemia Groups 0.hour 1.hour 3.hour 6.hour P 1 P 2 P 3 HIF1-alpha (pg/ml) Mean ± SD Control (n = 7) 105 ± 10 107 ± 9 108 ± 12 107 ± 10 0,175 0,203 0,105 Sham (n = 7) 104 ± 5 107 ± 3 107 ± 2 105 ± 4 0,173 0,128 0,257 Ischemia (n = 7) 101 ± 7 110 ± 4 136 ± 18 153 ± 12 0,090 0,018 0,018 Adrenomedullin (fmol/ml) Mean ± SD Control (n = 7) 9,6 ± 04 9,7 ± 0,6 9,6 ± 0,2 9,8 ± 0,4 0,497 0,932 0,059 Sham (n = 7) 9,6 ± 0,6 10,0 ± 0,4 9,9 ± 0,1 10,1 ± 0,2 0,248 0,465 0,207 Ischemia (n = 7) 9,7 ± 0,5 11,2 ± 0,5 12,7 ± 1,3 14,9 ± 1,4 0,018 0,018 0,018 *p 1 ; 0.hour-1.hour, p 2 ; 0.hour − 3.hour, p 3 ; 0.hour − 6.hour All analyses were performed using the Wilcoxon signed-rank test. HIF1-alpha levels were analyzed between the groups. While no statistically significant difference was observed between the 0th hour and 1st hour HIF1-alpha levels among the control, sham, and ischemia groups, a statistically significant difference was observed between the 3rd hour (p = 0.001) and 6th hour (p < 0.001) HIF1-alpha levels between the groups (Fig. 2 , Table 2 ). Table 2 Inter-group Analysis of HIF1-alpha Levels Control (n = 7) Sham (n = 7) Ischemia (n = 7) p value HIF1-alpha Mean ± SD Mean ± SD Mean ± SD Mean ± SD 0.hour 105 ± 10 104 ± 5 101 ± 7 0,694 1.hour 107 ± 9 107 ± 3 110 ± 4 0,633 3.hour 108 ± 12 107 ± 2 136 ± 18 0,001 6.hour 107 ± 10 105 ± 4 153 ± 12 < 0,001 Δ1HIF1- alpha * 3 (-2-7) 4 (-4-10) 11 (-8-24) 0,258 Δ2HIF1- alpha * 2 (-3-8) 3 (-4-10) 43 (2–56) 0,010 Δ3HIF1- alpha * 1 (-2-5) 0 (-1-6) 58 (24–75) 0,001 HIF1-alpha : Hypoxia-inducible factor 1 alpha; Δ1HIF1-alpha : Change in HIF1-alpha level between 1st hour and baseline (0 hour); Δ2HIF1-alpha : Change between 3rd hour and baseline; Δ3HIF1-alpha : Change between 6th hour and baseline. *Values are presented as median (min–max). Kruskal–Wallis test was used for non-parametric analyses; ANOVA was used for parametric comparisons. A statistically significant difference was observed between the groups regarding ΔHIF1-alpha level (p = 0.001). In pairwise analyses, it was observed that the change in HIF1-alpha level in the ischemia group was statistically higher than the sham group (p = 0.002) and the control group (p = 0.002). Statistically significant differences were observed between the groups regarding Δ2HIF1-alpha (p = 0.010) and Δ3HIF1-alpha (p = 0.001) levels. (Table 2 ). Adrenomedullin levels were analyzed within the group. No statistically significant change was observed in adrenomedullin levels at any time in the control and sham groups. 6th-hour adrenomedullin levels were at similar levels as the 0th-hour adrenomedullin levels. In the ischemia group, 1st-hour adrenomedullin levels were statistically significantly higher than 0th-hour levels (p = 0.007), 3rd-hour levels were statistically significantly higher than 0th-hour levels (p = 0.018), and 6th-hour levels were statistically significantly higher than 0th-hour levels (p = 0.018). In the ischemia group, adrenomedullin levels increased regularly until the 6th hour (Fig. 3 , Table 1 ). Adrenomedullin levels were analyzed between the groups. While no statistically significant difference was observed between the 0th-hour adrenomedullin levels among the control, sham, and ischemia groups, a statistically significant difference was observed between the 1st-hour (p < 0.001), 3rd-hour (p < 0.001) and 6th-hour (p < 0.001) adrenomedullin levels among the groups (Fig. 4 , Table 3 ). Table 3 Inter-group Analysis of Adrenomedullin Levels Control (n = 7) Sham (n = 7) Ischemia (n = 7) p value Adrenomedullin Mean ± SD Mean ± SD Mean ± SD Mean ± SD 0.hour 9,6 ± 04 9,6 ± 0,6 9,7 ± 0,5 0,952 1.hour 9,7 ± 0,6 10,0 ± 0,4 11,2 ± 0,5 < 0,001 3.hour 9,6 ± 0,2 9,9 ± 0,1 12,7 ± 1,3 < 0,001 6.hour 9,8 ± 0,4 10,1 ± 0,2 14,9 ± 1,4 < 0,001 Δ1 Adrenomedullin * 0,1 (-0,7 − 0,7) 0,3 (-0,4 − 1,9) 1,5 (0,3–3,2) 0,034 Δ2 Adrenomedullin * -0,3 (-0,5 − 0,6) 0 (-0,4 − 1,6) 3,8 (0,8 − 4,6) 0,002 Δ3 Adrenomedullin * 0,1 (0–0,6) 0,1 (0–2,3) 4,6 (2,8 − 7,3) 0,001 Δ1Adrenomedullin : Change in adrenomedullin level between 1st hour and baseline (0 hour); Δ2Adrenomedullin : Change between 3rd hour and baseline; Δ3Adrenomedullin : Change between 6th hour and baseline. *Values are presented as median (min–max). Kruskal–Wallis test was used for non-parametric comparisons; ANOVA was applied for parametric analyses. Statistically significant differences were observed between the groups in terms of Δ1Adrenomedullin (p = 0.034), Δ2Adrenomedullin (p = 0.002), and Δ3Adrenomedullin (p = 0.001) levels. In pairwise analyses, it was observed that the change in adrenomedullin level between 1st hour and 0th hour in the ischemia group was statistically higher than the control group (p = 0.015). It was observed that the change in adrenomedullin level between the 3rd hour and the 0th hour in the ischemia group was statistically higher than the control group (p = 0.002) and sham group (p = 0.004). There was no statistically significant difference between the other groups. Finally, the change in adrenomedullin level between the 6th hour and 0th hour in the ischemia group was higher than in the sham group (p = 0.002) and the control group (p = 0.002) (Table 3 ). 4. DISCUSSION Based on intestinal hypoxia and vasodilation are important in the pathogenesis of acute mesenteric ischemia, our study has shown that hypoxia-sensitive HIF-1 alpha and vasodilation-sensitive adrenomedullin levels in rabbits with mesenteric ischemia were increased in the early period compared to the control and sham groups. Previously, markers such as lactate, heparin-binding protein, ischemia-modified albumin, d-dimer, intestinal fatty acid binding protein, and alpha-glutathione have been evaluated. However, studies are ongoing to improve diagnostic sensitivity [ 8 – 11 ]. Therefore, our study evaluated the diagnostic importance of HIF-1 alpha, an early hypoxia indicator, and adrenomedullin, which is associated with vasodilation, in an acute mesenteric ischemia model. Compared to the control and sham groups, HIF-1 alpha levels in the ischemia group began to rise after the 1st hour and continued to until the 6th hour, indicating that HIF-1 alpha could be used in the early diagnosis of acute mesenteric ischemia. The relationship between HIF-1 alpha and intestinal ischemia has been evaluated in limited animal studies [ 12 ] and clinical studies [ 13 , 14 ]. In all of these studies, similar to our findings, it was stated that HIF-1 alpha levels increased in the presence of intestinal ischemia. In the study by Kanan et al. [ 12 ], intestinal ischemia/reperfusion injury was induced by creating 3 hours of reperfusion following 45 minutes of isolated superior mesenteric artery occlusion. Afterward, HIF-1 alpha levels were evaluated. In the sham group, the abdomen was opened but closed without performing occlusion. As a result of the study, it was observed that HIF-1 alpha levels were higher in the ischemia group compared to the sham group. Histopathological examination also showed that HIF-1 alpha levels were associated with intestinal barrier disruption. In the study conducted by Kurt et al. [ 14 ] in 2022, HIF-1 alpha levels were evaluated in acute mesenteric ischemia, abdominal pain, and healthy control groups that applied to the emergency department. It was reported that HIF-1 alpha levels were higher in acute mesenteric ischemia patients than in abdominal pain and control groups, and it was stated that HIF-1 alpha could be used in the early diagnosis of acute mesenteric ischemia. Unlike acute mesenteric ischemia, HIF-1 alpha levels have been evaluated in various inflammatory intestinal diseases characterized by hypoxia, and similar results have been reported. HIF-1 alpha plays an important role in the pathogenesis of inflammatory bowel diseases. Both in clinical studies and in animal models, HIF-1 alpha has been shown to be important in inflammatory bowel diseases [ 15 , 16 ]. In the study by Harki et al. [ 13 ], 61 patients with helicobacter pylori gastritis, ischemic colitis, infectious colitis, and inflammatory bowel disease (chronic gastrointestinal ischemia group) were compared with a control group of 22 people. Unlike our study, HIF-1 alpha levels were evaluated immunohistochemically. In the study, it was observed that there were more patients with positive HIF-1 alpha staining in the chronic gastrointestinal ischemia group compared to the control group. In our study, the acute mesenteric ischemia model was evaluated. In light of these findings, HIF-1 alpha may increase not only in acute mesenteric ischemia but also in other gastrointestinal problems characterized by inflammation and ischemia. In diagnosing acute mesenteric ischemia, instead of using HIF-1 alpha alone, combining it with the patient's medical history, physical examination, and imaging findings may yield more reliable results. In our study, HIF-1 alpha levels significantly differed in the ischemia group from the other groups starting from the 3rd hour. Our findings showed that HIF-1 alpha is not helpful in the very early period. However, there is a delay between the onset of symptoms and admission to the hospital in most patients with acute mesenteric ischemia [ 17 ]. Therefore, patients will generally have elevated HIF-1 alpha levels at admission. However, clinical studies need to demonstrate the temporal relationship and diagnostic significance of HIF-1 alpha levels in patients with acute mesenteric ischemia. It is known that HIF-1 alpha is sensitive to ischemia and responds rapidly in the event of ischemia. The intestinal epithelial cell barrier allows the transport of necessary nutrients and fluids while preventing the entry of harmful luminal agents. In acute mesenteric ischemia, decreased tissue oxygen levels eliminate the epithelial barrier and create a hypoxic environment. Functional, vascular, and metabolic adaptations to hypoxia cause HIF-1 alpha activation. HIF-1 alpha activation triggers alternative energy production and oxygen absorption pathways necessary for cell metabolism and survival. Therefore, the HIF-1 alpha response that occurs during hypoxia is a defense mechanism [ 18 , 19 ]. Similar to HIF-1 alpha levels, in our study, adrenomedullin levels increased in the ischemia group, and this increase was higher than in the control and sham groups. Adrenomedullin levels were higher in the ischemia group from the 1st hour onwards than in the other groups. Studies on adrenomedullin focus on the results of adrenomedullin applied for therapeutic purposes after intestinal ischemia and reperfusion injury [ 20 – 22 ]. In our study, the potential of adrenomedullin for early diagnosis rather than therapeutic purposes was evaluated in an acute mesenteric ischemia model created by complete occlusion of the superior mesenteric artery. In the study by Zhang et al. [ 20 ], intestinal ischemia and reperfusion injury were created in rats, and then adrenomedullin and adrenomedullin binding protein were infused at different dosages. When evaluated 4 hours after the treatment, it was observed that proinflammatory cytokine levels were lower in the treated rats. In a similar study by Higuchi et al. [ 21 ], an intestinal ischemia/reperfusion model was created in rats, and it was shown that intestinal mucosal hyperpermeability decreased after adrenomedullin and adrenomedullin binding protein infusion was given for treatment. It was stated that adrenomedullin and adrenomedullin binding protein could be used in the treatment since they are important components of intestinal ischemia. Unlike these studies, our study showed that adrenomedullin levels increased in the acute mesenteric ischemia model and that it could be used for early diagnosis of acute mesenteric ischemia rather than for therapeutic purposes. The most important physiological properties of adrenomedullin, which can be produced by many cells such as the adrenal medulla, endothelial cells, smooth muscle cells, and myocardial cells, are vasodilation and natriuresis. It supports endothelial barrier functions in the gastrointestinal system and contributes to the mucosal defense line [ 23 ]. The decrease in splanchnic blood flow is tolerated to a certain extent by adaptation mechanisms. When blood flow decreases, the decreased blood flow is tolerated by collateral circulation and vasodilation of the vessels. However, when adaptive mechanisms are insufficient, irreversible ischemia and necrosis occur with vasoconstriction[ 24 ]. Increased adrenomedullin levels in mesenteric ischemia indicate that it plays a role in the pathophysiology of acute mesenteric ischemia and may have therapeutic importance. Survival in acute mesenteric ischemia is closely related to early diagnosis and early treatment. In particular, delayed treatment increases mortality. The biggest obstacle to treatment is delayed diagnosis [ 25 , 26 ]. In patients presenting to the emergency department with acute mesenteric ischemia, especially in the presence of risk factors such as advanced age, atherosclerosis, cardiovascular disease, or the use of vasoconstrictor medications, the addition of HIF-1 alpha and adrenomedullin levels to the diagnostic process may enable early diagnosis and, consequently, early treatment, thereby improving patient prognosis. Our study had certain limitations. The results of our study using an acute mesenteric ischemia model in rabbits should be confirmed by clinical studies. In addition, HIF-1 alpha and adrenomedullin levels may be affected by other pathologies, such as inflammatory bowel diseases that cause hypoxia. The fact that HIF-1 alpha and adrenomedullin levels are not specific to acute mesenteric ischemia may affect the diagnostic process. The diagnostic performance of HIF-1 alpha and adrenomedullin can be evaluated through studies comparing acute mesenteric ischemia and the diseases included in its differential diagnosis. CONCLUSION AND RECOMMENDATIONS HIF-1 alpha and adrenomedullin increased in the early period compared to the control and sham groups. It was considered that adrenomedullin and HIF-1 alpha could be used in the early diagnosis of acute mesenteric ischemia. The mortality of acute mesenteric ischemia can be reduced through early diagnosis. Integrating HIF-1 alpha and adrenomedullin levels with patients' medical history, physical examination, and laboratory findings may facilitate early diagnosis. By validating our findings through clinical studies, the diagnostic performance of HIF-1 alpha and adrenomedullin, their impact on early diagnosis, and their association with survival can be evaluated in patients presenting to the emergency department. Declarations Ethics Committee Approve: The study was approved by the Necmettin Erbakan University Animal Experiments Local Ethics Committee (Approval No: 2023-057). Funding: This study was supported by the Necmettin Erbakan University Scientific Research Projects Board (Project No: 24TU18010). All expenses related to the hypoxia-inducible factor 1-alpha and adrenomedullin ELISA kits, along with the purchase and care of 21 New Zealand rabbits, were supported by the project budget. Conflict of Interest: The authors declare no conflict of interest Availability of data and materials: The datasets generated and/or analysed during the current study are not publicly available due [The datasets generated and/or analyzed during the current study are not publicly available due to ethical restrictions but are available from the corresponding author on reasonable request.] but are available from the corresponding author on reasonable request. Ethical Compliance: All experimental procedures were performed in accordance with the Directive of the Local Ethics Committee for Animal Experiments, in line with Articles 9 and 17 of the Turkish Animal Protection Law (Law No. 5199) and the European Union Directive 2010/63/EU, and were reported in compliance with the ARRIVE guidelines. Author Contributions: Enes Bayındır contributed to the conception and design of the study, data collection, analysis and interpretation, manuscript drafting, and supervision. Kadir Küçükçeran contributed to the conception and design, data collection, analysis and interpretation, critical revision, and supervision. Muhammet Raşit Özer, Mustafa Kürşat Ayrancı, İbrahim Kılınç, Naile Kökbudak, and Gamze Kaygısız Bayındır contributed to data collection, analysis and interpretation, and critical revision of the manuscript. All authors read and approved the final version of the manuscript. References Oehler H, Eichler K, Derwich W, Schnitzbauer AA, Schreckenbach T. [Epidemiology and diagnostics of mesenteric ischemia]. Chirurgie (Heidelb). 2024;95(5):347-52. Stewart B, Khanduri P, McCord C, Ohene-Yeboah M, Uranues S, Vega Rivera F, et al. Global disease burden of conditions requiring emergency surgery. Br J Surg. 2014;101(1):e9-22. Pezzuto A, Carico E. Role of HIF-1 in Cancer Progression: Novel Insights. A Review. Curr Mol Med. 2018;18(6):343-51. Malekan M, Ebrahimzadeh MA, Sheida F. The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma. Biomed Pharmacother. 2021;141:111873. Schönauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - new perspectives of a potent peptide hormone. J Pept Sci. 2017;23(7-8):472-85. Fuglseth H, Søreide K, Vetrhus M. Acute mesenteric ischaemia. Br J Surg. 2023;110(9):1030-4. Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg. 1970;101(4):478-83. Zafirovski A, Zafirovska M, Kuhelj D, Pintar T. The Impact of Biomarkers on the Early Detection of Acute Mesenteric Ischemia. Biomedicines. 2023;12(1). Kocak S, Acar T, Ertekin B, Güven M, Dundar ZD. The role of heparin-binding protein in the diagnosis of acute mesenteric ischemia. Ulus Travma Acil Cerrahi Derg. 2019;25(3):205-12. Dundar ZD, Cander B, Gul M, Karabulut KU, Kocak S, Girisgin S, et al. Serum intestinal fatty acid binding protein and phosphate levels in the diagnosis of acute intestinal ischemia: an experimental study in rabbits. J Emerg Med. 2012;42(6):741-7. Dundar ZD, Cander B, Gul M, Karabulut KU, Girisgin S. Serum ischemia-modified albumin levels in an experimental acute mesenteric ischemia model. Acad Emerg Med. 2010;17(11):1233-8. Kannan KB, Colorado I, Reino D, Palange D, Lu Q, Qin X, et al. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2011;300(5):G853-61. Harki J, Sana A, van Noord D, van Diest PJ, van der Groep P, Kuipers EJ, et al. Hypoxia-inducible factor 1-α in chronic gastrointestinal ischemia. Virchows Arch. 2015;466(2):125-32. Kurt E, Tekin E, Kurt N, Bayramoglu A. The role of adropin, HIF-1α and apelin biomarkers in the diagnosis of acute mesentaric ischemia. Am J Emerg Med. 2022;51:223-7. Bäcker V, Cheung FY, Siveke JT, Fandrey J, Winning S. Knockdown of myeloid cell hypoxia-inducible factor-1α ameliorates the acute pathology in DSS-induced colitis. PLoS One. 2017;12(12):e0190074. Dvornikova KA, Platonova ON, Bystrova EY. Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int J Mol Sci. 2023;24(3). Yıldırım D, Hut A, Tatar C, Dönmez T, Akıncı M, Toptaş M. Prognostic factors in patients with acute mesenteric ischemia. Turk J Surg. 2017;33(2):104-9. Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, et al. Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol. 2003;56(3):209-13. Manresa MC, Taylor CT. Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function. Cell Mol Gastroenterol Hepatol. 2017;3(3):303-15. Zhang F, Wu R, Zhou M, Blau SA, Wang P. Human adrenomedullin combined with human adrenomedullin binding protein-1 is protective in gut ischemia and reperfusion injury in the rat. Regul Pept. 2009;152(1-3):82-7. Higuchi S, Wu R, Zhou M, Marini CP, Ravikumar TS, Wang P. Gut hyperpermiability after ischemia and reperfusion: attenuation with adrenomedullin and its binding protein treatment. Int J Clin Exp Pathol. 2008;1(5):409-18. Dwivedi AJ, Wu R, Nguyen E, Higuchi S, Wang H, Krishnasastry K, et al. Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion. J Am Coll Surg. 2007;205(2):284-93. Martínez-Herrero S, Martínez A. Adrenomedullin regulates intestinal physiology and pathophysiology. Domest Anim Endocrinol. 2016;56 Suppl:S66-83. Tendler DA LJ. Overview of intestinal ischemia in adults. UpToDate. Otto CC, Czigany Z, Heise D, Bruners P, Kotelis D, Lang SA, et al. Prognostic Factors for Mortality in Acute Mesenteric Ischemia. J Clin Med. 2022;11(13). Sumbal R, Ali Baig MM, Sumbal A. Predictors of Mortality in Acute Mesenteric Ischemia: A Systematic Review and Meta-Analysis. J Surg Res. 2022;275:72-86. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7397493\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":511832529,\"identity\":\"03b7e83d-4d12-4343-8977-2cf74bef00b5\",\"order_by\":0,\"name\":\"Enes BAYINDIR\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIiWNgGAWjYJACZiDmYWBIbGD4UGEDZDM2HiBaC+OMM2kgLQ1EaQGCBAZmzrbDYCZeLfzSzYc/F9QcljFnT277zMB23m5t+2GgLTU20bi0SM45liY949hhHsueh82zC3huJ287kwjUciwttwGHFoMbOWbMPGyHeQxuJDYzz5C4nWx2AKiFseEwTi32N/I/f+b5B9XCY3Au2ez8Q/xaDCRyGKR522BaEg7Ymd0gYIvEjTQz6Zl96TwGZx42M844kJxgdgNoSwIev/DPSH78ueCbtb3B8fTHDB//2dmbnU9/+OBDjQ1OLVDQDGclglUm4FcOAnVwlj1hxaNgFIyCUTDSAAAzTWZ99oWLEQAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Konya Numune Hospital\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Enes\",\"middleName\":\"\",\"lastName\":\"BAYINDIR\",\"suffix\":\"\"},{\"id\":511832530,\"identity\":\"f31bff6c-44a3-412d-9b02-9165227f384b\",\"order_by\":1,\"name\":\"Kadir KÜÇÜKCERAN\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Necmettin Erbakan University Medical Faculty Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kadir\",\"middleName\":\"\",\"lastName\":\"KÜÇÜKCERAN\",\"suffix\":\"\"},{\"id\":511832531,\"identity\":\"d0ee4210-3156-4c06-a8d9-200a0a30cdcb\",\"order_by\":2,\"name\":\"Muhammet Raşit ÖZER\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Necmettin Erbakan University Medical Faculty Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Muhammet\",\"middleName\":\"Raşit\",\"lastName\":\"ÖZER\",\"suffix\":\"\"},{\"id\":511832532,\"identity\":\"7f7a8200-bcb7-46fb-979d-cd9670b4c6bb\",\"order_by\":3,\"name\":\"Mustafa Kürşat AYRANCI\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Necmettin Erbakan University Medical Faculty Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mustafa\",\"middleName\":\"Kürşat\",\"lastName\":\"AYRANCI\",\"suffix\":\"\"},{\"id\":511832533,\"identity\":\"1f407797-6ef1-4987-a79d-19b4c7a29fec\",\"order_by\":4,\"name\":\"İbrahim KILINÇ\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Necmettin Erbakan University Medical Faculty Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"İbrahim\",\"middleName\":\"\",\"lastName\":\"KILINÇ\",\"suffix\":\"\"},{\"id\":511832534,\"identity\":\"76410cb2-39db-41d6-8e1c-cdd05f120bad\",\"order_by\":5,\"name\":\"Naile KÖKBUDAK\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Necmettin Erbakan University Medical Faculty Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Naile\",\"middleName\":\"\",\"lastName\":\"KÖKBUDAK\",\"suffix\":\"\"},{\"id\":511832535,\"identity\":\"61985627-bd35-4b62-b290-9522bb81995e\",\"order_by\":6,\"name\":\"Gamze KAYGISIZ BAYINDIR\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Selcuk University Medical Faculty Hospital\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Gamze\",\"middleName\":\"KAYGISIZ\",\"lastName\":\"BAYINDIR\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-08-18 08:38:25\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-7397493/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-7397493/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":90909652,\"identity\":\"06a945e0-b5d0-4c46-b5b6-1621d457c4ec\",\"added_by\":\"auto\",\"created_at\":\"2025-09-09 13:31:36\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":94827,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eIntra-group Changes in HIF-1 Alpha Levels\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7397493/v1/9e35e2ad5e87074f79719895.png\"},{\"id\":90909650,\"identity\":\"f89a50f2-4914-40a9-8284-9fe662217d5f\",\"added_by\":\"auto\",\"created_at\":\"2025-09-09 13:31:35\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":75727,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eComparison of HIF-1 Alpha Levels Between Groups\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7397493/v1/c7544bde0f07efa3fd9bc194.png\"},{\"id\":90911134,\"identity\":\"21edfde2-8087-438d-a9cb-b257439c53fb\",\"added_by\":\"auto\",\"created_at\":\"2025-09-09 13:39:36\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":100758,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eIntra-group Changes in Adrenomedullin Levels\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7397493/v1/e504dbd605bb5958275058a2.png\"},{\"id\":90909655,\"identity\":\"f73e9a06-61e5-4b10-9b61-c287d1d23a7d\",\"added_by\":\"auto\",\"created_at\":\"2025-09-09 13:31:36\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":80816,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eComparison of Adrenomedullin Levels Between Groups\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7397493/v1/60bc5ba6dc2684d51c29e26d.png\"},{\"id\":95529593,\"identity\":\"558f19db-4d93-4aad-9f78-423e41a72052\",\"added_by\":\"auto\",\"created_at\":\"2025-11-10 10:17:16\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1057452,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7397493/v1/2aba5f4c-4147-4d90-970a-1c65738d545b.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Diagnostic Value of Hypoxia-Inducible Factor 1 Alpha and Adrenomedullin in Acute Mesenteric Ischemia\",\"fulltext\":[{\"header\":\"1. INTRODUCTION\",\"content\":\"\\u003cp\\u003eAlthough acute mesenteric ischemia is relatively rare, it is a disease with high mortality that may require emergency surgery. Although its incidence is reported as 0.63\\u0026ndash;12.9/100,000, it is among the most common causes of death among surgical diseases worldwide[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Early diagnosis and treatment are the main factors determining the prognosis of acute mesenteric ischemia. Objective findings are needed for correct diagnosis and differential diagnosis in the emergency department [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/p\\u003e\\u003cp\\u003eHypoxia Inducible Factor-1 (HIF-1) alpha is a major regulator of tissue hypoxia resulting from low oxygen levels. Although HIF1-alpha has been studied in many diseases associated with hypoxic pathophysiology, there are not enough studies on its diagnostic importance in acute mesenteric ischemia, where intestinal hypoxia is the primary mechanism [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eAdrenomedullin, a member of the calcitonin gene-related peptide family (CGRP), has vasodilator potential [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. In acute mesenteric ischemia, vasodilation mechanisms are activated to relieve hypoxia in the intestines and ensure adequate perfusion [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eIn our study, we aimed to examine the levels of adrenomedullin and HIF1-alpha, which we think may help in the early diagnosis of acute mesenteric ischemia in the emergency department, in an animal model in which we created experimental acute mesenteric ischemia.\\u003c/p\\u003e\"},{\"header\":\"2. MATERIALS AND METHODS\",\"content\":\"\\u003cp\\u003e Our study was approved by the Local Ethics Committee for Animal Experiments of Necmettin Erbakan University Hospital and conducted in accordance with the ARRIVE guidelines for animal experiments. The number of animals required for our study was calculated using G.Power. Twenty-one male New Zealand rabbits, 14\\u0026ndash;18 weeks old and weighing 2.5-3.0 kg, were used in the experiment. The New Zealand rabbits were obtained from the Experimental Medicine Application and Research Center (KON\\u0026Uuml;DAM) of Necmettin Erbakan University.\\u003c/p\\u003e\\u003cp\\u003eAll animals were given 50 mg/kg of Ketamine and 15 mg/kg of Xylazine intramuscularly in their hind legs. After anesthesia, a 26 G intravenous catheter was used to obtain blood and administer fluids to the rabbits' dorsal ear veins.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eControl Group\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eNo other procedure was performed on the control group except for establishing vascular access. Samples were taken to evaluate HIF1-alpha and adrenomedullin levels at 0, 1, 3, and 6 hours. A gel and clot activator (Vacusera \\u0026reg;) tube (2 ml) was used to collect the samples.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eSham Group\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eAfter the 0th-hour sample was taken, 2 ml of 0.9% NaCl was administered intravenously for irrigation. Following blood collection, the subjects' abdominal area was shaved and cleaned with 10% povidone-iodine. A laparotomy was performed with a standard midline incision. After the peritoneum was passed, the abdominal wall and peritoneum were resutured with 2/0 silk. 2 ml samples were retaken at 1, 3, and 6 hours after the operation. Following each blood collection, 2 ml of 0.9% NaCl was administered intravenously for irrigation. No tissue samples were taken from this group.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eIschemia group\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eAfter the zero-hour sample was taken, 2 ml of 0.9% NaCl was administered intravenously for irrigation. After blood was drawn, the abdominal area was shaved and cleaned with 10% povidone-iodine. A laparotomy was performed with a midline incision. After the small intestine and cecum were identified, the superior mesenteric artery was isolated and carefully ligated. After ligation, acute mesenteric ischemia was confirmed by the pallor of the intestines. Afterward, the abdominal contents were placed again, and the peritoneum and abdominal wall were closed by suturing with 2/0 silk. 2 ml samples were retaken at 1, 3, and 6 hours after the operation. Following each blood draw, 2 ml of 0.9% NaCl was administered intravenously for irrigation. After 6 hours of ischemia, the rabbits were sacrificed with high-dose Ketamine. After sacrificing the subjects, a 10 cm ileal loop was excised for histopathological examination, and samples were taken.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eSTORAGE OF THE SAMPLES\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eEach 2 ml blood sample taken into the Gel \\u0026amp; Clot Activator (Vacusera \\u0026reg;) tube was centrifuged for 10 minutes at 4500 rpm at a temperature setting of +\\u0026thinsp;4\\u0026ndash;8 degrees Celsius after waiting for a maximum of 30 minutes. The samples were stored at -20\\u0026deg;C until biochemical evaluation. The 10 cm ileal loop samples taken for histopathological examination were stored in 10% formaldehyde solution after being washed with sterile saline solution.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eBIOCHEMICAL EVALUATION\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eHIF-1 alpha and adrenomedullin levels were studied by Enzyme-linked immunosorbent assay (ELISA) kits. This ELISA kit uses the quantitative ELISA technique.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eHISTOPATHOLOGICAL EVALUATION\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eFor histopathological examination, 10 cm long ileal loop materials were excised and fixed in 10% formaldehyde solution for 24 hours, and then 0.5 cm long samples were taken. Standard Hematoxylin/Eosin staining was applied to the sections. The sections were examined by a single pathologist. The degree of morphological damage in tissues due to ischemia was classified according to the Chiu score [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eChiu Scoring\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eStage 0: Normal-appearing mucosal villi\\u003c/p\\u003e\\u003cp\\u003eStage 1: Low-level hydropic degeneration of the surface epithelium\\u003c/p\\u003e\\u003cp\\u003eStage 2: Low-level necrosis at the superficial villus epithelium apex\\u003c/p\\u003e\\u003cp\\u003eStage 3: Severe epithelial shedding of the villi, exposure of the villus tips\\u003c/p\\u003e\\u003cp\\u003eStage 4: Severe degeneration of the villi, mucosal necrosis in all layers\\u003c/p\\u003e\\u003cp\\u003eStage 5: Transmural necrosis\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eSTATISTICAL ANALYSIS\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003eStatistical analyses were performed using the SPSS version 22.0 package program. Normally distributed continuous variables were compared within the group using the \\\"Dependent groups t-test,\\\" and non-normally distributed continuous variables were compared within the group using the \\\"Wilcoxon signed rank test.\\\" One Way ANOVA and Kruskal Wallis test were used to compare HIF1-alpha and adrenomedullin levels between groups. In the statistical analyses of the study, comparisons with a p-value below 0.05 were considered statistically significant.\\u003c/p\\u003e\"},{\"header\":\"3. RESULTS\",\"content\":\"\\u003cp\\u003eHistological examination in the ischemia group showed that stage 4 ischemia occurred in 2 subjects, and stage 5 ischemia occurred in 5 subjects. In the intragroup analysis of the change in HIF1-alpha levels, no statistically significant difference was observed in HIF1-alpha levels in the control and sham groups during the study period. No statistically significant difference was observed between the 0-1st hour in the ischemia group. In contrast, the 3rd hour HIF1-alpha level was higher than the 0th hour (p\\u0026thinsp;=\\u0026thinsp;0.018), and the 6th hour HIF1-alpha level was higher than the 0th hour (p\\u0026thinsp;=\\u0026thinsp;0.018) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e, Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eIntra-group Analysis of HIF1-alpha and Adrenomedullin Levels in the Control, Sham, and Ischemia Groups\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"9\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0.hour\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e1.hour\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e3.hour\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e6.hour\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003eP\\u003csup\\u003e1\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eP\\u003csup\\u003e2\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003eP\\u003csup\\u003e3\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eHIF1-alpha (pg/ml)\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eControl (n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e105\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;9\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e108\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0,175\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0,203\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0,105\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSham (n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e104\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e105\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0,173\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0,128\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0,257\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eIschemia (n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e101\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e110\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e136\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;18\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e153\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0,090\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,018\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,018\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003eAdrenomedullin (fmol/ml)\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eControl (n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e9,6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;04\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e9,7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e9,6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e9,8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0,497\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0,932\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0,059\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eSham (n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e9,6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e10,0\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e9,9\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e10,1\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0,248\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0,465\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0,207\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eIschemia (n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e9,7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e11,2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e12,7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1,3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e14,9\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1,4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,018\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,018\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,018\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"9\\\"\\u003e*p\\u003csup\\u003e1\\u003c/sup\\u003e; 0.hour-1.hour, p\\u003csup\\u003e2\\u003c/sup\\u003e; 0.hour \\u0026minus;\\u0026thinsp;3.hour, p\\u003csup\\u003e3\\u003c/sup\\u003e; 0.hour \\u0026minus;\\u0026thinsp;6.hour\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"9\\\"\\u003eAll analyses were performed using the Wilcoxon signed-rank test.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eHIF1-alpha levels were analyzed between the groups. While no statistically significant difference was observed between the 0th hour and 1st hour HIF1-alpha levels among the control, sham, and ischemia groups, a statistically significant difference was observed between the 3rd hour (p\\u0026thinsp;=\\u0026thinsp;0.001) and 6th hour (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) HIF1-alpha levels between the groups (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e, Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eInter-group Analysis of HIF1-alpha Levels\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"5\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eControl\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSham\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIschemia\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep value\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eHIF1-alpha\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e0.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e105\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e104\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e101\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0,694\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;9\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e110\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0,633\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e3.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e108\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e136\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;18\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e6.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e107\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;10\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e105\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e153\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eΔ1HIF1- alpha *\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3 (-2-7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e4 (-4-10)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e11 (-8-24)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0,258\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eΔ2HIF1- alpha *\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e2 (-3-8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3 (-4-10)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e43 (2\\u0026ndash;56)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,010\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eΔ3HIF1- alpha *\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e1 (-2-5)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (-1-6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e58 (24\\u0026ndash;75)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e\\u003cb\\u003eHIF1-alpha\\u003c/b\\u003e: Hypoxia-inducible factor 1 alpha; \\u003cb\\u003eΔ1HIF1-alpha\\u003c/b\\u003e: Change in HIF1-alpha level between 1st hour and baseline (0 hour); \\u003cb\\u003eΔ2HIF1-alpha\\u003c/b\\u003e: Change between 3rd hour and baseline; \\u003cb\\u003eΔ3HIF1-alpha\\u003c/b\\u003e: Change between 6th hour and baseline.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e*Values are presented as median (min\\u0026ndash;max). Kruskal\\u0026ndash;Wallis test was used for non-parametric analyses; ANOVA was used for parametric comparisons.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eA statistically significant difference was observed between the groups regarding ΔHIF1-alpha level (p\\u0026thinsp;=\\u0026thinsp;0.001). In pairwise analyses, it was observed that the change in HIF1-alpha level in the ischemia group was statistically higher than the sham group (p\\u0026thinsp;=\\u0026thinsp;0.002) and the control group (p\\u0026thinsp;=\\u0026thinsp;0.002). Statistically significant differences were observed between the groups regarding Δ2HIF1-alpha (p\\u0026thinsp;=\\u0026thinsp;0.010) and Δ3HIF1-alpha (p\\u0026thinsp;=\\u0026thinsp;0.001) levels. (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eAdrenomedullin levels were analyzed within the group. No statistically significant change was observed in adrenomedullin levels at any time in the control and sham groups. 6th-hour adrenomedullin levels were at similar levels as the 0th-hour adrenomedullin levels. In the ischemia group, 1st-hour adrenomedullin levels were statistically significantly higher than 0th-hour levels (p\\u0026thinsp;=\\u0026thinsp;0.007), 3rd-hour levels were statistically significantly higher than 0th-hour levels (p\\u0026thinsp;=\\u0026thinsp;0.018), and 6th-hour levels were statistically significantly higher than 0th-hour levels (p\\u0026thinsp;=\\u0026thinsp;0.018). In the ischemia group, adrenomedullin levels increased regularly until the 6th hour (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e, Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003eAdrenomedullin levels were analyzed between the groups. While no statistically significant difference was observed between the 0th-hour adrenomedullin levels among the control, sham, and ischemia groups, a statistically significant difference was observed between the 1st-hour (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), 3rd-hour (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) and 6th-hour (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) adrenomedullin levels among the groups (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e, Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eInter-group Analysis of Adrenomedullin Levels\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"5\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eControl\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eSham\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eIschemia\\u003c/p\\u003e\\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;7)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep value\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAdrenomedullin\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003eMean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e0.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9,6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;04\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e9,6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e9,7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0,952\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e1.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9,7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,6\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10,0\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e11,2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,5\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e3.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9,6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e9,9\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e12,7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1,3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003e6.hour\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9,8\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e10,1\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0,2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e14,9\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1,4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eΔ1 Adrenomedullin *\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0,1 (-0,7\\u0026thinsp;\\u0026minus;\\u0026thinsp;0,7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0,3 (-0,4\\u0026thinsp;\\u0026minus;\\u0026thinsp;1,9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e1,5 (0,3\\u0026ndash;3,2)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,034\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eΔ2 Adrenomedullin *\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-0,3 (-0,5\\u0026thinsp;\\u0026minus;\\u0026thinsp;0,6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0 (-0,4\\u0026thinsp;\\u0026minus;\\u0026thinsp;1,6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e3,8 (0,8\\u0026thinsp;\\u0026minus;\\u0026thinsp;4,6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,002\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eΔ3 Adrenomedullin *\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0,1 (0\\u0026ndash;0,6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0,1 (0\\u0026ndash;2,3)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e4,6 (2,8\\u0026thinsp;\\u0026minus;\\u0026thinsp;7,3)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0,001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e\\u003cb\\u003eΔ1Adrenomedullin\\u003c/b\\u003e: Change in adrenomedullin level between 1st hour and baseline (0 hour); \\u003cb\\u003eΔ2Adrenomedullin\\u003c/b\\u003e: Change between 3rd hour and baseline; \\u003cb\\u003eΔ3Adrenomedullin\\u003c/b\\u003e: Change between 6th hour and baseline.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003e*Values are presented as median (min\\u0026ndash;max). Kruskal\\u0026ndash;Wallis test was used for non-parametric comparisons; ANOVA was applied for parametric analyses.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eStatistically significant differences were observed between the groups in terms of Δ1Adrenomedullin (p\\u0026thinsp;=\\u0026thinsp;0.034), Δ2Adrenomedullin (p\\u0026thinsp;=\\u0026thinsp;0.002), and Δ3Adrenomedullin (p\\u0026thinsp;=\\u0026thinsp;0.001) levels. In pairwise analyses, it was observed that the change in adrenomedullin level between 1st hour and 0th hour in the ischemia group was statistically higher than the control group (p\\u0026thinsp;=\\u0026thinsp;0.015). It was observed that the change in adrenomedullin level between the 3rd hour and the 0th hour in the ischemia group was statistically higher than the control group (p\\u0026thinsp;=\\u0026thinsp;0.002) and sham group (p\\u0026thinsp;=\\u0026thinsp;0.004). There was no statistically significant difference between the other groups. Finally, the change in adrenomedullin level between the 6th hour and 0th hour in the ischemia group was higher than in the sham group (p\\u0026thinsp;=\\u0026thinsp;0.002) and the control group (p\\u0026thinsp;=\\u0026thinsp;0.002) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e\"},{\"header\":\"4. DISCUSSION\",\"content\":\"\\u003cp\\u003eBased on intestinal hypoxia and vasodilation are important in the pathogenesis of acute mesenteric ischemia, our study has shown that hypoxia-sensitive HIF-1 alpha and vasodilation-sensitive adrenomedullin levels in rabbits with mesenteric ischemia were increased in the early period compared to the control and sham groups.\\u003c/p\\u003e\\u003cp\\u003ePreviously, markers such as lactate, heparin-binding protein, ischemia-modified albumin, d-dimer, intestinal fatty acid binding protein, and alpha-glutathione have been evaluated. However, studies are ongoing to improve diagnostic sensitivity [\\u003cspan additionalcitationids=\\\"CR9 CR10\\\" citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e–\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. Therefore, our study evaluated the diagnostic importance of HIF-1 alpha, an early hypoxia indicator, and adrenomedullin, which is associated with vasodilation, in an acute mesenteric ischemia model.\\u003c/p\\u003e\\u003cp\\u003eCompared to the control and sham groups, HIF-1 alpha levels in the ischemia group began to rise after the 1st hour and continued to until the 6th hour, indicating that HIF-1 alpha could be used in the early diagnosis of acute mesenteric ischemia. The relationship between HIF-1 alpha and intestinal ischemia has been evaluated in limited animal studies [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e] and clinical studies [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. In all of these studies, similar to our findings, it was stated that HIF-1 alpha levels increased in the presence of intestinal ischemia.\\u003c/p\\u003e\\u003cp\\u003eIn the study by Kanan et al. [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e], intestinal ischemia/reperfusion injury was induced by creating 3 hours of reperfusion following 45 minutes of isolated superior mesenteric artery occlusion. Afterward, HIF-1 alpha levels were evaluated. In the sham group, the abdomen was opened but closed without performing occlusion. As a result of the study, it was observed that HIF-1 alpha levels were higher in the ischemia group compared to the sham group. Histopathological examination also showed that HIF-1 alpha levels were associated with intestinal barrier disruption.\\u003c/p\\u003e\\u003cp\\u003eIn the study conducted by Kurt et al. [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e] in 2022, HIF-1 alpha levels were evaluated in acute mesenteric ischemia, abdominal pain, and healthy control groups that applied to the emergency department. It was reported that HIF-1 alpha levels were higher in acute mesenteric ischemia patients than in abdominal pain and control groups, and it was stated that HIF-1 alpha could be used in the early diagnosis of acute mesenteric ischemia.\\u003c/p\\u003e\\u003cp\\u003eUnlike acute mesenteric ischemia, HIF-1 alpha levels have been evaluated in various inflammatory intestinal diseases characterized by hypoxia, and similar results have been reported. HIF-1 alpha plays an important role in the pathogenesis of inflammatory bowel diseases. Both in clinical studies and in animal models, HIF-1 alpha has been shown to be important in inflammatory bowel diseases [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. In the study by Harki et al. [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e], 61 patients with helicobacter pylori gastritis, ischemic colitis, infectious colitis, and inflammatory bowel disease (chronic gastrointestinal ischemia group) were compared with a control group of 22 people. Unlike our study, HIF-1 alpha levels were evaluated immunohistochemically. In the study, it was observed that there were more patients with positive HIF-1 alpha staining in the chronic gastrointestinal ischemia group compared to the control group. In our study, the acute mesenteric ischemia model was evaluated. In light of these findings, HIF-1 alpha may increase not only in acute mesenteric ischemia but also in other gastrointestinal problems characterized by inflammation and ischemia. In diagnosing acute mesenteric ischemia, instead of using HIF-1 alpha alone, combining it with the patient's medical history, physical examination, and imaging findings may yield more reliable results.\\u003c/p\\u003e\\u003cp\\u003eIn our study, HIF-1 alpha levels significantly differed in the ischemia group from the other groups starting from the 3rd hour. Our findings showed that HIF-1 alpha is not helpful in the very early period. However, there is a delay between the onset of symptoms and admission to the hospital in most patients with acute mesenteric ischemia [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]. Therefore, patients will generally have elevated HIF-1 alpha levels at admission. However, clinical studies need to demonstrate the temporal relationship and diagnostic significance of HIF-1 alpha levels in patients with acute mesenteric ischemia.\\u003c/p\\u003e\\u003cp\\u003eIt is known that HIF-1 alpha is sensitive to ischemia and responds rapidly in the event of ischemia. The intestinal epithelial cell barrier allows the transport of necessary nutrients and fluids while preventing the entry of harmful luminal agents. In acute mesenteric ischemia, decreased tissue oxygen levels eliminate the epithelial barrier and create a hypoxic environment. Functional, vascular, and metabolic adaptations to hypoxia cause HIF-1 alpha activation. HIF-1 alpha activation triggers alternative energy production and oxygen absorption pathways necessary for cell metabolism and survival. Therefore, the HIF-1 alpha response that occurs during hypoxia is a defense mechanism [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e].\\u003c/p\\u003e\\u003cp\\u003eSimilar to HIF-1 alpha levels, in our study, adrenomedullin levels increased in the ischemia group, and this increase was higher than in the control and sham groups. Adrenomedullin levels were higher in the ischemia group from the 1st hour onwards than in the other groups. Studies on adrenomedullin focus on the results of adrenomedullin applied for therapeutic purposes after intestinal ischemia and reperfusion injury [\\u003cspan additionalcitationids=\\\"CR21\\\" citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e–\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. In our study, the potential of adrenomedullin for early diagnosis rather than therapeutic purposes was evaluated in an acute mesenteric ischemia model created by complete occlusion of the superior mesenteric artery.\\u003c/p\\u003e\\u003cp\\u003eIn the study by Zhang et al. [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e], intestinal ischemia and reperfusion injury were created in rats, and then adrenomedullin and adrenomedullin binding protein were infused at different dosages. When evaluated 4 hours after the treatment, it was observed that proinflammatory cytokine levels were lower in the treated rats. In a similar study by Higuchi et al. [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e], an intestinal ischemia/reperfusion model was created in rats, and it was shown that intestinal mucosal hyperpermeability decreased after adrenomedullin and adrenomedullin binding protein infusion was given for treatment. It was stated that adrenomedullin and adrenomedullin binding protein could be used in the treatment since they are important components of intestinal ischemia. Unlike these studies, our study showed that adrenomedullin levels increased in the acute mesenteric ischemia model and that it could be used for early diagnosis of acute mesenteric ischemia rather than for therapeutic purposes.\\u003c/p\\u003e\\u003cp\\u003eThe most important physiological properties of adrenomedullin, which can be produced by many cells such as the adrenal medulla, endothelial cells, smooth muscle cells, and myocardial cells, are vasodilation and natriuresis. It supports endothelial barrier functions in the gastrointestinal system and contributes to the mucosal defense line [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. The decrease in splanchnic blood flow is tolerated to a certain extent by adaptation mechanisms. When blood flow decreases, the decreased blood flow is tolerated by collateral circulation and vasodilation of the vessels. However, when adaptive mechanisms are insufficient, irreversible ischemia and necrosis occur with vasoconstriction[\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. Increased adrenomedullin levels in mesenteric ischemia indicate that it plays a role in the pathophysiology of acute mesenteric ischemia and may have therapeutic importance.\\u003c/p\\u003e\\u003cp\\u003eSurvival in acute mesenteric ischemia is closely related to early diagnosis and early treatment. In particular, delayed treatment increases mortality. The biggest obstacle to treatment is delayed diagnosis [\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. In patients presenting to the emergency department with acute mesenteric ischemia, especially in the presence of risk factors such as advanced age, atherosclerosis, cardiovascular disease, or the use of vasoconstrictor medications, the addition of HIF-1 alpha and adrenomedullin levels to the diagnostic process may enable early diagnosis and, consequently, early treatment, thereby improving patient prognosis.\\u003c/p\\u003e\\u003cp\\u003eOur study had certain limitations. The results of our study using an acute mesenteric ischemia model in rabbits should be confirmed by clinical studies. In addition, HIF-1 alpha and adrenomedullin levels may be affected by other pathologies, such as inflammatory bowel diseases that cause hypoxia. The fact that HIF-1 alpha and adrenomedullin levels are not specific to acute mesenteric ischemia may affect the diagnostic process. The diagnostic performance of HIF-1 alpha and adrenomedullin can be evaluated through studies comparing acute mesenteric ischemia and the diseases included in its differential diagnosis.\\u003c/p\\u003e\"},{\"header\":\"CONCLUSION AND RECOMMENDATIONS\",\"content\":\"\\u003cp\\u003eHIF-1 alpha and adrenomedullin increased in the early period compared to the control and sham groups. It was considered that adrenomedullin and HIF-1 alpha could be used in the early diagnosis of acute mesenteric ischemia.\\u003c/p\\u003e\\u003cp\\u003eThe mortality of acute mesenteric ischemia can be reduced through early diagnosis. Integrating HIF-1 alpha and adrenomedullin levels with patients' medical history, physical examination, and laboratory findings may facilitate early diagnosis. By validating our findings through clinical studies, the diagnostic performance of HIF-1 alpha and adrenomedullin, their impact on early diagnosis, and their association with survival can be evaluated in patients presenting to the emergency department.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics Committee Approve:\\u0026nbsp;\\u003c/strong\\u003eThe study was approved by the Necmettin Erbakan University Animal Experiments Local Ethics Committee (Approval No: 2023-057).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding:\\u0026nbsp;\\u003c/strong\\u003eThis study was supported by the Necmettin Erbakan University Scientific Research Projects Board (Project No: 24TU18010). All expenses related to the hypoxia-inducible factor 1-alpha and adrenomedullin ELISA kits, along with the purchase and care of 21 New Zealand rabbits, were supported by the project budget.\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of Interest:\\u0026nbsp;\\u003c/strong\\u003eThe authors declare no conflict of interest\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials:\\u0026nbsp;\\u003c/strong\\u003eThe datasets generated and/or analysed during the current study are not publicly available due [The datasets generated and/or analyzed during the current study are not publicly available due to ethical restrictions but are available from the corresponding author on reasonable request.] but are available from the corresponding author on reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthical Compliance:\\u0026nbsp;\\u003c/strong\\u003eAll experimental procedures were performed in accordance with the Directive of the Local Ethics Committee for Animal Experiments, in line with Articles 9 and 17 of the Turkish Animal Protection Law (Law No. 5199) and the European Union Directive 2010/63/EU, and were reported in compliance with the ARRIVE guidelines.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor Contributions:\\u003c/strong\\u003e Enes Bayındır contributed to the conception and design of the study, data collection, analysis and interpretation, manuscript drafting, and supervision. Kadir K\\u0026uuml;\\u0026ccedil;\\u0026uuml;k\\u0026ccedil;eran contributed to the conception and design, data collection, analysis and interpretation, critical revision, and supervision. Muhammet Raşit \\u0026Ouml;zer, Mustafa K\\u0026uuml;rşat Ayrancı, İbrahim Kılın\\u0026ccedil;, Naile K\\u0026ouml;kbudak, and Gamze Kaygısız Bayındır contributed to data collection, analysis and interpretation, and critical revision of the manuscript. All authors read and approved the final version of the manuscript.\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eOehler H, Eichler K, Derwich W, Schnitzbauer AA, Schreckenbach T. [Epidemiology and diagnostics of mesenteric ischemia]. Chirurgie (Heidelb). 2024;95(5):347-52.\\u003c/li\\u003e\\n\\u003cli\\u003eStewart B, Khanduri P, McCord C, Ohene-Yeboah M, Uranues S, Vega Rivera F, et al. Global disease burden of conditions requiring emergency surgery. Br J Surg. 2014;101(1):e9-22.\\u003c/li\\u003e\\n\\u003cli\\u003ePezzuto A, Carico E. Role of HIF-1 in Cancer Progression: Novel Insights. A Review. Curr Mol Med. 2018;18(6):343-51.\\u003c/li\\u003e\\n\\u003cli\\u003eMalekan M, Ebrahimzadeh MA, Sheida F. The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma. Biomed Pharmacother. 2021;141:111873.\\u003c/li\\u003e\\n\\u003cli\\u003eSch\\u0026ouml;nauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin - new perspectives of a potent peptide hormone. J Pept Sci. 2017;23(7-8):472-85.\\u003c/li\\u003e\\n\\u003cli\\u003eFuglseth H, S\\u0026oslash;reide K, Vetrhus M. Acute mesenteric ischaemia. Br J Surg. 2023;110(9):1030-4.\\u003c/li\\u003e\\n\\u003cli\\u003eChiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg. 1970;101(4):478-83.\\u003c/li\\u003e\\n\\u003cli\\u003eZafirovski A, Zafirovska M, Kuhelj D, Pintar T. The Impact of Biomarkers on the Early Detection of Acute Mesenteric Ischemia. Biomedicines. 2023;12(1).\\u003c/li\\u003e\\n\\u003cli\\u003eKocak S, Acar T, Ertekin B, G\\u0026uuml;ven M, Dundar ZD. The role of heparin-binding protein in the diagnosis of acute mesenteric ischemia. Ulus Travma Acil Cerrahi Derg. 2019;25(3):205-12.\\u003c/li\\u003e\\n\\u003cli\\u003eDundar ZD, Cander B, Gul M, Karabulut KU, Kocak S, Girisgin S, et al. Serum intestinal fatty acid binding protein and phosphate levels in the diagnosis of acute intestinal ischemia: an experimental study in rabbits. J Emerg Med. 2012;42(6):741-7.\\u003c/li\\u003e\\n\\u003cli\\u003eDundar ZD, Cander B, Gul M, Karabulut KU, Girisgin S. Serum ischemia-modified albumin levels in an experimental acute mesenteric ischemia model. Acad Emerg Med. 2010;17(11):1233-8.\\u003c/li\\u003e\\n\\u003cli\\u003eKannan KB, Colorado I, Reino D, Palange D, Lu Q, Qin X, et al. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2011;300(5):G853-61.\\u003c/li\\u003e\\n\\u003cli\\u003eHarki J, Sana A, van Noord D, van Diest PJ, van der Groep P, Kuipers EJ, et al. Hypoxia-inducible factor 1-\\u0026alpha; in chronic gastrointestinal ischemia. Virchows Arch. 2015;466(2):125-32.\\u003c/li\\u003e\\n\\u003cli\\u003eKurt E, Tekin E, Kurt N, Bayramoglu A. The role of adropin, HIF-1\\u0026alpha; and apelin biomarkers in the diagnosis of acute mesentaric ischemia. Am J Emerg Med. 2022;51:223-7.\\u003c/li\\u003e\\n\\u003cli\\u003eB\\u0026auml;cker V, Cheung FY, Siveke JT, Fandrey J, Winning S. Knockdown of myeloid cell hypoxia-inducible factor-1\\u0026alpha; ameliorates the acute pathology in DSS-induced colitis. PLoS One. 2017;12(12):e0190074.\\u003c/li\\u003e\\n\\u003cli\\u003eDvornikova KA, Platonova ON, Bystrova EY. Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int J Mol Sci. 2023;24(3).\\u003c/li\\u003e\\n\\u003cli\\u003eYıldırım D, Hut A, Tatar C, D\\u0026ouml;nmez T, Akıncı M, Toptaş M. Prognostic factors in patients with acute mesenteric ischemia. Turk J Surg. 2017;33(2):104-9.\\u003c/li\\u003e\\n\\u003cli\\u003eGiatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, et al. Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol. 2003;56(3):209-13.\\u003c/li\\u003e\\n\\u003cli\\u003eManresa MC, Taylor CT. Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function. Cell Mol Gastroenterol Hepatol. 2017;3(3):303-15.\\u003c/li\\u003e\\n\\u003cli\\u003eZhang F, Wu R, Zhou M, Blau SA, Wang P. Human adrenomedullin combined with human adrenomedullin binding protein-1 is protective in gut ischemia and reperfusion injury in the rat. Regul Pept. 2009;152(1-3):82-7.\\u003c/li\\u003e\\n\\u003cli\\u003eHiguchi S, Wu R, Zhou M, Marini CP, Ravikumar TS, Wang P. Gut hyperpermiability after ischemia and reperfusion: attenuation with adrenomedullin and its binding protein treatment. Int J Clin Exp Pathol. 2008;1(5):409-18.\\u003c/li\\u003e\\n\\u003cli\\u003eDwivedi AJ, Wu R, Nguyen E, Higuchi S, Wang H, Krishnasastry K, et al. Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion. J Am Coll Surg. 2007;205(2):284-93.\\u003c/li\\u003e\\n\\u003cli\\u003eMart\\u0026iacute;nez-Herrero S, Mart\\u0026iacute;nez A. Adrenomedullin regulates intestinal physiology and pathophysiology. Domest Anim Endocrinol. 2016;56 Suppl:S66-83.\\u003c/li\\u003e\\n\\u003cli\\u003eTendler DA LJ. Overview of intestinal ischemia in adults. UpToDate.\\u003c/li\\u003e\\n\\u003cli\\u003eOtto CC, Czigany Z, Heise D, Bruners P, Kotelis D, Lang SA, et al. Prognostic Factors for Mortality in Acute Mesenteric Ischemia. J Clin Med. 2022;11(13).\\u003c/li\\u003e\\n\\u003cli\\u003eSumbal R, Ali Baig MM, Sumbal A. Predictors of Mortality in Acute Mesenteric Ischemia: A Systematic Review and Meta-Analysis. J Surg Res. 2022;275:72-86.\\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\":\"info@researchsquare.com\",\"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\":\"Acute mesenteric ischemia, Hypoxia inducible factor 1 alpha, Adrenomedullin, Animal model\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7397493/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7397493/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eINTRODUCTION\\u003c/h2\\u003e\\u003cp\\u003eThis study aims to evaluate the diagnostic significance of adrenomedullin and hypoxia-inducible factor 1 alpha (HIF1-alpha) levels in an animal model of acute mesenteric ischemia.\\u003c/p\\u003e\\u003ch2\\u003eMATERIALS AND METHODS\\u003c/h2\\u003e\\u003cp\\u003eIn our study, a total of 21 male New Zealand rabbits were used, and the animals were divided into three groups for the study. Blood samples were taken for adrenomedullin and HIF1-alpha levels at 0, 1, 3, and 6 hours from the control, sham, ischemia groups.\\u003c/p\\u003e\\u003ch2\\u003eRESULTS\\u003c/h2\\u003e\\u003cp\\u003eHIF levels of the ischemia group at the 3rd and 6th hours were statistically significantly higher than those in the sham (p\\u0026thinsp;=\\u0026thinsp;0.002, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, respectively) and control groups (p\\u0026thinsp;=\\u0026thinsp;0.002, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, respectively). Adrenomedullin levels of the ischemia group at the 1st, 3rd, and 6th hours were statistically significantly higher than those in the sham (p\\u0026thinsp;=\\u0026thinsp;0.004, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, respectively) and control groups (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001 respectively).\\u003c/p\\u003e\\u003ch2\\u003eCONCLUSION\\u003c/h2\\u003e\\u003cp\\u003eHIF1-alpha and adrenomedullin have significant potential in the early diagnosis of acute mesenteric ischemia. In the emergency department setting, consideration of these markers and the patient's symptoms and signs may facilitate the diagnostic process.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Diagnostic Value of Hypoxia-Inducible Factor 1 Alpha and Adrenomedullin in Acute Mesenteric Ischemia\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-09-09 13:31:31\",\"doi\":\"10.21203/rs.3.rs-7397493/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"29fecece-b6b9-4a57-a191-7129480823be\",\"owner\":[],\"postedDate\":\"September 9th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[{\"id\":54357308,\"name\":\"Health sciences/Biomarkers\"},{\"id\":54357309,\"name\":\"Health sciences/Diseases\"},{\"id\":54357310,\"name\":\"Health sciences/Medical research\"},{\"id\":54357311,\"name\":\"Biological sciences/Physiology\"}],\"tags\":[],\"updatedAt\":\"2025-11-10T07:25:02+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-09-09 13:31:31\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7397493\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7397493\",\"identity\":\"rs-7397493\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}