Protective Effects of Bosentan via Endothelin Receptor Antagonism in Experimental Ischemia-Reperfusion Injury in the Lower Limb of Rats

被引：0

作者：

Demirtas, Hueseyin

Oezer, Abdullah

Guelcan, Mehmet Burak

Yigman, Zeynep ^{[1
,2
]}

Kuecuek, Ayseguel

Tekin, Esra ^{[3
]}

Uenal, Yusuf

Dursun, Ali Dogan ^{[5
,6
,7
]}

Dagli, Asli ^{[1
,8
]}

Arslan, Mustafa ^{[4
,9
,10
]}

机构：

[1] Gazi Univ, Fac Med, Dept Histol & Embryol, Ankara, Turkiye

[2] Gazi Univ, Neurosci & Neurotechnol Ctr Excellence NOROM, Ankara, Turkiye

[3] Kutahya Hlth Sci Univ, Fac Med, Dept Physiol, Kutahya, Turkiye

[4] Gazi Univ, Fac Med, Dept Anesthesiol & Reaminat, Mevlana Blvd 29, TR-06510 Ankara, Turkiye

[5] Atilim Univ, Fac Med, Dept Physiol, Ankara, Turkiye

[6] Atilim Univ, Vocat Sch Hlth Serv, Ankara, Turkiye

[7] Medicana Int Ankara Hosp, Ankara, Turkiye

[8] Atilim Univ, Vocat Sch Hlth Serv, Dept Med Serv & Tech, Vocat Sch Hlth Serv, TR-06830 Ankara, Turkiye

[9] Gazi Univ, Applicat & Res Ctr Life Sci, Ankara, Turkiye

[10] Gazi Univ, Ctr Lab Anim Breeding & Expt Res GUDAM, Ankara, Turkiye

来源：

DRUG DESIGN DEVELOPMENT AND THERAPY | 2025年 / 19卷

关键词：

bosentan; ischemia-reperfusion; lower limb; oxidative stress; TAS; TOS; endothelin receptor antagonism; PERIPHERAL ARTERY-DISEASE; SKELETAL-MUSCLE ISCHEMIA; MYOCARDIAL-ISCHEMIA; SYSTEMIC-SCLEROSIS; SPINAL-CORD; ERYTHROCYTE DEFORMABILITY; HYPERTENSION; MANAGEMENT; EFFICACY; TISSUE;

D O I：

10.2147/DDDT.S510885

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Objective: This study aimed to evaluate the protective effects of bosentan, a dual endothelin receptor antagonist, against skeletal muscle ischemia-reperfusion injury (IRI) in rats. Methods: A total of 24 male Wistar Albino rats were divided into four groups: control (C, n=6), bosentan-treated (B, n=6), ischemiareperfusion (IR, n=6), and bosentan plus ischemia-reperfusion (B+IR, n=6). Bosentan (10 mg/kg) was administered 30 minutes prior to reperfusion. In the IR and B+IR groups, ischemia was induced using vascular bulldog clamps for 45 minutes, followed by 120 minutes of reperfusion. Results: Histological and biochemical assessments revealed significant differences among the groups. The disorganization and degeneration scores of the muscle cells in the B+IR group were significantly lower than those in the IR group (P = 0.001). The degree of interstitial edema in the IR group was markedly more severe than in the C and B groups (all P < 0.001), while the interstitial edema score in the B+IR group was significantly lower than that in the IR group (P < 0.001). The total muscle injury scores were markedly reduced in the B+IR group compared to the IR group (P < 0.001). Biochemically, TAS levels were significantly higher in the B+IR group compared to the IR group (1.03 f 0.18 vs 0.59 f 0.10 mmol/L, P = 0.016). Conversely, TOS (1.97 f 0.39 vs 2.86 f 0.43 IU/mg, P < 0.001) and OSI levels (P < 0.001) were significantly lower in the B+IR group. Additionally, paraoxonase (PON-1) enzyme activity was significantly reduced in the B+IR group compared to the IR group (P < 0.001). These findings suggest that bosentan exerts its protective effects by antagonizing endothelin-1 receptors, thereby mitigating vasoconstriction, oxidative stress, and inflammation. The observed reductions in muscle cell disorganization, interstitial edema, hemorrhage, neutrophil infiltration and oxidative stress markers underscore bosentan's potential as a therapeutic agent for managing ischemia-reperfusion injury. Conclusion: Bosentan demonstrates significant protective effects against skeletal muscle IRI by reducing oxidative stress and inflammation through endothelin receptor antagonism. These findings underscore bosentan's potential as a therapeutic agent for mitigating ischemia-reperfusion injury in vascular surgeries and managing critical limb ischemia in clinical settings. Further research is warranted to explore the long-term effects of bosentan on muscle recovery and systemic health following ischemia-reperfusion injury.

引用

页码：1561 / 1573

页数：13

共 37 条

[1] Fowkes FGR, Rudan D, Rudan I, Et al., Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis, Lancet, 382, 9901, pp. 1329-1340, (2013)
[2] Hess CN, Huang Z, Patel MR, Et al., Acute limb ischemia in peripheral artery disease, Circulation, 140, 7, pp. 556-565, (2019)
[3] Jones WS, Dolor RJ, Hasselblad V, Et al., Comparative effectiveness of endovascular and surgical revascularization for patients with peripheral artery disease and critical limb ischemia: systematic review of revascularization in critical limb ischemia, Am Heart J, 167, 4, pp. 489-498, (2014)
[4] Gornik HL, Aronow HD, Goodney PP, Et al., ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines, Circulation, 149, 24, (2024)
[5] Bjorck M, Earnshaw JJ, Acosta S, Et al., Editor’s choice-European society for vascular surgery (ESVS) 2020 clinical practice guidelines on the management of acute limb ischaemia, Eur J Vasc Endovasc Surg, 59, 2, pp. 173-218, (2020)
[6] Ozer A, Demirtas H, Comu FM, Et al., Protective effect of erdosteine on erythrocyte deformability in a rat model of lower limb ischemia/reperfusion injury, Turk J Med Sci, 48, pp. 187-190, (2018)
[7] Ozturk L, Dogan HT, Kilicarslan A, Et al., Effect of different doses of pregabalin on skeletal muscle ischaemia-reperfusion injury in rats, Bratisl Med J, 118, 7, pp. 417-422, (2017)
[8] Ozer A, Erel S, Kucuk A, Et al., Evaluation of the effect of enriched hydrogen saline solution on distant organ (lung) damage in skeletal muscle ischemia reperfusion in rats, Sci Prog, 107, 2, pp. 1-13, (2024)
[9] Liu C, Zhang X., Bosentan, an endothelin receptor-1 antagonist, exerts cardioprotective effects during myocardial ischemia-reperfusion injury in experimental rats, Int J Pharm, 20, 4, pp. 611-621, (2024)
[10] Iriz E, Iriz A, Take G, Et al., Iloprost and vitamin C attenuate acute myocardial injury induced by suprarenal aortic ischemia-reperfusion in rabbits, Bratisl Med J, 116, 10, pp. 627-631, (2015)

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