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.
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收藏
页码:1561 / 1573
页数:13
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