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

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-06 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S510885

Hüseyin Demirtaş, Abdullah Özer, Mehmet Burak Gülcan, Zeynep Yığman, Ayşegül Küçük, Esra Tekin, Yusuf Ünal, Ali Doğan Dursun, Aslı Dağlı, Mustafa Arslan

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引用次数: 0

Abstract

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), ischemia-reperfusion (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 ± 0.18 vs 0.59 ± 0.10 mmol/L, P = 0.016). Conversely, TOS (1.97 ± 0.39 vs 2.86 ± 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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研究目的本研究旨在评估波生坦（一种双重内皮素受体拮抗剂）对大鼠骨骼肌缺血再灌注损伤（IRI）的保护作用：将24只雄性Wistar Albino大鼠分为四组：对照组（C，n=6）、波生坦处理组（B，n=6）、缺血再灌注组（IR，n=6）和波生坦加缺血再灌注组（B+IR，n=6）。博生坦（10 毫克/千克）在再灌注前 30 分钟给药。在IR组和B+IR组中，使用血管钳诱导缺血45分钟，然后再灌注120分钟：结果：组织学和生化评估显示各组之间存在显著差异。B+IR组肌肉细胞的紊乱和变性评分明显低于IR组（P = 0.001）。IR 组的间质水肿程度明显比 C 组和 B 组严重（均 P <0.001），而 B+IR 组的间质水肿评分明显低于 IR 组（P <0.001）。与 IR 组相比，B+IR 组的肌肉总损伤评分明显降低（P < 0.001）。生化指标方面，B+IR 组的 TAS 水平明显高于 IR 组（1.03 ± 0.18 vs 0.59 ± 0.10 mmol/L，P = 0.016）。相反，B+IR 组的 TOS（1.97 ± 0.39 vs 2.86 ± 0.43 IU/mg，P < 0.001）和 OSI 水平（P < 0.001）明显低于 IR 组。此外，与 IR 组相比，B+IR 组的副氧合酶（PON-1）酶活性明显降低（P < 0.001）。这些研究结果表明，波生坦通过拮抗内皮素-1受体发挥保护作用，从而减轻血管收缩、氧化应激和炎症反应。观察到的肌肉细胞紊乱、间质水肿、出血、中性粒细胞浸润和氧化应激标记物的减少，强调了波生坦作为控制缺血再灌注损伤治疗剂的潜力：结论：波生坦通过内皮素受体拮抗作用降低氧化应激和炎症反应，对骨骼肌IRI具有明显的保护作用。这些发现凸显了波生坦作为一种治疗药物在减轻血管手术中的缺血再灌注损伤和控制临床环境中关键肢体缺血方面的潜力。还需要进一步研究博生坦对缺血再灌注损伤后肌肉恢复和全身健康的长期影响。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.