McAllister Sandra E, Moses Michael A, Jindal Kunaal, Ashrafpour Homa, Cahoon Neil J, Huang Ning, Neligan Peter C, Forrest Christopher R, Lipa Joan E, Pang Cho Y
The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
J Appl Physiol (1985). 2009 Jan;106(1):20-8. doi: 10.1152/japplphysiol.91069.2008. Epub 2008 Nov 20.
Administration of Na(+)/H(+) exchange isoform-1 (NHE-1) inhibitors before ischemia has been shown to attenuate myocardial infarction in several animal models of ischemia-reperfusion injury. However, controversy still exists as to the efficacy of NHE-1 inhibitors in protection of myocardial infarction when administered at the onset of reperfusion. Furthermore, the efficacy of NHE-1 inhibition in protection of skeletal muscle from infarction (necrosis) has not been studied. This information has potential clinical applications in prevention or salvage of skeletal muscle from ischemia-reperfusion injury in elective and trauma reconstructive surgery. The objective of this research project is to test our hypothesis that the NHE-1 inhibitor cariporide is effective in protection of skeletal muscle from infarction when administered at the onset of sustained ischemia or reperfusion and to study the mechanism of action of cariporide. In our studies, we observed that intravenous administration of cariporide 10 min before ischemia (1 or 3 mg/kg) or reperfusion (3 mg/kg) significantly reduced infarction in pig latissimus dorsi muscle flaps compared with the control, when these muscle flaps were subjected to 4 h of ischemia and 48 h of reperfusion (P < 0.05; n = 5 pigs/group). Both preischemic and postischemic cariporide treatment (3 mg/kg) induced a significant decrease in muscle myeloperoxidase activity and mitochondrial-free Ca(2+) content and a significant increase in muscle ATP content within 2 h of reperfusion (P < 0.05; n = 4 pigs/group). Preischemic and postischemic cariporide treatment (3 mg/kg) also significantly inhibited muscle NHE-1 protein expression within 2 h of reperfusion after 4 h of ischemia, compared with the control (P < 0.05; n = 3 pigs/group). These observations support our hypothesis that cariporide attenuates skeletal muscle infarction when administered at the onset of ischemia or reperfusion, and the mechanism involves attenuation of neutrophil accumulation and mitochondrial-free Ca(2+) overload and preservation of ATP synthesis in the early stage of reperfusion.
在多种缺血再灌注损伤动物模型中，缺血前给予钠氢交换体1（NHE - 1）抑制剂已显示可减轻心肌梗死。然而，关于在再灌注开始时给予NHE - 1抑制剂对心肌梗死的保护效果仍存在争议。此外，尚未研究NHE - 1抑制对骨骼肌梗死（坏死）的保护作用。该信息在择期和创伤重建手术中预防或挽救骨骼肌缺血再灌注损伤方面具有潜在的临床应用价值。本研究项目的目的是检验我们的假设，即NHE - 1抑制剂卡立泊来德在持续缺血或再灌注开始时给药可有效保护骨骼肌免于梗死，并研究卡立泊来德的作用机制。在我们的研究中，我们观察到，与对照组相比，在缺血（1或3mg/kg）前10分钟或再灌注（3mg/kg）时静脉注射卡立泊来德，可显著减少猪背阔肌皮瓣的梗死面积，这些肌肉皮瓣经历4小时缺血和48小时再灌注（P < 0.05；每组n = 5头猪）。缺血前和缺血后卡立泊来德治疗（3mg/kg）均导致再灌注2小时内肌肉髓过氧化物酶活性和线粒体游离钙含量显著降低，肌肉ATP含量显著增加（P < 0.05；每组n = 4头猪）。与对照组相比，缺血4小时后再灌注2小时内，缺血前和缺血后卡立泊来德治疗（3mg/kg）还显著抑制肌肉NHE - 1蛋白表达（P < 0.05；每组n = 3头猪）。这些观察结果支持我们关于卡立泊来德在缺血或再灌注开始时给药可减轻骨骼肌梗死的假设，其机制包括减轻中性粒细胞积聚和线粒体游离钙过载，并在再灌注早期维持ATP合成。
