Schultz J J, Hsu A K, Gross G J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
J Mol Cell Cardiol. 1997 May;29(5):1355-62. doi: 10.1006/jmcc.1996.0369.
Previously, our laboratory has shown that opioid receptors are involved in ischemic preconditioning (PC) in the intact rat heart; however, it is not known whether this cardioprotection is mediated by central or peripheral mechanisms. To test this hypothesis, both naloxone (NL), the non-selective opioid receptor antagonist and naloxone methiodide (QNL), its quaternary derivative which does not cross the blood-brain barrier, were used to determine if opioid receptor-induced myocardial protection occurs via a central or peripheral locus of action in inactin-anesthetized, open-chested, Wistar rats. In group I, the control group was subjected to 30 min of occlusion and 2 h of reperfusion. In group II, ischemic PC was elicited by three 5-min occlusion periods interspersed with 5 min of reperfusion. In group III, QNL (10 mg/kg, i.v.) was administered 10 min before the 30 min of occlusion. Groups IV and V consisted of a dose-response effect of QNL on ischemic PC in which QNL (0.3 or 10 mg/kg, i.v., respectively) was given 10 min prior to ischemic PC. In addition, in groups VI and VII, one of two doses of naloxone (1 or 3 mg/kg, i.v.) was administered 10 min before ischemic PC. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by tetrazolium staining. Ischemic PC reduced IS to 9 +/- 2% (P < 0.05) v control (53 +/- 4%). The low dose of QNL partially blocked the cardioprotective effect of ischemic PC; whereas the high dose completely abolished its cardioprotective effect. The high dose of QNL had no effect on IS alone. Similarly, the low dose of NL did not antagonize the cardioprotective effect of ischemic PC; however, the high dose completely abolished ischemic PC. These results indicate that the cardioprotective effect of ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart.
此前，我们实验室已表明阿片受体参与完整大鼠心脏的缺血预处理（PC）；然而，尚不清楚这种心脏保护作用是由中枢机制还是外周机制介导的。为验证这一假设，使用非选择性阿片受体拮抗剂纳洛酮（NL）及其不能透过血脑屏障的季铵衍生物甲硫纳洛酮（QNL），来确定阿片受体诱导的心肌保护作用是通过中枢还是外周作用位点在戊巴比妥麻醉、开胸的Wistar大鼠中发挥作用。在第一组（对照组）中，进行30分钟的阻断和2小时的再灌注。在第二组中，通过三个5分钟的阻断期并穿插5分钟的再灌注来诱导缺血预处理。在第三组中，在30分钟阻断前10分钟静脉注射QNL（10毫克/千克）。第四组和第五组由QNL对缺血预处理的剂量反应效应组成，其中在缺血预处理前10分钟分别静脉注射QNL（0.3或10毫克/千克）。此外，在第六组和第七组中，在缺血预处理前10分钟静脉注射两种剂量纳洛酮（1或3毫克/千克）中的一种。通过四氮唑染色确定梗死面积（IS）占危险面积（AAR）的百分比。缺血预处理将梗死面积降至9±2%（P<0.05），而对照组为53±4%。低剂量的QNL部分阻断了缺血预处理的心脏保护作用；而高剂量则完全消除了其心脏保护作用。高剂量的QNL单独对梗死面积无影响。同样，低剂量的NL并未拮抗缺血预处理的心脏保护作用；然而，高剂量则完全消除了缺血预处理。这些结果表明，缺血预处理的心脏保护作用是由完整大鼠心脏中的外周阿片受体机制介导的。
