Ischemic and pharmacological preconditioning of rat myocardium: Effects on ischemia-reperfusion injury.

摘要

Ischemic heart disease remains the major cause of morbidity and mortality in industrialized countries despite the improvement in clinical management of the disease. The search for therapeutic agents aimed at the protection against ischemia-reperfusion (I-R) injury has been an area of intensive research. This thesis work examined and compared the effects of ischemic preconditioning (IPC), produced by brief periods of myocardial ischemia followed by reperfusion, and pharmacological preconditioning (PPC), using active extracts or compounds derived from Chinese tonifying herbs of different functionality, on I-R injury in isolated-perfused hearts prepared from male and female rats. Adult female rat hearts were found to be less susceptible to I-R injury than that of male hearts. Correlation analysis indicated that mitochondrial reduced glutathione (GSH) and alpha-tocopherol (alpha-TOC) levels as well as Se-glutathione peroxidase (GPX) activity are crucial factors involved in the development of myocardial I-R injury. IPC could alter myocardial mitochondrial antioxidant component levels/activities and protect against myocardial I-R injury in a gender-independent manner. PPC produced differential effects on mitochondrial functional ability and antioxidant components and protected against myocardial I-R injury. While the methanolic extract of Herba Cynomorii and the saponin fraction of a mixture of Radix Ginseng and Radix Ophiopogonis (SF) produced a more favorable effect on male hearts, oleanolic acid (OA) and emodin (EMD) seemed to be more effective in female hearts. Both alpha-TOC and alpha-lipoic acid pretreatments were found to be more beneficial in protecting against I-R injury in female than in male hearts. The gender difference in cardioprotection afforded by PPC might be attributed to the differential response in mitochondrial functional ability and antioxidant components in non-I-R and I-R conditions. Biochemical mechanisms involved in the cardioprotection afforded by OA/EMD include the enhancement of GSH or its related antioxidant actions such as GSH-dependent recycling of alpha-TOC and the induction of heat shock protein 25/70 expression. Results obtained from studies using a combination of preconditioning pretreatments indicated that IPC and PPC (afforded by OA/EMD pretreatment) protected against myocardial I-R injury via similar but not identical biochemical mechanism. In vitro studies on mitochondrial susceptibility to peroxide-induced oxidation of lipids and Ca2+/PO43--induced permeability transition indicated that the cardioprotective mechanism of IPC and PPC may involve the enhancement of mitochondrial antioxidant capacity and resistant to calcium loading. The use of a combination of preconditioning agents may provide a better cardioprotection against I-R injury.