IMPAIRED ENDOTHELIUM-DEPENDENT RELAXATION AFTER CORONARY REPERFUSION INJURY - EVIDENCE FOR G-PROTEIN DYSFUNCTION

This study was done to determine whether abnormal receptor-dependent r elease of endothelium-derived relaxing factor (EDRF) might be caused b y G-protein dysfunction. Dogs were exposed to global myocardial ischem ia (45 minutes, induced by aortic cross-clamping) followed by reperfus ion (60 minutes) while on cardiopulmonary bypass, and coronary arterie s were then studied in vitro in organ chamber experiments. After reper fusion, endothelium-dependent relaxation to the receptor-dependent ago nists adenosine diphosphate and acetylcholine was significantly impair ed as well as to sodium fluoride, which acts on a pertussis toxin-sens itive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (mol ecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway , was unaffected by ischemia and reperfusion. These experiments sugges t that global myocardial ischemia and reperfusion selectively impair r eceptor-mediated release of EDRF (nitric oxide) but that the ability o f the endothelial cell to produce EDRF or generate endothelium-depende nt relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfu nction in the endothelium.