OXYGEN RADICAL-MEDIATED VASCULAR INJURY SELECTIVELY INHIBITS RECEPTOR-DEPENDENT RELEASE OF NITRIC-OXIDE FROM CANINE CORONARY-ARTERIES

Reperfusion after global cardiac ischemia may injure coronary artery e ndothelium and lead to vasospasm and thrombosis. Oxygen-derived radica ls have been implicated as mediators of this process, but the precise mechanism of injury is unknown. We hypothesized that oxygen-derived ra dicals impair coronary endothelial production of nitric oxide, a poten t endogenous vasodilator and inhibitor of platelet adhesion. To test t his theory, we developed an in vitro model of reperfusion injury in wh ich segments of epicardial canine coronary artery were suspended in or gan chambers (physiologic salt solution, 37 degrees C, 95% oxygen and 5% carbon dioxide) and exposed to oxygen-derived radicals (generated b y adding xanthine [10(-4) mol/L] and xanthine oxidase [100 mU/ml] to t he bathing solution for 70 minutes). After exposure to oxygen-derived radicals, epicardial coronary artery smooth muscle exhibited normal co ntraction to potassium ions (20 mmol/L) and prostaglandin F-2 (4 X 10( -6) mol/L); also, the rings relaxed normally on exposure to isoprotere nol and sodium nitroprusside (10(-9) to 10(-4) mol/L) (n = 6). In cont rast, endothelium-dependent vasodilatation to receptor-dependent agoni sts acetylcholine and adenosine diphosphate (10(-9) to 10(-4) mol/L) w as impaired as compared with the reaction of control vessels not expos ed to oxygen-derived radicals (n = 18, P < 0.001, and n = 10, P < 0.00 2, respectively). Importantly, receptor-independent, endothelium-depen dent relaxation to the calcium ionophore A23187 was normal (n = 6). Fu rther, endothelium-dependent vasodilatation to receptor-dependent agon ist bradykinin (non-nitric oxide pathway) was normal after-exposure to oxygen-derived radicals. This is the first study to demonstrate that oxygen-derived radicals selectively impair receptor-dependent nitric o xide production by the coronary endothelium. Diminished nitric oxide p roduction is a likely mechanism of vasospasm and thrombosis after repe rfusion of the ischemic heart.