ACTIVATION OF VASCULAR THROMBIN RECEPTORS MEDIATES CARDIAC RESPONSE TO ALPHA-THROMBIN IN ISOLATED, PERFUSED GUINEA-PIG HEART

alpha-Thrombin alters vascular tone via a cell surface receptor. We us ed isolated guinea pig hearts perfused with buffer at constant flow to assess the effects of thrombin-receptor activation on coronary perfus ion pressure, left ventricular function, and electrocardiogram. alpha- Thrombin produced concentration dependent (0.03-1 U/ml), transient dec reases in perfusion pressure followed by sustained increases. Concurre ntly, alpha-thrombin markedly reduced ventricular function. SFLLRN, a peptide that directly activates thrombin receptors, had qualitatively similar effects, except that it was less potent (0.1-30 mu M). FSLLRN, a structurally similar peptide that does not activate thrombin recept ors, had no effect. alpha-Thrombin and SFLLRN also changed S-T segment level and T-wave morphology. Previous alpha-thrombin exposure markedl y inhibited the response to alpha-thrombin but only moderately attenua ted the response to SFLLRN. However, previous SFLLRN exposure did not alter subsequent response to alpha-thrombin or SFLLRN. Pretreatment wi th hirudin (3 U/ml), an inhibitor of thrombin's proteolytic action, pr evented alpha-thrombin but not SFLLRN responses. Cromakalim (0.5 mu M) , a coronary vasodilator, reversed the effects of alpha-thrombin and S FLLRN on ventricular function, suggesting that depression of ventricul ar function resulted, in part, from vasoconstriction-induced myocardia l perfusion deficit. Our results show that alpha-thrombin, at physiolo gically relevant concentrations, has marked effects on coronary vascul ar resistance and ventricular function in isolated guinea pig hearts t hat are mediated by the proteolytically activated thrombin receptor.