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 used isolated guinea pig hearts perfused with buffer at constant flow to assess the effects of thrombin-receptor activation on coronary perfusion pressure, left ventricular function, and electrocardiogram. alpha-Thrombin produced concentration-dependent (0.03-1 U/ml), transient decreases in perfusion pressure followed by sustained increases. Concurrently, 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 microM). FSLLRN, a structurally similar peptide that does not activate thrombin receptors, had no effect. alpha-Thrombin and SFLLRN also changed S-T segment level and T-wave morphology. Previous alpha-thrombin exposure markedly inhibited the response to a alpha-thrombin but only moderately attenuated the response to SFLLRN. However, previous SFLLRN exposure did not alter subsequent response to alpha-thrombin or SFLLRN. Pretreatment with hirudin (3 U/ml), an inhibitor of thrombin's proteolytic action, prevented alpha-thrombin but not SFLLRN responses. Cromakalim (0.5 microM), a coronary vasodilator, reversed the effects of alpha-thrombin and SFLLRN on ventricular function, suggesting that depression of ventricular function resulted, in part, from vasoconstriction-induced myocardial perfusion deficit. Our results show that alpha-thrombin at physiologically relevant concentrations, has marked effects on coronary vascular resistance and ventricular function in isolated guinea pig hearts that are mediated by the proteolytically activated thrombin receptor.