Activation of vascular thrombin receptors mediates cardiac responses to [alpha]-thrombin in isolated perfused guinea pig heart. Damiano, Bruce P., John A. Mitchell, Wai-Man Cheung, Robert Falotico. Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477
APStracts 2:0441H, 1995.
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 ECG. [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 NM). FSLLRN, a structurally similar peptide that does not activate thrombin receptors, had no effect. [alpha]-Thrombin and SFLLRN also changed ST segment level and T-wave morphology . Previous [alpha] -thrombin exposure markedly inhibited the response to [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 r-hirudin (3 U/ml), an inhibitor of thrombin's proteolytic action, prevented [alpha] -thrombin but not SFLLRN responses. Cromakalim (0.5 NM), 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. 

Received 6 February 1995; accepted in final form 18 September
1995.
APS Manuscript Number H106-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95