Bp. Damiano et al., ACTIVATION OF VASCULAR THROMBIN RECEPTORS MEDIATES CARDIAC RESPONSE TO ALPHA-THROMBIN IN ISOLATED, PERFUSED GUINEA-PIG HEART, American journal of physiology. Heart and circulatory physiology, 39(5), 1996, pp. 1585-1596
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.