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.
Damiano
B P
BP
R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA.
Mitchell
J A
JA
Cheung
W M
WM
Falotico
R
R
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D019806:Cromakalim; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006629:Hirudins / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000187:drug effects* / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left
D001578:Benzopyrans; D006629:Hirudins; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011758:Pyrroles; D018179:Receptors, Thrombin; D014665:Vasodilator Agents; C082835:thrombin receptor peptide (42-47); D019806:Cromakalim; D013917:Thrombin