CARDIOVASCULAR ACTIONS OF THROMBIN RECEPTOR ACTIVATION IN-VIVO

Thrombin's cellular actions are mediated by a novel G-protein coupled transmembrane receptor. We infused SFLLRN, a peptide that directly act ivates thrombin receptors, into the left circumflex coronary artery (C FX) of anesthetized dogs to evaluate the cardiovascular effects of thr ombin receptor activation in vivo. Intracoronary SFLLRN, 0.9, 9 and 90 nmol/min, produced transient, dose-related increases in CFX blood flo w, followed by sustained decreases in CFX and left anterior descending (LAD) blood flow. SFLLRN also decreased positive and negative dP/dt(m ax), arterial pressure, cardiac output and heart rate. Peripheral vasc ular resistance transiently decreased and then increased. SFLLRN decre ased systolic wall thickening (WT) and increased ST segment level with in the CFX perfusion area. In contrast, WT was increased, and ST segme nt was unchanged in the LAD perfusion area. CFX flow, but not LAD flow , increased transiently above control after SFLLRN infusion. FSLLRN, a peptide that does not activate thrombin receptors, had no effect at 9 0 nmol/min. The response to intravenous SFLLRN was greatly attenuated when compared with intracoronary infusion, and regional changes in cor onary flow and function were absent. Decreases in arterial pressure, h eart rate, coronary blood flow, and positive and negative dP/dt(max), were inhibited after bilateral vagotomy. Moreover, arterial pressure a nd peripheral resistance increased in response to SFLLRN after vagotom y. Initial CFX flow increase, regional dysfunction, ST level changes a nd hyperemic response were comparable but attenuated after vagotomy. E x vivo platelet function was not affected by SFLLRN up to 100 mu M. We conclude that regional myocardial ischemia and cardiac dysfunction re sult from thrombin receptor-mediated local coronary vasoconstriction. Thus, thrombin generation at a site of vascular injury or thrombus may significantly affect vascular tone and myocardial perfusion.