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BP Damiano, WM Cheung, JA Mitchell and R Falotico
R. W. Johnson Pharmaceutical Research Institute Spring House, Pennsylvania, USA.
Thrombin's cellular actions are mediated by a novel G-protein coupled transmembrane receptor. We infused SFLLRN, a peptide that directly activates thrombin receptors, into the left circumflex coronary artery (CFX) of anesthetized dogs to evaluate the cardiovascular effects of thrombin receptor activation in vivo. Intracoronary SFLLRN, 0.9, 9 and 90 nmol/min, produced transient, dose-related increases in CFX blood flow, followed by sustained decreases in CFX and left anterior descending (LAD) blood flow. SFLLRN also decreased positive and negative dP/dtmax, arterial pressure, cardiac output and heart rate. Peripheral vascular resistance transiently decreased and then increased. SFLLRN decreased systolic wall thickening (WT) and increased ST segment level within the CFX perfusion area. In contrast, WT was increased, and ST segment 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 90 nmol/min. The response to intravenous SFLLRN was greatly attenuated when compared with intracoronary infusion, and regional changes in coronary flow and function were absent. Decreases in arterial pressure, heart rate, coronary blood flow, and positive and negative dP/dtmax, were inhibited after bilateral vagotomy. Moreover, arterial pressure and peripheral resistance increased in response to SFLLRN after vagotomy. Initial CFX flow increase, regional dysfunction, ST level changes and hyperemic response were comparable but attenuated after vagotomy. Ex vivo platelet function was not affected by SFLLRN up to 100 microM. We conclude that regional myocardial ischemia and cardiac dysfunction result 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.
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