INHIBITION BY THE COMBINED CA2-HT2 RECEPTOR ANTAGONIST NEXOPAMIL (LU-49938) OF INTRACORONARY THROMBUS FORMATION IN A CANINE MODEL OF ARTERIAL-STENOSIS AND INTIMAL DAMAGE( AND 5)

We investigated the effects of nexopamil, a combined Ca2+/5-HT2 antago nist on thrombus formation in vivo and on platelet aggregation in vitr o. In anesthetized mongrel dogs, cyclic flow reductions (CFRs) in the left anterior descending coronary artery (LAD) were induced by implant ing a constrictor after the endothelium was injured mechanically. The CFRs were due to intracoronary thrombus formation. After CFRs were rec orded for 1 h, the test compounds were injected intravenously (i.v.) f or 2 min. Measurements were made for another hour. Nexopamil (0.05 mg/ kg) completely abolished CFRs during the first 30 min after applicatio n without significantly altering hemodynamics. The same effect was not ed with 0.02 mg/kg ketanserin (5-HT2/alpha1 antagonist). The Ca2+ anta gonist gallopamil reduced CFRs only in the highest hemodynamically tol erable dose by 40%. Serotonin-induced platelet aggregation in dog plat elet-rich plasma (PRP) in vitro was most potently inhibited by ketanse rin (IC50 0.55 x 10(-8) M), followed by nexopamil (IC50) 0.81 x 10(-7) M) and gallopamil (IC50 1.76 x 10(-6) M). Because serotonin is an imp ortant pathophysiologic mediator in unstable angina, 5-HT2 receptor an tagonism should be of considerable benefit by preventing platelet acti vation and aggregation. The combination with calcium-antagonistic acti vity leads to an increase in coronary blood flow (CBF) and a decrease in cardiac oxygen demand. Therefore, the effects noted with nexopamil should be of importance in treating patients with coronary artery dise ase.