Inhibition of platelet aggregation by papaverine-like drugs: Evidence for a novel mechanism of action

Abstract

Trimethoquinol [6,7-dihydroxy-1-(3′,4′,5′-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (TMQ) was chosen as a model compound for studying inhibition of platelet aggregation in vitro, because of its β-adrenoceptor agonist properties and structural resemblance to the anti-aggregatory agent, papaverine. TMQ inhibited collagen-induced aggregation of human platelet-rich plasma (I 50, 2 μM), the second wave of aggregation induced by 2.5 μM ADP (I 50, 0.9 μM), and the second wave of aggregation induced by 45 μM epinephrine (I 50, 2.5 μM). Collagen-induced aggregation of human washed platelets was inhibited by TMQ (I 50, 1 μM). TMQ was a better inhibitor than aspirin and papaverine and had an inhibitory activity similar to indomethacin in all of the systems studied. TMQ retained inhibitory activity in the presence of both β-adrenoceptor antagonist: propranolol (50 μM), and α-adrenoceptor antagonist: phentolamine (2.5 μM). Platelet adenylate cyclase was not activated and neither cAMP nor cGMP-phosphodiesterase activities were inhibited by TMQ, PGF 2α, biosynthesis by aggregating platelets during the coagulation of blood obtained from rats pretreated with aspirin (10 mg/kg, p.o.) or indomethacin (1 mg/kg, p.o.) was inhibited. However, similar pretreatment with TMQ (100 mg.kg, p.o.) and papaverine hydrochloride (100 mg/kg, p.o.) had no effect. TMQ acted synergistically with the aggregation inhibitors: papaverine, aspirin, and PGE 1. The in vitro inhibitory action of papaverine, aspirin, and TMQ was enhanced by increasing calcium concentration. These data indicate that the platelet anti-aggregation activity of TMQ, in contrast to its myocardial stimulating and bronchodilating mechanism, is independent of adrenergic activation. Cyclic AMP accumulation or prostaglandin biosynthesis also seem not to be involved in TMQ action. Therefore, it appears that TMQ may have a novel anti-aggregatory mechanism of action.