Mepacrine-induced inhibition of human platelet cyclic-GMP phosphodiesterase

Abstract

The effect of mepacrine ( DL-quinacrine-HCl), a specific inhibitor of phospholipase C, on cyclic-GMP levels in human platelets was investigated. The concentrations of mepacrine producing 50% inhibition of human platelet aggregation induced by 5 μM ADP and 3 μg/ml of collagen were 50±8 and 70 ± 15 μM, respectively. Addition of mepacrine to human platelet suspension resulted in increases in cyclic GMP. In contrast to cyclic-GMP levels, cyclic-AMP content was not affected by mepacrine. Mepacrine did not stimulate guanylate cyclase, but did specifically inhibit human platelet cyclic-GMP phosphodiesterase, separated from cyclic-AMP phosphodiesterase or other forms of phosphodiesterase on DEAE-cellulose columns. Stimulation by cyclicGMP of human platelet cyclic-GMP-stimulated cyclic-AMP-phosphodiesterase activity was not inhibited by mepacrine. The IC 50 value of the drug for cyclic-GMP phosphodiesterase was 40μM, and IC 50 for cyclic-AMP phosphodiesterase was 1.2 mM. Mepacrine was 30-times more potent as an inhibitor of human platelet cyclic GMP than of cyclic-AMP phosphodiesterase. Mepacrine blocks arachidonate release from human platelets by inhibiting phosphatidylinositol-specific phospholipase C. The increase in cyclic-GMP levels produced by addition of mepacrine will explain part of the pharmacological action of this drug.