A structurally novel inhibitor of cGMP phosphodiesterase with vasodilator activity

Abstract

A novel, potent, competitive inhibitor of smooth muscle cGMP phosphodiesterase is described (Compound I, [4-[2- n-butyl-5-chloro-1-(2-chlorobenzyl)imidazolyl]methyl] acetate). The compound is highly selective for inhibiting cGMP phosphodiesterase compared with cAMP phosphodiesterase. Compound I inhibits the contraction of smooth muscle in response to a variety of agonists in the same concentration range to that which inhibits the enzyme. Compound I produced a dose-related reduction in the pressor responses to angiotensin II infusion while not inhibiting the responses to bolus doses of angiotensin II. Two structural analogues of Compound I which did not inhibit cGMP phosphodiesterase failed to inhibit smooth muscle contraction in vitro and did not affect angiotensin II pressor responses in vivo. We propose a mechanism to account for the effects of a cGMP phosphodiesterase inhibitor on smooth muscle contraction in vitro and in vivo.