Smooth muscle K+ channel openers; their pharmacology and clinical potential.

Abstract

Introduction The f'LrSt description of vasodilator action consistent with the opening of smooth muscle potassium (K +) channels was given by Furukawa et al. (1981). These workers described an electrophysiological study of the action of nicorandil on porcine and guinea-pig coronary arteries. The significance of this finding was clouded by the observation that nicorandil was also capable of activating soluble guanylate cyclase in smooth muscle (Holzmann i983). Thus it was uncertain whether K + channel opening in smooth muscle was a separate entity or whether it was causally linked to guanylate cyclase activation. The situation was clarified when Hamilton et al. (1986) showed that the vasodilator cromakalim had K + channel opening properties which were exerted without any detectable effect on guanylate cyclase (ColdweU and Howlett 1987; Taylor et al. 1988). Since these initial observations on nicorandil and cromakalim, it has been demonstrated that pinacidil, an agent under development since 1972, exerts its vasodilator effects via K + channel opening (Bray et al. 1987; Cook et al. 1988a). Furthermore, the vasodilators minoxidil sulphate and diazoxide, both of which were synthesised before pinacidil, and new developments like RP 49356 (Aloup et al. 1987), are now also known to be capable of opening K + channels (Bray et al. 1988; Meisheri et al. 1988; Mondot et al. 1988). The objective of this brief overview is to outline the pharmacology of the group of drugs now known as the K + channel openers. Although nicorandil possesses K + channel opening properties, its ability to activate guanylate cyclase renders uncertain the extent to which activation of K + channel or guanylate cyclase contributes to its observed effects. For this reason, the review will emphasise the pharmacology of cromakalim and pinacidil, the two agents most widely studied to date. The synthesis of precursors of cromakalim (BRL 34915) was described by Evans et al. (1983) and the derivation of cromakalim itself was detailed by Ashwood et al. (1986). BRL 34915 contains two adjacent chiral carbon atoms within its structure, with the substituants of these two atoms in the trans configuration. Cromakalim is the generic name allocated to the racemic mixture of the two trans enantiomers which have been designated BRL 38226 [(+)-3R, 4S enantiomer] and BRL 38227 [(-)-3S, 4R enantiomer]. Vasorelaxant activity resides in the (-)-trans enantiomer BRL 38227 and this form together with cromakalim are both under development for clinical use.