Latest developments in K-channel modulator pharmacology

Synthetic modulators of smooth muscle potassium (K) channels now comprise a large number of chemically-diverse molecules which possess either K-channel-opening or K-channel-blocking properties. First-generation openers are typified by the benzopyran, BRL38227 which exhibits little tissue selectivity in vivo or in vitro. Under current development are second-generation molecules such as the benzopyran, HOE234, and the guanidine, LY211808, both of which exhibit some tissue selectivity. Until recently, tetraethylammonium, the aminopyridines and the sulphonylureas like glibenclamide were the most important types of synthetic K-channel blocker available. Recent work has now identified several novel K-channel blockers active in smooth muscle. These include the bradycardic agents tedisamil and alinidine and the anorectic agent ciclazindol. The effects of K-channel openers on transmitter release are now under detailed study. Although postganglionic neuroeffector transmission in blood vessels seems little affected, transmitter release in bronchial, gastrointestinal and genitourinary preparations is reduced. Whether these effects are primarily pre- or post-ganglionic is unclear. Transmitter release is also reduced in certain areas of the CNS. No clear picture of the type of smooth muscle K-channel with which the openers interact has yet emerged. The ability of glibenclamide to antagonise the effects of K-channel openers apparently favours the involvement of KATP, although the selectivity of glibenclamide and the existence of KATP in smooth muscle remain to be firmly established.