Potassium channel openers as potential therapeutic weapons in ion channel disease

Abstract

therapeutic targets. Drugs already marketed that open K ϩ Potassium channel openers as potential therapeutic weapons in channels were discovered empirically, and most have serious ion channel disease. The opening of potassium (K ϩ ) channels, safety and efficacy problems. New scientific methods, utilizing causing hyperpolarization of the cell membrane, is a physiologimolecular insight, are implicating K ϩ channel dysfunction in cal means of decreasing cell excitability. Thus, drugs with this numerous disease states and are identifying new targets for property will demonstrate a broad clinical potential. The identithe future generation of K ϩ channel opening drugs. fication of synthetic molecules that evoke physiological responses (for example smooth muscle relaxation) by the opening of K ϩ channels led to a new direction in the pharmacology of ion channels. The term "potassium channel openers" wasThe transmembrane movement of Na ϩ , K ϩ , Ca 2ϩ and initially associated with a group of chemically diverse agents Cl Ϫ ions is a principal pathway by which stimuli to the (for example, cromakalim, pinacidil, nicorandil) that evoke K ϩ efflux through adenosine 5Ј-triphosphate (ATP)-sensitive K ϩ extracellular membrane are transduced to the cytoplasm. channels (K ATP ). This finding initiated a search to identify mole-Modified efflux and influx of these ions through specific cules that specifically open other K ϩ channel subtypes (for plasmalemma channels will evoke changes in the memexample large conductance calcium-activated K ϩ channels brane potential that are associated with the initiation, [BK Ca ]). K ϩ channel opening properties have been demonmodulation or termination of cellular activities. The efstrated in a diverse range of synthetic chemical structures and endogenous substances. Second generation K ATP channel openflux of K ϩ ions following opening of K ϩ channels is a ers (K ATP COs) demonstrate heterogeneous pharmacology inmechanism that cells use to maintain or restore a resting dicative of independent sites of action for the different agents. state or attenuate the level of depolarizing effects pro-Successful cloning of the K ATP channel has shed light on the

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone

“…Potassium channels regulate membrane potential and modulate smooth muscle tone. 6 Recent studies both in vitro and in vivo have documented the potential physiologicalapathophysiological importance of potassium channels to the modulation of corpus cavernosal smooth muscle tone. 15 ± 18 The K ATP and maxi-K potassium channel subtypes are thought to be the two most physiologically relevant potassium channels expressed in corpus cavernosal smooth muscle.…”

“…6,20 Recently, in limited clinical studies in humans, the prototypic potassium channel openers such as pinacidil 11 and PNU-83587 19 when injected intracavernosally, were found to be effective in the initiation and maintenance of penile erection. Unlike intracavernosal injection of PGE 1 there were no complaints of penile pain often associated with injection.…”

“…6,7 At physiologic ATP levels, K ATP channels remain mostly in their closed state while at low ATP levels, the channels open. Potassium channel openers (KCOs) such as L-cromakalim, diazoxide, pinacidil and its analogue P1075 activate K ATP channels producing hyperpolarization of vascular and non-vascular smooth muscle membranes which reduce Ca 2 in¯ux through voltage-activated L-type Ca 2 channels, thus resulting in smooth muscle relaxation.…”

“…Potassium channel openers (KCOs) such as L-cromakalim, diazoxide, pinacidil and its analogue P1075 activate K ATP channels producing hyperpolarization of vascular and non-vascular smooth muscle membranes which reduce Ca 2 in¯ux through voltage-activated L-type Ca 2 channels, thus resulting in smooth muscle relaxation. 6 Recently, the prototypic potassium channel openers such as L-cromakalim and pinacidil, when administered as intracavernosal injections, have been found effective in the initiation and maintenance of penile erection in experimental animal models 8 ± 10 and in clinical study in humans. 11 Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate ester) is an orally ef®cacious anti-anginal drug.…”

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

“…The different composition, tissue expression patterns, and functional roles of the K ATP channel subtypes suggests that KCOs might be useful in a broad spectrum of therapeutic applications [19]. However, very few KCOs are in clinical use today.…”