Posters

Pinacidil opens the ATP-sensitive and Ca-dependent K channel in smooth muscle cells of the rat and rabbit portal veins

Potassium (K) channel openers comprise a diverse group of molecules capable of opening K channels in excitable cells. These agents exhibit their greatest potency in the smooth muscle system but K channels in cardiac muscle, neurones and in secretory cells are also affected. The development of tissue selectivity is currently one major focus of research and evidence is starting to emerge that this can be achieved. The profound effects of the K channel openers in vivo has led to the suggestion that an endogenous K channel opener might exist and exert an important role in blood pressure homeostasis. The discovery of such a substance—endothelium-derived hyperpolarising factor—has many implications and its role in cardiovascular regulation is currently under investigation. In vivo, initial studies with the K channel openers emphasized their antihypertensive properties. However, later studies have concentrated on the improvement to coronary blood flow produced by these substances together with their protective effect on the ischaemic myocardium, the basis of which is not fully understood. In spite of great efforts, the K channel which forms the target of these agents in smooth muscle is a matter of controversy. The ability of glibenclamide to antagonize the actions of the K channel openers initially led to the suggestion that an ATP-dependent K channel was their site of action in smooth muscle although the most recent data have implicated a smaller conductance K channel.

Opening of plasmalemmal K⁺ channels leads to cellular hyper-polarization which, in excitable tissues possessing voltage-dependent Ca²⁺ channels, prevents the opening of such channels and thus prevents excitation. In the last few years an increasing number of compounds have been identified which elicit their effects by opening K⁺ channels, preferentially in smooth muscle, but also in other excitable tissues. These include the novel benzopyrans cromakalim and SDZ PCO 400 and also well known antihypertensives like minoxidil sulphate, diazoxide and pinacidil. After a short overview of the various families of K⁺ channel openers (KCOs), their basic pharmacological properties including inhibition by the sulfonylureas (like glibenclamide) will be presented. The therapeutic potential of these compounds in the cardiovascular field (as antihypertensives and, in particular, as antiischemic agents in heart and skeletal muscle), and in asthma (where they reverse established airway hyperreactivity) will also be discussed.

Despite recent progress in our understanding of the mechanism of action of the KCOs, major questions remain open, e.g. concerning the type of K⁺ channel(s) opened by these compounds and the mechanism(s) of vasorelaxation. An improved understanding of the action of these compounds at the molecular level is instrumental for the design of novel and more specific KCOs.

This chapter discusses the high level of interest in the physiology and pharmacology of potassium (K+) channels, the structure–activity relationships of compounds that modulate such channels, and the diverse indications for these agents. There has been an enormous growth of interest in the area since the elucidation of the mechanism of action of cromakalim—that is, the action enhancing the movement of potassium ions through smooth muscle cell membranes. Potassium channel activators (KCAs) inhibit spontaneous tone in portal vein or contractions evoked by a range of spasmogens in arterial preparations. KCAs shorten the action potential duration and produce a negative inotropic effect in cardiac tissues. These events have been observed at concentrations higher than those required to produce vasorelaxation, indicating selectivity for the vascular smooth muscle. The ability to shorten auditory processing disorder (APD) and to decrease automaticity to arrhythmogenic stimuli has suggested that KCAs may have potential as antiarrhythmic agents. The effects of KCAs on airways, gastrointestinal smooth muscle, detrusor and ureter smooth muscle, uterine smooth muscle, the central nervous system (CNS), and other tissues are also discussed in the chapter.