PHARMACOLOGY OF THE POTASSIUM CHANNEL OPENERS

The potassium-channel openers comprise a large number of molecules that can be classified into three basic groups: (1) agents like leveromakalim that open a small-conductance (10-30 pS) glibenclamide-sensitive K+ channel currently known as the ATP-sensitive K+ channel, K-ATP; (2) hybrid molecules, such as nicorandil, that open K-ATP channels and that also activate the enzyme-soluble guanylate cyclase; (3) molecules like dehydrosaponin 1 that open the large-conductance (100-150 pS) calcium-dependent K+ channel, BKCa. K+-channel openers in groups 1 and 2 are most potent on smooth muscle, but K-ATP channels in cardiac muscle, neurones and the pancreatic beta cell are also affected. In vivo, moderate to high doses produce a fall in diastolic pressure with reflex tachycardia; low doses may exert selective dilator effects on specific vascular beds with little effect on systemic pressure. In vitro, all smooth muscles are relaxed with loss of spontaneous electric and mechanical activity; hyperpolarization to the region of E(K) is often observed. These effects can be antagonized by glibenclamide and also by imidazolines and guanidines, such as phentolamine, guanethidine, and antazoline, agents that also inhibit the smooth muscle delayed rectifier channel, K-V. The mode and site of action of the group 1 and 2 K+-channel openers is the subject of intense study. Irrespective of their specific mode of action, the K+-channel openers, especially the hybrid molecules such as nicorandil, constitute a novel and promising approach to the treatment of cardiovascular disease.