PHARMACOLOGY OF THE POTASSIUM CHANNEL OPENERS

The potassium-channel openers comprise a large number of molecules tha t can be classified into three basic groups: (1) agents like leveromak alim 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 th at also activate the enzyme-soluble guanylate cyclase; (3) molecules l ike dehydrosaponin 1 that open the large-conductance (100-150 pS) calc ium-dependent K+ channel, BKCa. K+-channel openers in groups 1 and 2 a re most potent on smooth muscle, but K-ATP channels in cardiac muscle, neurones and the pancreatic beta cell are also affected. In vivo, mod erate to high doses produce a fall in diastolic pressure with reflex t achycardia; low doses may exert selective dilator effects on specific vascular beds with little effect on systemic pressure. In vitro, all s mooth muscles are relaxed with loss of spontaneous electric and mechan ical activity; hyperpolarization to the region of E(K) is often observ ed. These effects can be antagonized by glibenclamide and also by imid azolines and guanidines, such as phentolamine, guanethidine, and antaz oline, agents that also inhibit the smooth muscle delayed rectifier ch annel, K-V. The mode and site of action of the group 1 and 2 K+-channe l openers is the subject of intense study. Irrespective of their speci fic mode of action, the K+-channel openers, especially the hybrid mole cules such as nicorandil, constitute a novel and promising approach to the treatment of cardiovascular disease.