FUNCTIONAL EVIDENCE FOR A GLIBENCLAMIDE-SENSITIVE K-MUSCLE( CHANNEL IN RAT ILEAL SMOOTH)

The motor activity of gastrointestinal smooth muscle is closely relate d to the membrane potential. Controlling the membrane potential via mo dulation of K+ channels is essential for the action of neurotransmitte rs on smooth muscle. In the present study the effect of the K+ channel activator, lemakalim, on longitudinal smooth muscle of the rat ileum was investigated. Segments of rat ileum were stimulated by the muscari nic receptor agonist, carbachol (10(-6) M). Lemakalim (10(-10) to 3 x 10(-5) M) induced a dose-dependent inhibition of the carbachol-induced contraction. This inhibitory effect of lemakalim was not modified by neural blockade with tetrodotoxin (10(-6) M, n = 9). Glibenclamide (10 (-7) to 10(-5) M), a specific blocker of ATP-dependent K+ channels ant agonized dose dependently the relaxant effect of lemakalim (IC50: 3.4 x 10(-6) M, n = 11, P < 0,001). In contrast, apamin (10(-7) M, n = 9, n.s.) and charybdotoxin (10(-7) M, n = 9, n.s.), specific blockers of Ca2+-dependent K+ channels and the non-specific K+ channel blocker, te traethylammonium (10(-4) to 10(-1) M), had no influence on the inhibit ory effect of lemakalim. Contractions induced by the Ca2+ channel acti vator, Bay-K-8644, were completely inhibited by lemakalim (10(-5) M, n = 12). This inhibitory effect was also selectively antagonized by gli benclamide (10(-5) M). Potential non-adrenergic non-cholinergic (NANC) inhibitory mediators like ATP, nitric oxide (NO) or neurotensin showe d no sensitivity to glibenclamide. These functional data indicate that the relaxant effect of lemakalim is due to a specific activation of g libenclamide-sensitive K+ channels, which in turn can modulate the act ivity of dihydropyridine-sensitive (voltage-dependent) Ca2+ channels. A physiological or pathophysiological role of the glibenclamide-sensit ive K+ channels in intestinal smooth muscle is discussed; however, the y seem not to be involved in the effect of the NANC inhibitory mediato rs tested.