Functional evidence for a glibenclamide-sensitive K+ channel in rat ileal smooth muscle.
The motor activity of gastrointestinal smooth muscle is closely related to the membrane potential. Controlling the membrane potential via modulation of K+ channels is essential for the action of neurotransmitters 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 muscarinic 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 antagonized 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, tetraethylammonium (10(-4) to 10(-1) M), had no influence on the inhibitory effect of lemakalim. Contractions induced by the Ca2+ channel activator, Bay-K-8644, were completely inhibited by lemakalim (10(-5) M, n = 12). This inhibitory effect was also selectively antagonized by glibenclamide (10(-5) M). Potential non-adrenergic non-cholinergic (NANC) inhibitory mediators like ATP, nitric oxide (NO) or neurotensin showed no sensitivity to glibenclamide. These functional data indicate that the relaxant effect of lemakalim is due to a specific activation of glibenclamide-sensitive K+ channels, which in turn can modulate the activity of dihydropyridine-sensitive (voltage-dependent) Ca2+ channels. A physiological or pathophysiological role of the glibenclamide-sensitive K+ channels in intestinal smooth muscle is discussed; however, they seem not to be involved in the effect of the NANC inhibitory mediators tested.
Franck
H
H
Department of Internal Medicine II, Technical University of Munich, Germany.
Puschmann
A
A
Schusdziarra
V
V
Allescher
H D
HD
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002217:Carbachol; D015740:Calcitonin Gene-Related Peptide; D005905:Glyburide