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

被引:41
作者
FRANCK, H [1 ]
PUSCHMANN, A [1 ]
SCHUSDZIARRA, V [1 ]
ALLESCHER, HD [1 ]
机构
[1] TECH UNIV MUNICH,DEPT INTERNAL MED 2,MED KLIN & POLIKLIN 2,D-81675 MUNICH,GERMANY
关键词
LEMAKALIM; GLIBENCLAMIDE; ATP-SENSITIVE CA2+ CHANNEL; APAMIN; CHARYBDOTOXIN; NITRIC OXIDE (NO);
D O I
10.1016/0014-2999(94)90797-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
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页码:379 / 386
页数:8
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