大鼠回肠平滑肌中对格列本脲敏感的钾离子通道的功能证据
Functional evidence for a glibenclamide-sensitive K+ channel in rat ileal smooth muscle.
作者信息
Franck H, Puschmann A, Schusdziarra V, Allescher H D
机构信息
Department of Internal Medicine II, Technical University of Munich, Germany.
出版信息
Eur J Pharmacol. 1994 Dec 27;271(2-3):379-86. doi: 10.1016/0014-2999(94)90797-8.
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.
胃肠道平滑肌的运动活性与膜电位密切相关。通过调节钾通道来控制膜电位对于神经递质作用于平滑肌至关重要。在本研究中，研究了钾通道激活剂雷马卡林对大鼠回肠纵行平滑肌的作用。用毒蕈碱受体激动剂卡巴胆碱（10⁻⁶ M）刺激大鼠回肠段。雷马卡林（10⁻¹⁰至3×10⁻⁵ M）诱导对卡巴胆碱诱导的收缩产生剂量依赖性抑制。雷马卡林的这种抑制作用不受河豚毒素（10⁻⁶ M，n = 9）神经阻滞的影响。格列本脲（10⁻⁷至10⁻⁵ M），一种ATP依赖性钾通道的特异性阻滞剂，剂量依赖性地拮抗雷马卡林的舒张作用（IC50：3.⁴×10⁻⁶ M，n = 11，P < 0.001）。相反，蜂毒明肽（10⁻⁷ M，n = 9，无显著性差异）和蝎毒素（10⁻⁷ M，n = 9，无显著性差异），钙依赖性钾通道的特异性阻滞剂和非特异性钾通道阻滞剂四乙铵（10⁻⁴至10⁻¹ M），对雷马卡林的抑制作用没有影响。钙通道激活剂Bay-K-8644诱导的收缩被雷马卡林（10⁻⁵ M，n = 12）完全抑制。这种抑制作用也被格列本脲（10⁻⁵ M）选择性拮抗。潜在的非肾上腺素能非胆碱能（NANC）抑制介质如ATP、一氧化氮（NO）或神经降压素对格列本脲不敏感。这些功能数据表明，雷马卡林的舒张作用是由于格列本脲敏感的钾通道的特异性激活，这反过来又可以调节二氢吡啶敏感（电压依赖性）钙通道的活性。讨论了格列本脲敏感的钾通道在肠道平滑肌中的生理或病理生理作用；然而，它们似乎不参与所测试的NANC抑制介质的作用。
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