Van Crombruggen K, Lefebvre R A
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
Neurogastroenterol Motil. 2004 Feb;16(1):81-98. doi: 10.1046/j.1365-2982.2003.00454.x.
Responses of rat distal colon circular muscle strips to exogenous nitric oxide (NO) and adenosine 5'-triphosphate (ATP) and to electrical field stimulation (EFS) were assessed in the absence/presence of various agents that interfere with nitrergic-purinergic pathways. Exogenous NO (10-6 to 10-4 mol L-1) elicited concentration-dependent, tetrodotoxin (TTX)-insensitive relaxations. The soluble guanylyl-cyclase (sGC) inhibitor 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced duration and amplitude; the small conductance Ca2+-sensitive K+ (SK)-channel blocker apamin (APA) only shortened the relaxations. ODQ + APA showed a marked inhibitory effect on duration and amplitude. TTX, APA, the NO-synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) and the purinergic receptor P2Y antagonist Reactive Blue 2 (RB2) shortened the relaxations by exogenous ATP (10-3 mol L-1) but did not influence the amplitude. ODQ had no effect. TTX + l-NAME did not yield a more pronounced inhibitory effect than TTX alone. The effect of ATP-gamma-S was similar to that of ATP. Electrical field stimulation (EFS) (40 V, 0.05 ms, 0.5-4 Hz for 30 s) yielded TTX-sensitive relaxations that were not altered by l-NAME, ODQ or RB2. APA shortened the relaxations. l-NAME + APA nearly abolished these relaxations. ODQ + APA and RB2 +l-NAME reduced the duration. These results suggest that distinct sets of small conductance SK-channels are involved in the amplitude and the duration of the relaxations and that NO increases their sensitivity to NO and ATP via guanosine 3',5'-cyclic monophosphate (cGMP). ATP elicits relaxations via P2Y receptors with subsequent activation of SK-channels and induces neuronal release of NO. Both nitrergic and purinergic pathways must be blocked to inhibit EFS-induced relaxations.
在存在/不存在各种干扰氮能-嘌呤能途径的药物的情况下，评估大鼠远端结肠环形肌条对外源性一氧化氮（NO）、5'-三磷酸腺苷（ATP）和电场刺激（EFS）的反应。外源性NO（10-6至10-4 mol/L）引起浓度依赖性、对河豚毒素（TTX）不敏感的舒张。可溶性鸟苷酸环化酶（sGC）抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）缩短了舒张的持续时间和幅度；小电导Ca2+敏感钾（SK）通道阻滞剂蜂毒明肽（APA）仅缩短了舒张时间。ODQ + APA对持续时间和幅度有显著抑制作用。TTX、APA、一氧化氮合酶抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）和嘌呤能受体P2Y拮抗剂活性蓝2（RB2）缩短了外源性ATP（10-3 mol/L）引起的舒张，但不影响幅度。ODQ没有作用。TTX + L-NAME没有比单独使用TTX产生更明显的抑制作用。ATP-γ-S的作用与ATP相似。电场刺激（EFS）（40 V，0.05 ms，0.5 - 4 Hz，持续30 s）产生对TTX敏感的舒张，L-NAME、ODQ或RB2对此无影响。APA缩短了舒张时间。L-NAME + APA几乎消除了这些舒张。ODQ + APA和RB2 + L-NAME缩短了持续时间。这些结果表明，不同组的小电导SK通道参与了舒张的幅度和持续时间，并且NO通过鸟苷3',5'-环磷酸（cGMP）增加了它们对NO和ATP的敏感性。ATP通过P2Y受体引起舒张，随后激活SK通道并诱导神经元释放NO。必须同时阻断氮能和嘌呤能途径才能抑制EFS诱导的舒张。
