Vaali K, Li L, Paakkari I, Vapaatalo H
Department of Pharmacology and Toxicology, University of Helsinki, Finland.
J Pharmacol Exp Ther. 1998 Jul;286(1):110-4.
The relaxing effects of the nitric oxide (NO) donors 1,2,3,4-oxatriazolium,3-(3-chloro-2-methylphenyl-5-[[(4-methoxyphe nyl) sulfonyl]amino]-,hydroxide inner salt (GEA 3268) 1,2,3,4-oxatriazolium,3-(3-chloro-2-methyphenyl-5-[methys ulfonyl)amino]- hydroxide inner salt (GEA 5145), 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP) were inhibited in vitro by iberiotoxin (IbTX) and charybdotoxin (ChTX), the two selective inhibitors of Ca(++)-activated K+ channels (KCa) in guinea pig trachea. When studied in cumulative concentrations in metacholine constriction, the relaxing effects of the NO donors were inhibited by at least 70% in the presence of the toxins, with the exception of SIN-1 in the presence of ChTX. The inhibitory effect of ChTX was less marked than that of IbTX. This suggests that the relaxing effects of the structurally different NO donors are mediated through KCa channels and that IbTX is more potent than ChTX. A selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one (ODQ), significantly inhibited the relaxing effects of GEA 3268 and GEA 5145 on metacholine and KCl constriction and almost totally inhibited the relaxing effects of SIN-1 and SNAP. The inhibitor of the delayed rectifier K+ channel current 4-aminopyridine did not influence the relaxations of the NO donors, and under the experimental conditions of this study, the ATP-sensitive K+ channel inhibitor glibenclamide had no effect. In conclusion, the relaxing effects of the structurally different NO-releasing compounds are mediated via KCa channels. However, the significance of some other possible mechanisms unrelated to K+ channels cannot be excluded.
一氧化氮（NO）供体1,2,3,4 - 恶二唑鎓，3 - （3 - 氯 - 2 - 甲基苯基） - 5 - [[（4 - 甲氧基苯基）磺酰基]氨基] - 氢氧化物内盐（GEA 3268）、1,2,3,4 - 恶二唑鎓，3 - （3 - 氯 - 2 - 甲基苯基） - 5 - [甲磺酰基）氨基] - 氢氧化物内盐（GEA 5145）、3 - 吗啉代 sydnonimine（SIN - 1）和S - 亚硝基 - N - 乙酰青霉胺（SNAP）的舒张作用在体外被iberiotoxin（IbTX）和charybdotoxin（ChTX）抑制，这两种是豚鼠气管中Ca（++）激活的K + 通道（KCa）的选择性抑制剂。当在乙酰甲胆碱收缩实验中以累积浓度进行研究时，在毒素存在的情况下，NO供体的舒张作用至少被抑制70%，ChTX存在时的SIN - 1除外。ChTX的抑制作用不如IbTX明显。这表明结构不同的NO供体的舒张作用是通过KCa通道介导的，并且IbTX比ChTX更有效。可溶性鸟苷酸环化酶的选择性抑制剂1H - [1,2,4]恶二唑并[4,3 - a]喹唑啉 - 1 - 酮（ODQ）显著抑制GEA 3268和GEA 5145对乙酰甲胆碱和氯化钾收缩的舒张作用，并且几乎完全抑制SIN - 1和SNAP的舒张作用。延迟整流K + 通道电流抑制剂4 - 氨基吡啶不影响NO供体的舒张作用，并且在本研究的实验条件下，ATP敏感性K + 通道抑制剂格列本脲没有作用。总之，结构不同的NO释放化合物的舒张作用是通过KCa通道介导的。然而，不能排除一些与K + 通道无关的其他可能机制的重要性。
