Feleder E C, Adler-Graschinsky E
Instituto de Investigaciones Farmacológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
Eur J Pharmacol. 1997 Jan 29;319(2-3):229-38. doi: 10.1016/s0014-2999(96)00843-6.
The effects of two 'K+ channel openers', (+/-)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl )-2 H-benzo[b]-pyran-3-ol (cromakalim) and 7-chloro-3-methyl-2 H-1,2,4-benzothiadiazine 1,1-dioxide (diazoxide), were studied on the rat isolated mesenteric bed. Differences in the perfusion pressure were measured as a parameter of vascular resistance. Cromakalim (0.1-700 microM) and diazoxide (1 microM-1 mM) reduced to 60% the contractions elicited by 10 microM noradrenaline and to 30% those evoked by 100 mM KCl. The relaxant effects of cromakalim and diazoxide on the noradrenaline-induced contractions were reduced by the K(+)-ATP channel blocker, 5-chloro-N-[2-[4-[[[(cyclohexylamino) carbonyl]amino]-sulfonyl]phenyl]ethyl]-2-methoxybenzamide (glibenclamide, 0.01-0.3 microM), endothelium removal with 0.1% saponin and pretreatment with the nitric oxide synthesis inhibitor, S(+/-)-N5-[imino(nitroamino)methyl]-L-ornithine methyl ester hydrochloride (L-NAME, 500 microM). Reductions in the relaxant responses after endothelium removal or L-NAME pretreatment were observed with 1-100 microM cromakalim and with 30 microM diazoxide but not with 100 and 300 microM diazoxide. Pretreatment with the inactive stereoisomer D-NAME as well as with the prostanoid synthesis inhibitor, 1-[p-chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid (indomethacin, 10 microM), did not affect the reductions in contractile responses to noradrenaline caused by either cromakalim or diazoxide. It is concluded that the relaxant effects of cromakalim and diazoxide in the rat mesenteric bed are endothelium-mediated and L-NAME-sensitive and could at least partially involve the participation of nitric oxide.
研究了两种“钾通道开放剂”，即（±）-6-氰基-3,4-二氢-2,2-二甲基-反式-4-（2-氧代-1-吡咯烷基）-2H-苯并[b]吡喃-3-醇（克罗卡林）和7-氯-3-甲基-2H-1,2,4-苯并噻二嗪1,1-二氧化物（二氮嗪）对大鼠离体肠系膜床的作用。测量灌注压力的差异作为血管阻力的参数。克罗卡林（0.1 - 700微摩尔）和二氮嗪（1微摩尔 - 1毫摩尔）可将10微摩尔去甲肾上腺素引起的收缩降低至60%，将100毫摩尔氯化钾引起的收缩降低至30%。钾-ATP通道阻滞剂5-氯-N-[2-[4-[[[(环己基氨基)羰基]氨基]-磺酰基]苯基]乙基]-2-甲氧基苯甲酰胺（格列本脲，0.01 - 0.3微摩尔）、用0.1%皂苷去除内皮以及用一氧化氮合成抑制剂S（±）-N5-[亚氨基（硝基氨基）甲基]-L-鸟氨酸甲酯盐酸盐（L-NAME，500微摩尔）预处理可降低克罗卡林和二氮嗪对去甲肾上腺素诱导收缩的舒张作用。在用1 - 100微摩尔克罗卡林和30微摩尔二氮嗪处理后观察到去除内皮或L-NAME预处理后舒张反应降低，但100和300微摩尔二氮嗪处理后未观察到这种情况。用无活性的立体异构体D-NAME以及前列腺素合成抑制剂1-[对氯苯甲酰基]-5-甲氧基-2-甲基吲哚-3-乙酸（吲哚美辛，10微摩尔）预处理，并不影响克罗卡林或二氮嗪引起的对去甲肾上腺素收缩反应的降低。得出结论，克罗卡林和二氮嗪在大鼠肠系膜床的舒张作用是内皮介导的且对L-NAME敏感，并且至少部分可能涉及一氧化氮的参与。
