Quast U, Baumlin Y
Sandoz Pharma Ltd., Basel, Switzerland.
Eur J Pharmacol. 1991 Aug 6;200(2-3):239-49. doi: 10.1016/0014-2999(91)90578-e.
The effects of the K+ channel opener cromakalim on phasic contractions induced by noradrenaline and caffeine were studied in the rat isolated mesenteric bed. In the presence of 1.4 mM Ca2+, 1-s pulses of noradrenaline increased the perfusion pressure of the preparation concentration dependently (midpoint at 92 +/- 10 microM noradrenaline). Cromakalim (0.3 and 1 microM) inhibited these contractions in a non-competitive manner. Contractions elicited by 1-s pulses of noradrenaline (100 microM) were inhibited by the dihydropyridine Ca2+ antagonist isradipine by maximally 24 +/- 1%, indicating that only a minor component of this contraction depended on Ca2+ entry via dihydropyridine-sensitive Ca2+ channels. Cromakalim was a much more effective inhibitor of these contractions (maximum inhibition by 80%, midpoint of the inhibition curve at 171 +/- 15 nM). The effect of cromakalim was stereoselective, inhibited by the sulphonylurea glibenclamide, and abolished in partially depolarizing media (KCl = 35 and 50 mM). In Ca(2+)-free medium, cromakalim inhibited the contraction induced by noradrenaline (100 microM) by maximally 69 +/- 4%, with a midpoint at 58 +/- 14 nM. The effect of cromakalim was again stereoselective, inhibited by glibenclamide, and abolished in the presence of 50 mM KCl. Contractions induced by caffeine (10 and 100 microM) were not affected by cromakalim (1 microM). The results indicate that, in rat mesenteric resistance vessels, cromakalim interferes with the ability of noradrenaline, but not caffeine, to mobilize Ca2+ from intracellular stores. The antivasoconstrictor effect of cromakalim against noradrenaline is inhibited by glibenclamide and appears to be linked to the ability of cromakalim to hyperpolarize the cell membrane.
在大鼠离体肠系膜床中研究了钾通道开放剂克罗卡林对去甲肾上腺素和咖啡因诱导的相性收缩的影响。在存在1.4 mM钙离子的情况下，1秒脉冲的去甲肾上腺素使标本的灌注压呈浓度依赖性增加（半数有效浓度为92±10 μM去甲肾上腺素）。克罗卡林（0.3和1 μM）以非竞争性方式抑制这些收缩。1秒脉冲的去甲肾上腺素（100 μM）引起的收缩被二氢吡啶类钙拮抗剂伊拉地平最大抑制24±1%，表明该收缩中只有一小部分依赖于通过二氢吡啶敏感性钙通道的钙内流。克罗卡林是这些收缩的更有效抑制剂（最大抑制率为80%，抑制曲线的半数有效浓度为171±15 nM）。克罗卡林的作用具有立体选择性，被磺酰脲类格列本脲抑制，并在部分去极化介质（氯化钾=35和50 mM）中消失。在无钙培养基中，克罗卡林最大抑制去甲肾上腺素（100 μM）诱导的收缩69±4%，半数有效浓度为58±14 nM。克罗卡林的作用再次具有立体选择性，被格列本脲抑制，并在50 mM氯化钾存在时消失。咖啡因（10和100 μM）诱导的收缩不受克罗卡林（1 μM）影响。结果表明，在大鼠肠系膜阻力血管中，克罗卡林干扰去甲肾上腺素而非咖啡因从细胞内储存中动员钙离子的能力。克罗卡林对去甲肾上腺素的抗血管收缩作用被格列本脲抑制，并且似乎与克罗卡林使细胞膜超极化的能力有关。
