Coldwell M C, Howlett D R
Beecham Pharmaceuticals, Medicinal Research Centre, Harlow, Essex, U.K.
Biochem Pharmacol. 1987 Nov 1;36(21):3663-9. doi: 10.1016/0006-2952(87)90017-7.
Experiments have been performed to investigate the specificity of the mechanism of action of the novel antihypertensive agent, BRL 34915. BRL 34915 (0.5-100 microM) and nicorandil (10-500 microM) stimulated the efflux of rubidium from preloaded rabbit isolated mesenteric arteries. BRL 34915 also caused an increase in the rubidium efflux rate constant in other vascular smooth muscles. Tetraethylammonium (0.1-30 mM) inhibited BRL 34915 (10 microM), nicorandil (100 microM) and potassium (30 mM) induced stimulations of rubidium efflux, but had no effect on noradrenaline (30 microM) induced efflux. Only noradrenaline induced efflux was inhibited by apamin (3-100 nM). Examination of other second messenger systems demonstrated that BRL 34915 (at concentrations up to 100 microM) did not have any appreciable effect on cGMP accumulation in rabbit mesenteric artery, cAMP or cGMP phosphodiesterase in rat heart, or cAMP and inositol phosphate accumulation in rat brain slices. Nicorandil (100 microM) caused a small increase in cGMP accumulation in rabbit mesenteric artery. Radioligand binding studies showed that BRL 34915 did not interact with dihydropyridine, 5-hydroxytryptamine, dopamine, alpha 1, alpha 2 or beta adrenoceptor binding sites. [3H]-BRL 34915 did not bind specifically to any site in any tissue studied, either in vitro or ex vivo. Thus we have been unable to demonstrate an effect of BRL 34915 other than of increasing potassium efflux in rabbit vascular smooth muscle. This lends support to other evidence suggesting that BRL 34915 relaxes vascular smooth muscle (and hence lowers blood pressure) by a novel, and specific, mechanism involving hyperpolarisation of the smooth muscle cell membrane.
已开展实验以研究新型抗高血压药物BRL 34915的作用机制特异性。BRL 34915（0.5 - 100微摩尔）和尼可地尔（10 - 500微摩尔）刺激了预先加载的兔离体肠系膜动脉中的铷外流。BRL 34915还使其他血管平滑肌中的铷外流速率常数增加。四乙铵（0.1 - 30毫摩尔）抑制BRL 34915（10微摩尔）、尼可地尔（100微摩尔）和钾（30毫摩尔）诱导的铷外流刺激，但对去甲肾上腺素（30微摩尔）诱导的外流无影响。只有蜂毒明肽（3 - 100纳摩尔）抑制去甲肾上腺素诱导的外流。对其他第二信使系统的研究表明，BRL 34915（浓度高达100微摩尔）对兔肠系膜动脉中的环鸟苷酸积累、大鼠心脏中的环腺苷酸或环鸟苷酸磷酸二酯酶，或大鼠脑片中的环腺苷酸和肌醇磷酸积累均无明显影响。尼可地尔（100微摩尔）使兔肠系膜动脉中的环鸟苷酸积累略有增加。放射性配体结合研究表明，BRL 34915不与二氢吡啶、5 - 羟色胺、多巴胺、α1、α2或β肾上腺素能受体结合位点相互作用。[3H] - BRL 34915在体外或体内均未特异性结合所研究的任何组织中的任何位点。因此，除了增加兔血管平滑肌中的钾外流外，我们无法证明BRL 34915有其他作用。这为其他证据提供了支持，表明BRL 34915通过一种涉及平滑肌细胞膜超极化的新型特异性机制使血管平滑肌松弛（从而降低血压）。
