Winquist R J, Heaney L A, Wallace A A, Baskin E P, Stein R B, Garcia M L, Kaczorowski G J
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania.
J Pharmacol Exp Ther. 1989 Jan;248(1):149-56.
BRL 34915 [6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl) 2H-benzo(b) pyran-3-ol], minoxidil sulfate and diazoxide may relax vascular smooth muscle via hyperpolarization due to an opening of membrane potassium channels. We therefore examined the effects of several potassium channel antagonists on the relaxation response to these vasodilators in isolated rat portal venous strips which were mounted in vitro for detecting changes in isometric force. BRL 34915 (IC50 = 4.7 X 10(-8) M), minoxidil sulfate (IC50 = 1.4 X 10(-7) M) and diazoxide (IC50 = 5 X 10(-6) M) elicited concentration-dependent relaxations of the spontaneous, myogenic contractions in venous strips. The relatively nonselective potassium channel antagonists tetraethylammonium ion (0.3-10 X 10(-3) M) and 4-aminopyridine (1-10 X 10(-3) M) caused concentration-dependent shifts (5- to 50-fold) in the relaxation responses to each vasodilator. Charybdotoxin (up to 10(-7) M) and apamin (up to 10(-7) M), known to be antagonists of high and low conductance calcium-activated potassium channels, respectively, had no inhibitory effect on the relaxation-response curves to BRL 34915, minoxidil sulfate or diazoxide. Glyburide (10(-7) to 3 X 10(-5) M), a sulfonylurea which has been shown to block the ATP-modulated potassium channel in insulin-secreting cells, caused concentration-dependent shifts to the right (up to 100-fold) of the IC50 value for BRL 34915 and diazoxide, and at 10(-6) M, abolished the relaxation response to minoxidil sulfate.(ABSTRACT TRUNCATED AT 250 WORDS)
BRL 34915 [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]、硫酸米诺地尔和二氮嗪可能通过膜钾通道开放导致的超极化作用来舒张血管平滑肌。因此，我们研究了几种钾通道拮抗剂对离体大鼠门静脉条带中这些血管舒张剂舒张反应的影响，这些门静脉条带被安装在体外以检测等长力的变化。BRL 34915（IC50 = 4.7×10⁻⁸ M）、硫酸米诺地尔（IC50 = 1.4×10⁻⁷ M）和二氮嗪（IC50 = 5×10⁻⁶ M）引起静脉条带中自发性肌源性收缩的浓度依赖性舒张。相对非选择性的钾通道拮抗剂四乙铵离子（0.3 - 10×10⁻³ M）和4-氨基吡啶（1 - 10×10⁻³ M）使对每种血管舒张剂的舒张反应产生浓度依赖性的位移（5至50倍）。已知分别为高电导和低电导钙激活钾通道拮抗剂的蝎毒素（高达10⁻⁷ M）和蜂毒明肽（高达10⁻⁷ M）对BRL 34915、硫酸米诺地尔或二氮嗪的舒张反应曲线没有抑制作用。格列本脲（10⁻⁷至3×10⁻⁵ M）是一种磺酰脲类药物，已被证明可阻断胰岛素分泌细胞中的ATP调节钾通道，它使BRL 34915和二氮嗪的IC50值产生浓度依赖性的右移（高达100倍），并且在10⁻⁶ M时，消除了对硫酸米诺地尔的舒张反应。（摘要截断于250字）
