Miura H, Liu Y, Gutterman D D
Veterans Administration Medical Center, the Department of Internal Medicine, and Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Circulation. 1999 Jun 22;99(24):3132-8. doi: 10.1161/01.cir.99.24.3132.
K+ channel activation in vascular smooth muscle cells (VSMCs) plays a key role in regulating vascular tone. It has been proposed that endothelium-derived hyperpolarizing factor (EDHF) contributes to microvascular dilation more than nitric oxide (NO) does. Whether hyperpolarization is important for coronary arteriolar dilation in humans is not known. Bradykinin (BK), an endogenous vasoactive substance, is released from ischemic myocardium and regulates coronary resistance. Therefore, we tested the effects of inhibiting NO synthase, cyclooxygenase, and K+ channels on the changes in diameter and membrane potential (Em) in response to BK in isolated human coronary microvessels.
Arterioles (97+/-4 micrometers; n=120) dissected from human right atrial appendages (n=78) were cannulated at a distending pressure of 60 mm Hg and zero flow. Changes in vessel diameter (video microscopy) and VSMC Em (glass microelectrodes) were measured simultaneously. In vessels constricted and depolarized (Em; -50+/-3 to -28+/-2 mV) with endothelin-1 (ET), dilation to BK was associated with greater membrane hyperpolarization (-48+/-3 mV at 10(-6) mol/L) than dilation to sodium nitroprusside (SNP) (-34+/-2 mV at 10(-4) mol/L) for similar degrees of dilation. Treatment with Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/L), an NO synthase inhibitor, partially decreased dilation to BK (maximum dilation 61+/-10% versus control 92+/-4%; P<0.05). Charybdotoxin (CTX; 10(-8) mol/L), a large-conductance Ca2+-activated K+ channel blocker, or apamin (10(-7) mol/L), a small-conductance Ca2+-activated K+ channel blocker, inhibited both dilation (CTX 22+/-6% and apamin 45+/-10% versus control 69+/-6%; P<0.05) and membrane hyperpolarization (CTX -31+/-2 mV and apamin -37+/-2 mV versus control -44+/-2 mV; P<0.05) to BK, whereas glibenclamide (10(-6) mol/L), an ATP-sensitive K+ channel blocker, was without effect.
Vasodilation of human coronary arterioles to BK is largely dependent on membrane hyperpolarization by Ca2+-activated K+ channel activation, with apparently less of a role for endothelium-derived NO. This suggests a role for K+ channel activation in regulating human coronary arteriolar tone.
血管平滑肌细胞（VSMC）中的钾离子通道激活在调节血管张力中起关键作用。有人提出，内皮衍生的超极化因子（EDHF）对微血管舒张的作用比一氧化氮（NO）更大。超极化对人类冠状动脉小动脉舒张是否重要尚不清楚。缓激肽（BK）是一种内源性血管活性物质，从缺血心肌中释放出来并调节冠状动脉阻力。因此，我们测试了抑制一氧化氮合酶、环氧化酶和钾离子通道对离体人冠状动脉微血管中BK引起的直径和膜电位（Em）变化的影响。
从人右心耳（n = 78）中分离出的小动脉（97±4微米；n = 120）在60 mmHg的扩张压力和零流量下插管。同时测量血管直径（视频显微镜）和VSMC的Em（玻璃微电极）。在用内皮素-1（ET）使血管收缩和去极化（Em；-50±3至-28±2 mV）后，对于相似程度的舒张，BK引起的舒张与比硝普钠（SNP）（10⁻⁴ mol/L时为-34±2 mV）更大的膜超极化（10⁻⁶ mol/L时为-48±3 mV）相关。用一氧化氮合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME；10⁻⁴ mol/L）处理，部分降低了对BK的舒张（最大舒张61±10%，而对照组为92±4%；P<0.05）。大电导钙激活钾通道阻滞剂蝎毒素（CTX；10⁻⁸ mol/L）或小电导钙激活钾通道阻滞剂蜂毒明肽（10⁻⁷ mol/L）抑制了对BK的舒张（CTX为22±6%，蜂毒明肽为45±10%，而对照组为69±6%；P<0.05）和膜超极化（CTX为-31±2 mV，蜂毒明肽为-37±2 mV，而对照组为-44±2 mV；P<0.05），而ATP敏感性钾通道阻滞剂格列本脲（10⁻⁶ mol/L）则无作用。
人冠状动脉小动脉对BK的舒张很大程度上依赖于钙激活钾通道激活引起的膜超极化，内皮衍生的NO作用明显较小。这表明钾通道激活在调节人冠状动脉小动脉张力中起作用。
