Liu Pengchong, Xi Qi, Ahmed Abu, Jaggar Jonathan H, Dopico Alejandro M
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18217-22. doi: 10.1073/pnas.0406096102. Epub 2004 Dec 16.
Binge drinking is associated with increased risk for cerebrovascular spasm and stroke. Acute exposure to ethanol at concentrations obtained during binge drinking constricts cerebral arteries in several species, including humans, but the mechanisms underlying this action are largely unknown. In a rodent model, we used fluorescence microscopy, patch-clamp electrophysiology, and pharmacological studies in intact cerebral arteries to pinpoint the molecular effectors of ethanol cerebrovascular constriction. Clinically relevant concentrations of ethanol elevated wall intracellular Ca(2+) concentration and caused a reversible constriction of cerebral arteries (EC(50) = 27 mM; E(max) = 100 mM) that depended on voltage-gated Ca(2+) entry into myocytes. However, ethanol did not directly increase voltage-dependent Ca(2+) currents in isolated myocytes. Constriction occurred because of an ethanol reduction in the frequency (-53%) and amplitude (-32%) of transient Ca(2+)-activated K(+) (BK) currents. Ethanol inhibition of BK transients was caused by a reduction in Ca(2+) spark frequency (-49%), a subsarcolemmal Ca(2+) signal that evokes the BK transients, and a direct inhibition of BK channel steady-state activity (-44%). In contrast, ethanol failed to modify Ca(2+) waves, a major vasoconstrictor mechanism. Selective block of BK channels largely prevented ethanol constriction in pressurized arteries. This study pinpoints the Ca(2+) spark/BK channel negative-feedback mechanism as the primary effector of ethanol vasoconstriction.
暴饮与脑血管痉挛和中风风险增加有关。在包括人类在内的多个物种中，暴饮期间达到的乙醇浓度急性暴露会使脑动脉收缩，但其作用的潜在机制在很大程度上尚不清楚。在一个啮齿动物模型中，我们使用荧光显微镜、膜片钳电生理学以及对完整脑动脉进行药理学研究，以确定乙醇引起脑血管收缩的分子效应器。临床相关浓度的乙醇会升高血管壁细胞内Ca(2+)浓度，并导致脑动脉可逆性收缩（半数有效浓度[EC(50)] = 27 mM；最大效应浓度[E(max)] = 100 mM），这取决于电压门控Ca(2+)进入心肌细胞。然而，乙醇并不会直接增加分离的心肌细胞中电压依赖性Ca(2+)电流。收缩的发生是因为乙醇使瞬时Ca(2+)激活的K(+)（BK）电流的频率（-53%）和幅度（-32%）降低。乙醇对BK瞬变的抑制是由于Ca(2+)火花频率降低（-49%），Ca(2+)火花是一种引起BK瞬变的肌膜下Ca(2+)信号，以及对BK通道稳态活性的直接抑制（-44%）。相比之下，乙醇未能改变Ca(2+)波，Ca(2+)波是一种主要的血管收缩机制。选择性阻断BK通道在很大程度上可防止乙醇对加压动脉的收缩作用。本研究确定Ca(2+)火花/BK通道负反馈机制是乙醇血管收缩的主要效应器。
