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Essential Role for Smooth Muscle BK Channels in Alcohol-Induced Cerebrovascular Constriction
Pengchong Liu, Qi Xi, Abu Ahmed, Jonathan H. Jaggar and Alejandro M. Dopico
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 52 (Dec. 28, 2004), pp. 18217-18222
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3374220
Page Count: 6
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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 Ca2+ concentration and caused a reversible constriction of cerebral arteries ( EC50=27 mM; E max=100 mM) that depended on voltage-gated Ca2+ entry into myocytes. However, ethanol did not directly increase voltage-dependent Ca2+ currents in isolated myocytes. Constriction occurred because of an ethanol reduction in the frequency (-53%) and amplitude (-32%) of transient Ca2+-activated Ca2+ (BK) currents. Ethanol inhibition of BK transients was caused by a reduction in Ca2+ spark frequency (-49%), a subsarcolemmal Ca2+ signal that evokes the BK transients, and a direct inhibition of BK channel steady-state activity (-44%). In contrast, ethanol failed to modify Ca2+ waves, a major vasoconstrictor mechanism. Selective block of BK channels largely prevented ethanol constriction in pressurized arteries. This study pinpoints the Ca2+ spark/BK channel negative-feedback mechanism as the primary effector of ethanol vasoconstriction.
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences