Essential role for smooth muscle BK channels in alcohol-induced cerebrovascular constriction

Pengchong Liu, Qi Xi, Abu Ahmed, Jonathan Jaggar, Alejandro Dopico

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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 (EC 50 = 27 mM; Emax = 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 K+ (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 Ca 2+ spark/BK channel negative-feedback mechanism as the primary effector of ethanol vasoconstriction.

Original languageEnglish (US)
Pages (from-to)18217-18222
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number52
DOIs
StatePublished - Dec 28 2004

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Large-Conductance Calcium-Activated Potassium Channels
Constriction
Smooth Muscle
Ethanol
Alcohols
Cerebral Arteries
Binge Drinking
Muscle Cells
Intracranial Vasospasm
Electrophysiology
Vasoconstrictor Agents
Vasoconstriction
Fluorescence Microscopy
Rodentia
Arteries
Stroke
Pharmacology

All Science Journal Classification (ASJC) codes

  • General

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Essential role for smooth muscle BK channels in alcohol-induced cerebrovascular constriction. / Liu, Pengchong; Xi, Qi; Ahmed, Abu; Jaggar, Jonathan; Dopico, Alejandro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 52, 28.12.2004, p. 18217-18222.

Research output: Contribution to journalArticle

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