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 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.