Increased Expression of Ca²⁺-Sensitive K⁺ Channels in the Cerebral Microcirculation of Genetically Hypertensive Rats

Evidence for Their Protection Against Cerebral Vasospasm

From the Department of Physiology, Cardiovascular Research Center (Y.L., A.G.H., N.J.R.), and the Department of Anesthesiology (A.G.H.), Medical College of Wisconsin, Milwaukee, and the Institute for Biochemical Pharmacology (H.-G.K.), University of Innsbruck (Austria).

Correspondence to Nancy J. Rusch, PhD, Associate Professor, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail nrusch{at}mcw.edu

Abstract—The Ca²⁺-sensitive K⁺ channel (K_Ca channel) plays a key role in buffering pressure-induced constriction of small cerebral arteries. An amplified current through this channel has been reported in vascular smooth muscle cells obtained from hypertensive animals, implying that the expression or properties of K_Ca channels may be regulated by in vivo blood pressure levels. In this study, we investigated this hypothesis and its functional relevance by comparing the properties, expression levels, and physiological role of K_Ca channels in cerebral resistance arteries from normotensive and genetically hypertensive rats. Whole-cell patch-clamp experiments revealed a 4.7-fold higher density of iberiotoxin-sensitive K_Ca channel current at physiological membrane potentials in spontaneously hypertensive rat (SHR) compared with Wistar-Kyoto (WKY) rat cerebrovascular smooth muscle cells (n=18 and 21, respectively). However, additional single-channel analysis in detached patches showed similar levels of unitary conductance, voltage, and Ca²⁺ sensitivity in K_Ca channels from WKY and from SHR membranes. In contrast, Western analysis using an antibody directed against the K_Ca channel -subunit revealed a 4.1-fold increase in the corresponding 125-kD immunoreactive signal in cerebrovascular membranes from SHR compared with WKY rats. The functional impact of this enhanced K_Ca channel expression was assessed in SHR and WKY rat pial arterioles, which were monitored by intravital microscopy through in situ cranial windows. Progressive pharmacological block of K_Ca channels by iberiotoxin (0.1 to 100 nmol/L) dose-dependently constricted pial arterioles from SHR and WKY rats (n=6 to 8). The arterioles in SHR constricted 2- to 4-fold more intensely, and vasospasm occurred in some vessels. These data provide the first direct evidence that elevated levels of in situ blood pressure induce K_Ca channel expression in cerebrovascular smooth muscle membranes. This homeostatic mechanism may critically regulate the resting tone of cerebral arterioles during chronic hypertension. Furthermore, the overexpression of distinct K⁺ channel types during specific cardiovascular pathologies may provide for the upregulation of novel disease-specific membrane targets for vasodilator therapies.

Key Words: cerebral circulation • K⁺ channel • vascular smooth muscle • hypertension • iberiotoxin

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