The goal of this project is to provide a profile of the disease-specific expression of the Shaker (Kv1) gene family of voltage-gated K+ channels in the cerebral microcirculation of hypertensive rats. Our early results suggest that Shaker Kv1 channels upregulate in the cerebral circulation of normal Wistar Kyoto (WKY) rats during the maturation of the animal to emerge as predominant contributors to cerebral arterial membrane potential and diameter. However, this progression is highly suppressed in spontaneously hypertensive rats (SHR), in which maturation results in the exposure of the cerebral microcirculation to progressively higher blood pressure levels in vivo. Indeed, patch-clamped cerebrovascular smooth muscle cells from adult SHR show reduced Shaker Kv1 current compared to cells from normal Wistar Kyoto (WKY) rats, and this alteration is associated with smooth muscle cell depolarization and constriction. Notably, this vasoconstriction is regarded as a fundamental adaptive response of small cerebral arteries to the development of high blood pressure in vivo, which minimizes the damaging transmission of the high systemic pressure to the blood brain barrier. Based on these findings, and our evidence that the remodeling of K+ channels in the cerebral circulation critically protects this vascular bed from the lethal effects of high blood pressure, we will: (a) combine RT-PCR gene expression studies, Western blotting, and patch-clamp techniques to examine the expression and function of Shaker Kv1 channels in rat cerebrovascular smooth muscle cells during the development of genetic and renal forms of hypertension, and after correction of hypertension by vasodilator drugs (b) assess the physiological impact of these changes in Shaker Kv1 channel expression on the membrane potential and diameter of isolated cerebral arteries in vitro and arterioles in vivo, and (c) test the hypothesis that pressure-induced membrane depolarization is a triggering stimulus for the remodeling of Shaker Kv1 channels in the vascular smooth muscle membranes of the cerebral circulation.

R01HL059238

1998-03-01

2006-11-30