The goals of this project are (a) to provide new information about the expression, regulation and protective influence of Ca2+- dependent K+ channels (K(Ca) channels) in cerebral arterial muscle membranes exposed to chronic hypertension, and (b) to determine if K(Ca) channels represent novel therapeutic targets to reduce cerebral vascular tone in this disease. Early results using Western methods show an increased expression of the alpha-subunit (pore-forming subunit) of K(Ca) channels in cerebral arterial muscle membranes from spontaneously hypertensive rats (SHR) as compared to normotensive Wistar Kyoto (WKY) rats. These data provide the first direct evidence that the expression of K(Ca) channels in cerebrovascular muscle membranes may be regulated by the in situ level of arterial blood pressure. Importantly, this increased expression of K(Ca) channels in cerebral smooth muscle membranes during hypertension appears to enhance K+ efflux through K(Ca) channels, because the PI observed higher levels of whole-cell and single-channel K(Ca) currents in patch-clamped vascular muscle membranes from hypertensive rats. Finally, vascular reactivity studies using the K(Ca) channel blocker, iberiotoxin, suggest that the upregulation of K(Ca) channels in cerebrovascular muscle membranes opposes vascular tone in the cerebral microcirculation during hypertension. First, iberiotoxin (100 nM)-induced block of K(Ca) channels profoundly depolarized and constricted isolated cerebral resistance arteries from SHR. Second, 10 nM iberiotoxin triggered intense constriction of in-situ SHR pial arterioles, whereas similar arterioles from WKY rats showed only moderate contractions in response to K(Ca) channel block. These results raise the possibility that an enhanced expression of K(Ca) channels in cerebrovascular muscle membranes may provide a powerful negative feedback pathway to oppose vascular constriction and promote cerebral perfusion during chronic hypertension. Based on these initial findings, the PI will investigate changes in the expression, functional role, and potential therapeutic benefit of cerebrovascular K(Ca) channels during chronic hypertension by: (a) applying Western methods to compare expression levels of K(Ca) channels in cerebral smooth muscle membranes from two models of normotensive and of hypertensive rats; (b) using patch-clamp methods to compare the whole-cell membrane density and single-channel properties of K(Ca) currents between cerebrovascular smooth muscle membranes from the same rats; and (c) employing the isolated vessel and the in-situ cranial window methods to evaluate the physiological role and therapeutic potential of K(Ca) channels as negative feedback pathways and therapeutic targets for opposing vascular tone in the cerebral microcirculation of hypertensive animals.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Pharmacology A Study Section (PHRA)
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Medical College of Wisconsin
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