Dilation of cerebral arteries increases blood flow in the brain. Cerebral artery tone is regulated by a number of substances including neurotransmitters, neuropeptides, endothelial-derived factors, metabolites, and pharmacological agents. Despite the importance of this vascular bed, rather little is known about the mechanisms of dilation. This proposal focuses on the mechanism of synthetic and physiological dilators of cerebral arteries that act through membrane hyperpolarization. The pharmacological agents (e.g. cromakalim and pinacidil) have generated substantial excitement as a promising new class of vasodilator. The physiological dilators that will be examined are a recently identified endothelial-derived hyperpolarizing factor (EDHF) of unknown composition and the peptide dilators, vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptide (CGRP). These peptides, which are among the most potent dilating substances known, have been shown to elevate cyclic AMP in smooth muscle. We will use a combination of approaches, including intact artery force and diameter measurements, smooth muscle membrane potential measurements from intact arteries, and single channel measurements from dissociated arterial smooth muscle cells, to investigate the mechanisms of vasodilator action in cerebral arteries. Specifically, we propose to test the hypothesis that pharmacological vasodilators and physiological vasodilators (EDHF, VIP, CGRP, cAMP) act by increasing currents through ATP-sensitive potassium channels. The mechanism of action of these vasodilators as well as of K+ channel blockers that reverse vasodilation will be determined directly at the single channel level. The possibility that VIP and CGRP also dilate by closing voltage-dependent calcium channels will be examined. Elucidation of the membrane mechanisms by which vasodilators act will represent a major advance in the understanding of ATP-sensitive K+ channels, of vasodilation and regulation of cerebral blood flow, and provide new possibilities for treatment of hypertension, cerebral vasospasm, vascular headache, angina and heart failure.
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