KCa channels and conducted vasodilation

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DESCRIPTION (provided by applicant): The conduction of vasodilation reflects the spread of hyperpolarizing current along the vessel wall through gap junction channels, and serves to coordinate responses in serial and parallel segments of the resistance vasculature. The calcium-activated potassium channels (KCa) initiate hyperpolarizing responses, but their functional role in the initiation of conducted hyperpolarization and vasodilation is unclear. Using isolated, pressurized hamster retractor feed arteries my central aim is to investigate the function of the KCa in the initiation of conducted hyperpolarization and vasodilation. Unlike resistance microvessels isolated from the brain, these feed arteries are long (3-4 mm) and unbranched, and therefore ideal for studying the mechanisms of conducted vasodilation. Utilizing selective KCa blocker application in conjunction with diameter and electrophysiological measurements I will answer: 1) which KCa are necessary for the initiation of a conducted hyperpolarization and vasodilation, and 2) is the functional coupling between muscarinic receptor and KCa activation localized within respective abluminal and luminal domains of endothelial cells. A key factor in diabetes, hypertension, atherosclerosis, and stroke is endothelial dysfunction associated with the impaired ability to oppose vasoconstriction. Understanding the role of specific ion channels and resolving the polarity of endothelial cell-mediated vasodilation will provide new insight that may enhance the prevention and treatment of pathologies associated with vascular disease.