The long term goal of this project is to gain a more complete understanding of the role of ion transport pathways in the regulation of pulmonary and renal arterial tone. This renewal application is based upon several advances made during the previous funding period and focuses on characterization of the role of intracellular Ca2+ stores and selected sarcolemmal ion channels in excitation-contraction coupling of isolated pulmonary and renal arterial smooth muscle cells (PASMC and RASMC). A combination of experimental approaches will be utilized to obtain cellular and molecular information which will be related back to the physiology of intact pulmonary and renal arteries. We will specifically determine the physiological role, biophysical and pharmacological properties and the molecular identity of nonselective cation channels and volume-regulated chloride channels in these specialized vascular beds. We will also examine the properties of ryanodine- and inositol triphosphate (IP3)-sensitive Ca2+i stores in RASMC and PASMC and identify any physiologically relevant interactions which may occur between these two stores and possible effects of Ca2+ released from these stores on sarcolemmal ion channels. Finally, we will test the hypotheses that alterations of Ca2+i stores, pHi, sarcolemmal K+, Ca2+ and/or CI- channels represent critical early events in the initiation of hypoxic pulmonary vasoconstriction. Despite the clinical relevance of these two vascular beds to a number of important disease processes, relatively little information is presently available on the role of ion channels and Ca2+i stores in the control of pulmonary and renal vascular tone. This study will help fill the existing gap of knowledge regarding the role of ion channels and Ca2+i stores in vascular reactivity of the renal and pulmonary circulation. The medical significance of this project is that the results obtained have significant potential of revealing new, important cellular mechanisms responsible for pulmonary and systemic hypertension and could lead to the development of new drugs and therapeutic strategies to treat or prevent these conditions.
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