This application requests support for a study characterizing the properties of ion channels in two different vascular smooth muscle preparations: renal and pulmonary arteries. Single smooth muscle cells will be dispersed from canine and rat arteries and whole-cell and single channel recording techniques will be used to characterize the properties of Ca2+, K+, CI- and receptor-operated channels in these cells. Elucidation of the properties of these ionic conductances will provide important fundamental information which will establish the viability and usefulness of these new preparations as appropriate single cell models of the renal and pulmonary vasculature for subsequent studies of ion channel regulation by a variety of hormones and physiological stimuli. The specific effects of hormones such as angiotensin II, arginine vasopressin, neuropeptide Y, norepinephrine and endothelin on ionic currents and intracellular [Ca2|] will be determined for the first time in these clinically relevant vascular preparations. The results of these studies should provide a quantitative description of the mechanism of hormonal modulation of vascular tone in renal and pulmonary arteries. The effects of physiological stimuli such as hypoxia will also be compared and contrasted in these two preparations in terms of alterations in ion channel function and changes in intracellular [Ca2+]. These studies should have direct relevance to several important clinical diseases. Systemic vascular responses to hypoxia represent physiological autoregulatory mechanisms for the local control of blood flow. Pulmonary vasoconstriction in response to hypoxia is a mechanism which diverts blood flow away from hypoxic alveoli to better ventilated regions of the lung. This acute hypoxic pressor response is unique to pulmonary arteries, since systemic vessels usually dilate in response to hypoxia. Although alterations in the hypoxic pulmonary response are implicated in diseases such as right ventricular hypertrophy and cor pulmonale, the underlying mechanism is unknown despite decades of intensive research. The possible role of ion channels in this response has not been investigated previously. The proposed studies on renal arterial cells are important since alterations in the regulation of renal blood flow have been implicated in various renal vascular disorders such as vasospasm and certain forms of hypertension. Despite the clinical relevance of these two vascular beds to a number of important disease processes, relatively little information is currently available on the properties of ion channels in these preparations or their role in excitation-contraction coupling. This study will help to fill the existing gap of knowledge regarding the relationship between ion channel modulation and vascular reactivity in the renal and pulmonary vasculature.
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