The major goal of this project is to elucidate the physiological and pathological role of endothelial and smooth muscle cells in the modulation of vascular responsiveness in normotensive and genetically hypertensive rat strains. The underlying hypothesis is that an abnormality in the regulation of cation transport in renal vascular smooth muscle cells predisposes the organism to hypertension; the critical lesion may be intrinsic to the smooth muscle cell or to the endothelium which regulates vascular reactivity. Renal vascular reactivity will be examined in Wistar (W), Wistar- Kyoto (WKY), and spontaneously hypertensive rat (SHR) strains in order to determine the role of the endothelium in the regulation of vascular function and responsiveness. The vasoregulatory role of our newly discovered endothelial inhibitor of the Na+ pump, as well as that of endothelium-derived relaxing and constricting factors, will be determined in normotensive and hypertensive rat strains. Smooth muscle and endothelial cells will be cultured from arteries and microvessels of W, WKY, and SHR strains. We will compare the following parameters in the smooth muscle cells cultured from the 3 rat strains: 1) basal and neurohormone- evoked increases in cytoplasmic free Ca2+; 2) Ca2+ channel activity; 3) passive Na+ permeability and the specific activities of 3 distinct Na+ transporters--the Na+/H+ antiporter, the Na+/Ca+ antiporter, and the Na+/K+/C1- cotransporter. We will integrate the results of the vascular reactivity and cell culture studies. By pharmacologically correcting specific defects in ion transport their contribution, if any, to the increased vascular responsiveness of isolated blood vessels from the SHR strain will be determined. Smooth muscle and endothelial cells from SHR and WKY strains will be co-cultured. The co-cultures will be used to determine how the endothelial cells modulate hormone-induced changes in free Ca2+ in the muscle cells and to find out if cultured endothelial cells produce a factor that inhibits the Na+ pump in the muscle cells. Cyclic GMP production by endothelium-derived relaxing factor will be measured in the co-cultures in order to determine if there is a defect in relaxing factor production or responsiveness in SHR.
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