The overall objective of this research is to provide an understanding of the integrated regulation of body fluid homeostasis and arterial blood pressure in experimental hypertension. A large body of evidence derived from both clinical and laboratory investigations illustrates the close relationship between these two important physiological processes, and points to an abnormality in this relationship as a likely factor in the pathogenesis of hypertension. The central hypothesis of this project is that humoral factors involved in regulating body fluid volume and electrolyte concentration contribute to hypertension development by affecting neurogenic control of arterial pressure. There is evidence that this neurohumoral mechanism is most important in long-term pressure regulation, and that its relative impact on arterial pressure is modulated by other physiological factors (e.g., salt intake). The proposed experiments will test the hypothesis that hypertension can be caused by increased responsiveness of this mechanism to blood-borne angiotensin II, a key hormone in body fluid homeostasis. A potential interaction of endothelin-a newly-discovered vasoactive peptide produced by endothelial cells-with angiotensin II in the long-term control of arterial pressure also will be explored. All studies will be conducted in conscious Sprague-Dawley rats instrumented for Chronic direct measurement of arterial pressure. Salt intake will be controlled by intravenous administration of sodium chloride, and sodium and water balance carefully quantitated in all experiments. Most protocols will involve long-term (1-2 weeks) intravenous infusion of angiotensin II or endothelin; and measurement of both immediate, and more slowly developing, increases in arterial pressure. Inhibitors of endogenous angiotensin II formation, and drugs-which block AT1 type angiotensin II receptors, will be employed as tools to dissect the role of circulating angiotensin 11 in various experimental models of hypertension, including: 2K,IC Goldblatt (renovascular); reduction in renal mass (subtotal nephrectomy) plus high salt intake; and chronic intravenous infusion of endothelin. These investigations should provide additional insight into the mechanism through which the renin-angiotensin system participates in the pathogenesis of hypertension and by extension, into the mechanism of action of antihypertensive drugs which interfere with this system.
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