The overall objective of this research program is to understand the mechanisms and physiologic significance of the renin-andiotensin-system, functioning locally within the kidney, in the control of renal function. The proposed studies will be performed in conscious dogs implanted with renal artery catheters. The initial experiments will be devoted to isolation of the renin-angiotensin system intrarenally, independent of systemic angiotensin action. Thus, the quantities of angiotensin II antagonist and angiotensin converting enzyme inhibitor which are confined to the kidney during intrarenal administration will be determined. Subsequently, the effects of these intrarenally contained blockers of the renin-angiotensin system on renal function will be ascertained. The quantitiy of angiotensin II restricted to the kidney dutring intrarenal administration also will be documented, and the specificity of the angiotension blockers will be calculated by concurrent administration of intrarenally confined angiotensin II and blocker. The renal effects of a new, specific dog renin inhibitor will be studied. The role of suppresssion of the renin-angiotensin system intrarenally in real escape from the sodium-retaining action of mineralocorticoids will be investigated. First, the degree of renin-angiotensin suppression during the escape phase of ll-deoxycorticosterone acetate (DOCA) administration will be observed. Subsequently, studies will attempt to demonstrate that the escape phase during DOCA administration is attenuated ot abolished by intrarenal administration of angiotensin II and can be enhanced by intrarenal administration of specific angiotension blocking agents. To elucidate the relative physiologic role of angitensin intra- and extra-renally, renal responses to intrarenal angiotensin blockers will be studied at differing levels of sodium balance. The mechanisms of the intrarenal action of angiotensin will be investigated systematically. An attempt will be made to dissociate renal tubular from vascular actions. The role of the kallekrein-kinin and prostaglandin systems will be investigated by means of selective intrerenal inhibition of kallekrein and cyclooxygenase during intrarenal administration of angiotensin inhibitors. The proposed studies will clarify the mechanisms and physiologic importance of angiotensin II acting as local modulator of renal sodium and water homeostasis. This issue is at the forefront of investigations of basic cardiovascular and renal control and mechanisms of edema-forming states and hypertension.
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