To date, renal effects of losartan on renal function in human CHF remains undefined. If renal ANG II activation precedes increases in circulating ANG II, this process may play a fundamental step in the transition from ALVD to overt CHF. The broad objective of the current proposal is to define the role of ANG II in the regulation of renal hemodynamics and tubular function and in the control of sodium regulating hormones in humans with mild CHF. The working hypothesis of the current proposal is that AT1 receptor antagonism in mild human CHF will result in an improvement in GFR, a reduction in renal vascular resistance (RVR),in association wit a decrease in tubular sodium reabsorption and an increase in sodium excretion. Alternatively, if AT1 receptor antagonism results in an excessive reduction in arterial pressure, the predicted improvement in renal function may be abrogated.
The specific aims of the current study are: 1) To determine renal hemodynamic and tubular function and circulating sodium regulating hormones in humans with mild CHF receiving diuretics. 2) To determine renal hemodynamic and tubular function and circulating sodium regulating hormones in humans with mild CHF on diuretics. A total of 10 subjects will be studied in a double blind, placebo-control and cross over design. After up to three weeks of a fixed sodium diet, subjects will be admitted to the GCRC at Mayo Clinic, Rochester, MN, where they will undergo renal clearance test before and after oral administration of 50 mg losartan/placebo to determine the renal effects of losartan. Urinary samples for determination of volume, sodium, potassiu, PAH, inulin, ET, cGMP, ANP and BNP will be obtained at the end of each clearance period. Venous blood samples for PAH, insulin, Na, hematocrit, PRA, aldo, ANP, BNP, CNP, ET, NE, cGMP, losartain and ANG II will be obtained at the middle of each clearance period. After a two week washout period, the subjects will return to the GCRC for the cross-over study. This study will etablish for the first time the renal hemodynaimc and tubular effects of acute AT1 receptor inhibition in patients with mild heart failure on chronic diuretics. Thus, these studies will provide a new understanding of the role of intra-renal renin-angiotensin system in mild heart failure. This study should lay the foundation for further long term studies testing the hypothesis that AT1 receptor antagonism may delay the transition of ALVD to overt CHF in part via renal mechanisms. One patient was studied in the GCRC. The remainder of the studies were conducted in the Renal Laboratory on the downtown Mayo campus.
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