Angiotensin II AT₁ receptor antagonism prevents detrimental renal actions of acute diuretic therapy in human heart failure

Although effective in relieving symptoms of edema in congestive heart failure (CHF), diuretic-induced natriuresis may be associated with reductions in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), which subsequently may reduce the duration of natriuresis. Moreover, recent studies have reported that the preservation of GFR is an important predictor of survival in human CHF. We hypothesized that the acute detrimental renal hemodynamic and tubular responses to furosemide in symptomatic human CHF will be attenuated by AT₁ receptor blockade with losartan. We defined the renal hemodynamic and tubular actions and aldosterone responses to furosemide (40 mg, orally) in the presence of acute AT₁ receptor antagonism (losartan, MSD, 50 mg orally) vs. placebo in 10 subjects with CHF (New York Heart Association II-III) in a double-blind, placebo-controlled crossover study. Furosemide with placebo increased sodium excretion and reduced ERPF and GFR (P < 0.05 vs. baseline). After 4 h, sodium excretion compared with baseline was decreased (P < 0.05). In contrast, furosemide with losartan resulted in a greater increase in sodium excretion but without reductions in ERPF and GFR (P < 0.05 vs. placebo). After 4 h, sodium excretion was greater compared with the placebo group. Importantly, plasma aldosterone tended to increase in the placebo group, whereas it was decreased (P < 0.05 vs. baseline) only in the losartan group. These studies underscore the pathophysiological role of the AT₁ receptor in mediating detrimental renal and adrenal properties of diuretics in human CHF. AT₁ receptor antagonism preserves GFR and renal blood flow and enhances sodium excretion during acute diuretic therapy in addition to inhibiting aldosterone secretion. These findings support the use of AT₁ receptor blockade for human CHF requiring acute diuretics to improve renal hemodynamic and tubular function and to suppress aldosterone.