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 AT(1) 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 AT(1) 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 AT(1) receptor in mediating detrimental renal and adrenal properties of diuretics in human CHF. AT(1) 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 AT(1) receptor blockade for human CHF requiring acute diuretics to improve renal hemodynamic and tubular function and to suppress aldosterone.
Chen
Horng H
HH
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA. chen.horng@mayo.edu
Redfield
Margaret M
MM
Nordstrom
Linda J
LJ
Cataliotti
Alessandro
A
Burnett
John C
JC
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D018592:Cross-Over Studies; D004232:Diuretics / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005665:Furosemide / Q000009:adverse effects* / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D019808:Losartan / Q000627:therapeutic use*; D044140:Receptor, Angiotensin, Type 1; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood
D057911:Angiotensin Receptor Antagonists; D004232:Diuretics; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000450:Aldosterone; D005665:Furosemide; D012083:Renin; D019808:Losartan