Losartan improves the natriuretic response to ANF in rats with high-output heart failure.
During severe congestive heart failure (CHF), a number of sodium-retaining and vasoconstricting mechanisms are activated, including the renin-angiotensin-aldosterone system. In CHF, the renal effects of atrial natriuretic factor (ANF) are attenuated. The interaction of these endocrine factors is a major determinant of the clinical course of CHF. This study was designed to evaluate the role of the renin-angiotensin-aldosterone system in the development of avid sodium retention in CHF, induced in rats by creation of an aorto-caval fistula. Rats with aorto-caval fistula either compensate and maintain a normal sodium balance (UNaV > 1400 microEq/day) or decompensate and develop severe sodium retention (UNaV < 200 microEq/day), which leads to severe CHF. Chronic treatment with losartan, an angiotensin II receptor blocker, 10 mg/day, resulted in dramatic natriuresis (UNaV > 1000 microEQ/day) in decompensated rats, but not in compensated rats or controls. ANF infusion (50 micrograms/kg/hr) increased fractional sodium excretion 46-fold in compensated rats, but only 18-fold in decompensated rats. A similar pattern of responsiveness to ANF was observed in urinary cyclic GMP excretion. Chronic losartan treatment restored the natriuretic and urinary cyclic GMP excretion responses of decompensated rats to ANF. The improvement in the natriuretic response after losartan treatment was associated with a suppression of the previously elevated plasma aldosterone. These results demonstrate the pivotal role of angiotensin II in the development of sodium retention and of the blunted renal response to ANF in CHF, and indicate why losartan is useful therapy for cardiac edema.
Abassi
Z A
ZA
Hypertension-Endocrine Branch, National Heart, Lund and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Kelly
G
G
Golomb
E
E
Klein
H
H
Keiser
H R
HR
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology* / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D019808:Losartan; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D009320:Atrial Natriuretic Factor; D012964:Sodium; D006152:Cyclic GMP; D019808:Losartan