LOSARTAN IMPROVES THE NATRIURETIC RESPONSE TO ANF IN RATS WITH HIGH-OUTPUT HEART-FAILURE

During severe congestive heart failure (CHF), a number of sodium-retai ning and vasoconstricting mechanisms are activated, including the reni n-angiotensin-aldosterone system. In CHF, the renal effects of atrial natriuretic factor (ANF) are attenuated. The interaction of these endo crine factors is a major determinant of the clinical course of CHF. Th is study was designed to evaluate the role of the renin-angiotensin-al dosterone system in the development of avid sodium retention in CHF, i nduced in rats by creation of an aorto-caval fistula. Rats with aorto- caval fistula either compensate and maintain a normal sodium balance ( UNaV > 1400 mu Eq/day) or decompensate and develop severe sodium reten tion (UNaV < 200 mu Eq/day), which leads to severe CHF. Chronic treatm ent with losartan, an angiotensin II receptor blocker, 10 mg/day, resu lted in dramatic natriuresis (UNaV > 1000 mu EQ/day) in decompensated rats, but not in compensated rats or controls. ANF infusion (50 mu g/k g/hr) increased fractional sodium excretion 46-fold in compensated rat s, but only 18-fold in decompensated rats. A similar pattern of respon siveness to ANF was observed in urinary cyclic GMP excretion. Chronic losartan treatment restored the natriuretic and urinary cyclic GMP exc retion responses of decompensated rats to ANF. The improvement in the natriuretic response after losartan treatment was associated with a su ppression 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.