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(Hypertension. 2007;49:625.)
© 2007 American Heart Association, Inc.

Original Articles, Part 2

Intrarenal Aminopeptidase N Inhibition Augments Natriuretic Responses to Angiotensin III in Angiotensin Type 1 Receptor–Blocked Rats

Shetal H. Padia; Brandon A. Kemp; Nancy L. Howell; Helmy M. Siragy; Marie-Claude Fournie-Zaluski; Bernard P. Roques; Robert M. Carey

From the Division of Endocrinology and Metabolism (S.H.P., B.A.K., N.L.H., H.M.S., R.M.C.), Department of Internal Medicine, University of Virginia Health System, Charlottesville; and Institut National de la Sante et de la Recherche Medicale U36 (M.-C.F.-Z., B.P.R.), UFR des Sciences Pharmaceutiques et Biologigues, Universite Rene Descartes, Paris, France.

Correspondence to Robert M. Carey, PO Box 801414, University of Virginia Health System, Charlottesville, VA 22908-1414. E-mail rmc4c{at}virginia.edu

The renal angiotensin angiotensin type 2 receptor has been shown to mediate natriuresis, and angiotensin III, not angiotensin II, may be the preferential angiotensin type 2 receptor activator of this response. Angiotensin III is metabolized to angiotensin IV by aminopeptidase N. The present study hypothesizes that inhibition of aminopeptidase N will augment natriuretic responses to intrarenal angiotensin III in angiotension type 1 receptor–blocked rats. Rats received systemic candesartan for 24 hours before the experiment. After a 1-hour control, cumulative renal interstitial infusion of angiotensin III at 3.5, 7, 14, and 28 nmol/kg per minute (each dose for 30 minutes) or angiotensin III combined with aminopeptidase N inhibitor PC-18 was administered into 1 kidney. The contralateral control kidney received renal interstitial infusion of vehicle. In kidneys infused with angiotensin III alone, renal sodium excretion rate increased from 0.05±0.01 µmol/min in stepwise fashion to 0.11±0.01 µmol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=3.68; P<0.01). In angiotensin III combined with PC-18, the renal sodium excretion rate increased from 0.05±0.01 to 0.32±0.08 µmol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=6.2; P<0.001). The addition of intrarenal PD-123319, an angiotensin type 2 receptor antagonist, to renal interstitial angiotensin III plus PC-18 inhibited the natriuretic response. Mean arterial blood pressure and renal sodium excretion rate from control kidneys were unchanged by angiotensin III ± PC-18 + PD-123319. Angiotensin III plus PC-18 induced a greater natriuretic response than Ang III alone (overall ANOVA F=16.9; P=0.0001). Aminopeptidase N inhibition augmented the natriuretic response to angiotensin III, suggesting that angiotensin III is a major agonist of angiotensin type 2 receptor–induced natriuresis.

Key Words: angiotensin • sodium • natriuresis • angiotensin III • AT₂ receptor • AT₁ receptor

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