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(Hypertension. 2008;51:460.)
© 2008 American Heart Association, Inc.

Original Articles Part 2

Conversion of Renal Angiotensin II to Angiotensin III Is Critical for AT₂ Receptor–Mediated Natriuresis In Rats

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

From the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville.

Correspondence to Dr Shetal H. Padia, P.O. Box 801414, University of Virginia Health System, Charlottesville, VA 22908-1414. E-mail shp6a{at}virginia.edu

In the kidney, angiotensin II (Ang II) is metabolized to angiotensin III (Ang III) by aminopeptidase A (APA). In turn, Ang III is metabolized to angiotensin IV by aminopeptidase N (APN). Renal interstitial (RI) infusion of Ang III, but not Ang II, results in angiotensin type-2 receptor (AT₂R)-mediated natriuresis. This response is augmented by coinfusion of PC-18, a specific inhibitor of APN. The present study addresses the hypotheses that Ang II conversion to Ang III is critical for the natriuretic response. Sprague-Dawley rats received systemic angiotensin type-1 receptor (AT₁R) blockade with candesartan (CAND; 0.01 mg/kg/min) for 24 hours before and during the experiment. After a control period, rats received either RI infusion of Ang II or Ang II+PC-18. The contralateral kidney received a RI infusion of vehicle in all rats. Mean arterial pressure (MAP) was monitored, and urinary sodium excretion rate (U_NaV) was calculated separately from experimental and control kidneys for each period. In contrast to Ang II–infused kidneys, U_NaV from Ang II+PC-18-infused kidneys increased from a baseline of 0.03±0.01 to 0.09±0.02 µmol/min (P<0.05). MAP was unchanged by either infusion. RI addition of PD-123319, an AT₂R antagonist, inhibited the natriuretic response. Furthermore, RI addition of EC-33, a selective APA inhibitor, abolished the natriuretic response to Ang II+PC-18. These data demonstrate that RI addition of PC-18 to Ang II enables natriuresis mediated by the AT₂R, and that conversion of Ang II to Ang III is critical for this response.

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