Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

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Abstract
Whereas angiotensin (Ang) II is the major effector peptide of the renin–angiotensin system, its metabolite, des-aspartyl1-Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT1) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT2) blocker, on Na+excretion (UNaV) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on UNaV with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na+intake, RI CAND increased UNaV from 0.07±0.08 to 0.82±0.17 μmol/min (P+restriction, CAND increased UNaV from 0.06±0.02 to 0.1±0.02 μmol/min (PNaV. However, with systemic CAND infusion, RI Ang III increased UNaV from 0.08±0.01 μmol/min to 0.18±0.04 μmol/min (PNaV remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter UNaV at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT1receptor blockade engenders natriuresis by activation of AT2receptors. AT2receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT1receptor blockade.