Intrarenal Aminopeptidase N Inhibition Restores Defective Angiotensin II Type 2–Mediated Natriuresis in Spontaneously Hypertensive Rats

The preferred ligand of angiotensin (Ang) II type 2 (AT2R)–mediated natriuresis is Ang III. The major enzyme responsible for the metabolism of Ang III is aminopeptidase N, which is selectively inhibited by compound PC-18. In this study, urine sodium excretion rates (UNaV), fractional excretion of sodium, fractional excretion of lithium, glomerular filtration rate, and mean arterial pressures were studied in prehypertensive and hypertensive spontaneously hypertensive rats (SHRs) and compared with age-matched Wistar-Kyoto rats (WKYs). Although renal interstitial infusion of Ang II type 1 receptor blocker candesartan increased UNaV in WKYs from a baseline of 0.050.01 to 0.170.04 mol/min (P0.01), identical infusions failed to increase UNaV in hypertensive SHRs. Coinfusion of AT2R antagonist PD-123319 abolished the natriuretic responses to candesartan in WKYs, indicating an AT2R-mediated effect. AT2R-mediated natriuresis was enabled in hypertensive SHRs by inhibiting the metabolism of Ang III with PC-18 (0.050.01 to 0.110.03 mol/min; P0.05).

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