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

Abstract

The preferred ligand of angiotensin (Ang) II type 2 (AT(2)R)-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 (U(Na)V), 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 U(Na)V in WKYs from a baseline of 0.05+/-0.01 to 0.17+/-0.04 micromol/min (P<0.01), identical infusions failed to increase U(Na)V in hypertensive SHRs. Coinfusion of AT(2)R antagonist PD-123319 abolished the natriuretic responses to candesartan in WKYs, indicating an AT(2)R-mediated effect. AT(2)R-mediated natriuresis was enabled in hypertensive SHRs by inhibiting the metabolism of Ang III with PC-18 (0.05+/-0.01 to 0.11+/-0.03 micromol/min; P<0.05). The defects in sodium excretion were present before the onset of hypertension in SHRs, because young WKYs demonstrated double the U(Na)V of SHRs (0.04+/-0.006 versus 0.02+/-0.003 micromol/min; P<0.01) at baseline. The increased U(Na)V of young WKYs was attributed to reduced renal proximal tubule sodium reabsorption, because increases in fractional excretion of sodium were paralleled by increases in fractional excretion of lithium. Renal interstitial PC-18 infusion ameliorated defective AT(2)R-mediated natriuresis in young SHRs by increasing fractional excretion of sodium and fractional excretion of lithium without changing the glomerular filtration rate. Thus, increased renal proximal tubule sodium retention is observed before the onset of hypertension in SHRs, and inhibition of the metabolism of Ang III ameliorates this pathophysiologic defect in sodium excretion.