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

S. H. Padia, B. A. Kemp, N. L. Howell, H. M. Siragy, M.-C. Fournie-Zaluski, B. P. Roques, R. M. Carey
2006 Hypertension  
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
more » ... 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 0.05Ϯ0.01 mol/min in stepwise fashion to 0.11Ϯ0.01 mol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA Fϭ3.68; PϽ0.01). In angiotensin III combined with PC-18, the renal sodium excretion rate increased from 0.05Ϯ0.01 to 0.32Ϯ0.08 mol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA Fϭ6.2; PϽ0.001). 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 Ϯ PC-18 ϩ PD-123319. Angiotensin III plus PC-18 induced a greater natriuretic response than Ang III alone (overall ANOVA Fϭ16.9; Pϭ0.0001). 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. (Hypertension. 2007;49[part 2]:625-630.)
doi:10.1161/01.hyp.0000254833.85106.4d pmid:17190872 fatcat:4fyx5ns2unde5gcac5qmhjk5pm