title: Intrarenal aminopeptidase N inhibition augments natriuretic responses to angiotensin III in angiotensin type 1 receptor-blocked rats.
abstract: 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 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 0.05+/-0.01 micromol/min in stepwise fashion to 0.11+/-0.01 micromol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=3.68; P<0.01). In angiotensin III combined with PC-18, the renal sodium excretion rate increased from 0.05+/-0.01 to 0.32+/-0.08 mumol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=6.2; P<0.001). 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 +/- PC-18 + PD-123319. Angiotensin III plus PC-18 induced a greater natriuretic response than Ang III alone (overall ANOVA F=16.9; P=0.0001). 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.
authors.affiliation: Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, VA 22908-1414, USA.
authors.forename: Shetal H
authors.initials: SH
authors.lastname: Padia
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Kemp
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Howell
authors.forename: Helmy M
authors.initials: HM
authors.lastname: Siragy
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournie-Zaluski
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000805:Angiotensin III / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D001713:Biphenyl Compounds; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D023421:Models, Animal; D009318:Natriuresis / Q000187:drug effects*; D045283:Natriuretic Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000187:drug effects*; D012964:Sodium / Q000652:urine; D013777:Tetrazoles / Q000008:administration & dosage
chemical_list: C472311:2-amino-4-methylsulfonyl butane thiol; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D045283:Natriuretic Agents; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000805:Angiotensin III; D012964:Sodium; D008715:Methionine; D018826:CD13 Antigens; C081643:candesartan