title: Conversion of renal angiotensin II to angiotensin III is critical for AT2 receptor-mediated natriuresis in rats.
abstract: In the kidney, angiotensin II (Ang II) is metabolized to angiotensin III (Ang III) by aminopeptidase A (APA). In turn, Ang III is metabolized to angiotensin IV by aminopeptidase N (APN). Renal interstitial (RI) infusion of Ang III, but not Ang II, results in angiotensin type-2 receptor (AT(2)R)-mediated natriuresis. This response is augmented by coinfusion of PC-18, a specific inhibitor of APN. The present study addresses the hypotheses that Ang II conversion to Ang III is critical for the natriuretic response. Sprague-Dawley rats received systemic angiotensin type-1 receptor (AT(1)R) blockade with candesartan (CAND; 0.01 mg/kg/min) for 24 hours before and during the experiment. After a control period, rats received either RI infusion of Ang II or Ang II+PC-18. The contralateral kidney received a RI infusion of vehicle in all rats. Mean arterial pressure (MAP) was monitored, and urinary sodium excretion rate (U(Na)V) was calculated separately from experimental and control kidneys for each period. In contrast to Ang II-infused kidneys, U(Na)V from Ang II+PC-18-infused kidneys increased from a baseline of 0.03+/-0.01 to 0.09+/-0.02 micromol/min (P<0.05). MAP was unchanged by either infusion. RI addition of PD-123319, an AT(2)R antagonist, inhibited the natriuretic response. Furthermore, RI addition of EC-33, a selective APA inhibitor, abolished the natriuretic response to Ang II+PC-18. These data demonstrate that RI addition of PC-18 to Ang II enables natriuresis mediated by the AT(2)R, and that conversion of Ang II to Ang III is critical for this response.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908-1414, USA. shp6a@virginia.edu
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: 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: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000805:Angiotensin III / Q000096:biosynthesis*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D018826:CD13 Antigens / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D005260:Female; D043384:Glutamyl Aminopeptidase / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D012982:Sodium, Dietary / Q000494:pharmacology; D013451:Sulfonic Acids / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C472311:2-amino-4-methylsulfonyl butane thiol; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C101968:EC 33; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D012982:Sodium, Dietary; D013451:Sulfonic Acids; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; C073402:PD 123319; D008715:Methionine; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase; C081643:candesartan