title: The angiotensin type II receptor tonically inhibits angiotensin- converting enzyme in AT2 null mutant mice.
abstract: BACKGROUND
  Pharmacologic inhibition of the angiotensin-converting enzyme (ACE) limits angiotensin II (Ang II)-induced vasoconstriction and cellular proliferation. There is emerging evidence that some of the beneficial effects of ACE inhibitors may be endogenously available through the angiotensin receptor type 2 (AT2).
  
  
  METHODS
  To evaluate whether AT2 modulates ACE activity, we used an high-performance liquid chromatography (HPLC)-based enzymatic assay in tissues from AT2 knockout mice (Agtr2-/y) and cultured cells. These studies were complimented by physiologic studies of pharmacologic inhibition of AT2.
  
  
  RESULTS
  Circulating (C) and tissue ACE activities in heart (H), lung (L), and kidney (K) were doubled in Agtr2-/y mice compared with wild-type mice [162.9 +/- 17.6 mU/mL (C), 97.7 +/- 20.7 (H), 6282.1 +/- 508.3 (L), and 2295.0 +/- 87.0 (K) mU/g tissue for Agtr2-/y vs. 65.3 +/- 35.4 mU/mL (C), 44.5 +/- 8.7 (H), 3392.4 +/- 495.2 (L), and 1146.1 +/- 217.3 (K) mU/g tissue for wild-type mice, P < or = 0.05, 0.025, 0.002, and 0.0001, respectively]. Acute pharmacologic inhibition of AT2 [PD123319 (PD), 50 microg/kg/min, i. v.] significantly increased ACE activity in kidneys of wild-type mice (1591.2 +/- 104.4 vs. 1233.6 +/- 88.0 mU/g tissue in saline-infused mice, P < 0.05; P < 0.01 vs. uninfused, wild-type mice). Moreover, ACE activity increased in A10 cells exposed to PD (10-6 mol/L) together with Ang II (10-7 mol/L), but not with an AT1 antagonist (losartan, 10-6 mol/L). This heightened ACE activity appears functionally relevant because infusion of angiotensin I caused more prompt hypertension in Agtr2-/y mice than in wild-type littermates. Likewise, infusion of bradykinin, also a substrate for ACE, caused significantly less hypotension in Agtr2-/y mice than controls.
  
  
  CONCLUSIONS
  These studies indicate that AT2 functions to decrease ACE activity tonically, which may, in part, underlie AT2's increasingly recognized attenuation of AT1-mediated actions.
authors.affiliation: Division of Pediatric Nephrology, Department of Biochemistry, and Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Hunley
authors.forename: M
authors.initials: M
authors.lastname: Tamura
authors.forename: B J
authors.initials: BJ
authors.lastname: Stoneking
authors.forename: H
authors.initials: H
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Ichiki
authors.forename: T
authors.initials: T
authors.lastname: Inagami
authors.forename: V
authors.initials: V
authors.lastname: Kon
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000032:analysis / Q000097:blood*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D013737:Testis / Q000201:enzymology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; C073402:PD 123319; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin