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The angiotensin type II receptor tonically inhibits angiotensin- converting enzyme in AT2 null mutant mice
T E Hunley1, M Tamura, B J Stoneking
1Division of Pediatric Nephrology, Department of Biochemistry, and Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA.
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.