The angiotensin type II receptor tonically inhibits angiotensin-convertingenzyme in AT2 null mutant mice

Background Pharmacologic inhibition of the angiotensin-converting enzyme (A CE) Limits angiotensin II (Ang II)-induced vasoconstriction and cellular pr oliferation. There is emerging evidence that some of the beneficial effects of ACE inhibitors may be endogenously available through the angiotensin re ceptor type 2 (AT2). Methods. To evaluate whether An modulates ACE activity, we used an high-per formance liquid chromatography (HPLC)-based enzymatic assay in tissues from AT2 knockout mice (Agtr2-/y) and cultured cells. These studies were compli mented by physiologic studies of pharmacologic inhibition of AT2. Results. Circulating (C) and tissue ACE activities in heart (H), lung (L), and kidney (1) were doubled in Agtr2-/y mice compared with wild-type mice [ 162.9 +/- 17.6 mU/mL (C), 97.7 +/- 20.7 (N), 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 less than or equal to 0.05, 0.025, 0.002, and 0.0001. re spectively]. Acute pharmacologic inhibition of ATL [PD123339 (PD), 50 mu g/ 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 mi ce, P < 0.05; P < 0.01 vs, uninfused, wild-type mice). Moreover, ACE activi ty increased in A10 cells exposed to PD (10(-6) mol/L) together with Ang ZI (10(-7) mol/L), but not with an ATI antagonist (losartan, 10(-6) mol/L). T his heightened ACE activity appears functionally relevant because infusion of angiotensin I caused more prompt hypertension in Agtr2-/y mice than in w ild-type littermates. Likewise, infusion of bradykinin, also a substrate fo r ACE, caused significantly less hypotension in Agtr2-/y mice than controls . Conclusions. These studies indicate that AT2 functions to decrease ACE acti vity tonically, which may, in part, underlie AT2's increasingly recognized attenuation of AT1-mediated actions.