Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT(2)) angiotensin receptor

The vast majority of the known biological effects of the renin-angiotensin system are mediated by the type-1 (AT(1)) receptor, and the functions of th e type-2 (AT(2)) receptor are largely unknown. We investigated the role of the AT2 receptor in the vascular and renal responses to physiological incre ases in angiotensin II (ANG II) in mice with targeted deletion of the AT(2) receptor gene. Mice lacking the AT(2) receptor (AT(2)-null mice) had sligh tly elevated systolic blood pressure (SEP) compared with that of wild-type (WT) control mice (P < 0.0001). In AT(2)-null mice, infusion of ANG II (4 p mol/kg/min) for 7 days produced a marked and sustained increase in SEP [fro m 116 +/- 0.5 to 208 +/- 1 mmHg (P < 0.0001) (1 mmHg = 133 Pa)] and reducti on in urinary sodium excretion (UNaV) [from 0.6 +/- 0.01 to 0.05 +/- 0.002 mM/day (P < 0.0001)] whereas neither SEP nor UNaV changed in WT mice. AT(2) -null mice had low basal levels of renal interstitial fluid bradykinin (BK) , and cyclic guanosine 3',5'-monophosphate, an index of nitric oxide produc tion, compared with WT mice. In WT mice, dietary sodium restriction or ANG II infusion increased renal interstitial fluid BK, and cyclic guanosine 3', 5'-monophosphate by approximate to 4-fold (P < 0.0001) whereas no changes w ere observed in AT(2)-null mice. These results demonstrate that the AT(2) r eceptor is necessary for normal physiological responses of BK and nitric ox ide to ANG II. Absence of the AT(2) receptor leads to vascular and renal hy persensitivity to ANG II, including sustained antinatriuresis and hypertens ion. These results strongly suggest that the AT(2) receptor plays a counter regulatory protective role mediated via BK and nitric oxide against the ant inatriuretic and presser actions of ANG II.