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 the type-2 (AT(2)) receptor are largely unknown. We investigated the role of the AT(2) receptor in the vascular and renal responses to physiological increases 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 slightly elevated systolic blood pressure (SBP) compared with that of wild-type (WT) control mice (P < 0.0001). In AT(2)-null mice, infusion of ANG II (4 pmol/kg/min) for 7 days produced a marked and sustained increase in SBP [from 116 ± 0.5 to 208 ± 1 mmHg (P < 0.0001) (1 mmHg = 133 Pa)] and reduction in urinary sodium excretion (U(Na)V) [from 0.6 ± 0.01 to 0.05 ± 0.002 mM/day (P < 0.0001)] whereas neither SBP nor U(Na)V 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 production, 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 ≈4-fold (P < 0.0001) whereas no changes were observed in AT(2)-null mice. These results demonstrate that the AT(2) receptor is necessary for normal physiological responses of BK and nitric oxide to ANG II. Absence of the AT(2) receptor leads to vascular and renal hypersensitivity to ANG II, including sustained antinatriuresis and hypertension. These results strongly suggest that the AT(2) receptor plays a counterregulatory protective role mediated via BK and nitric oxide against the antinatriuretic and pressor actions of ANG II.