The angiotensin subtype-l (AT(1)) receptor mediates renal prostaglandin E-2
(PGE(2)) production, and pharmacological blockade of the angiotensin subty
pe-2 (AT(2)) receptor potentiates the action of angiotensin II (Ang II) to
increase PGE(2) levels. We investigated the role of the AT(2) receptor in p
rostaglandin metabolism in mice with targeted deletion of the AT(2) recepto
r gene. Mice lacking the AT(2) receptor (AT(2)-null) had normal blood press
ure that was sightly elevated compared with that of wild-type (WT) control
mice. AT(2)-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF(
1 alpha) (a stable hydrolysis product of prostacyclin [PGI(2)]) and PGE(2)
levels than did WT mice, and had similar increases in PGE(2) and 6-keto-PGF
(1 alpha) in response to dietary sodium restriction and Ang II infusion. In
contrast, AT(2)-null mice had lower PGF(2 alpha) levels compared with WT m
ice during basal conditions and in response to dietary sodium restriction o
r infusion of Ang II. RIF cAMP was markedly higher in AT(2)-null mice than
in WT mice, both during basal conditions and during sodium restriction or A
ng II infusion. AT(1) receptor blockade with losartan decreased PGE(2), PGI
(2), and cAMP to levels observed in WT mice. To determine whether increased
vasodilator prostanoids prevented hypertension in AT(2)-null mice, we trea
ted AT(2)-null and WT mice with indomethacin for 14 days. PGI(2), PGE(2), a
nd cAMP were markedly decreased in both WT and AT(2)-null mice. Blood press
ure increased to hypertensive levels in AT(2)-null mice but was unchanged i
n WT. These results demonstrate that in the absence of the AT(2) receptor,
increased vasodilator prostanoids protect against the development of hypert
ension.