Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor

Citation
Hm. Siragy et al., Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor, J CLIN INV, 104(2), 1999, pp. 181-188
Citations number
33
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
00219738 → ACNP
Volume
104
Issue
2
Year of publication
1999
Pages
181 - 188
Database
ISI
SICI code
0021-9738(199907)104:2<181:IRVPPH>2.0.ZU;2-4
Abstract
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.