Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor.
The angiotensin subtype-1 (AT(1)) receptor mediates renal prostaglandin E(2) (PGE(2)) production, and pharmacological blockade of the angiotensin subtype-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 prostaglandin metabolism in mice with targeted deletion of the AT(2) receptor gene. Mice lacking the AT(2) receptor (AT(2)-null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT(2)-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF(1alpha) (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(1alpha) in response to dietary sodium restriction and Ang II infusion. In contrast, AT(2)-null mice had lower PGF(2alpha) levels compared with WT mice during basal conditions and in response to dietary sodium restriction or 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 Ang 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 treated AT(2)-null and WT mice with indomethacin for 14 days. PGI(2), PGE(2), and cAMP were markedly decreased in both WT and AT(2)-null mice. Blood pressure increased to hypertensive levels in AT(2)-null mice but was unchanged in WT. These results demonstrate that in the absence of the AT(2) receptor, increased vasodilator prostanoids protect against the development of hypertension.
Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
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HM
Siragy
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Senbonmatsu
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Ichiki
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Inagami
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Carey
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004039:Diet, Sodium-Restricted; D015232:Dinoprostone / Q000096:biosynthesis*; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D006973:Hypertension / Q000517:prevention & control*; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000502:physiology*; D014664:Vasodilation
D011945:Receptors, Angiotensin; D000804:Angiotensin II; D011464:Epoprostenol; D000242:Cyclic AMP; D015232:Dinoprostone; D007213:Indomethacin