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(Hypertension. 2002;40:735.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Essential Role of AT_1A Receptor in the Development of 2K1C Hypertension

Ludk ervenka; Vladislav Horáek; Ivana Vanková; Jaroslav A. Hubáek; Michael I. Oliverio; Thomas M. Coffman; L. Gabriel Navar

From the Center for Experimental Cardiovascular Research, Institute for Clinical and Experimental Medicine (L..), V.H., I.V., J.A.H.), Prague, Czech Republic; Department of Medicine, Duke University, Winston-Salem, and Durham Veterans Affairs Medical Center (M.I.O., T.M.C.), Durham, NC; Department of Physiology, Tulane University School of Medicine (L.G.N.), New Orleans, La; and Department of Physiology, Second Medical Faculty, Charles University (L..), Prague, Czech Republic.

Correspondence to Ludk ervenka, MD, PhD, Center for Experimental Cardiovascular Research, Institute for Clinical and Experimental Medicine, 1958/9 Videská, CZ-140 21 Prague 4, Czech Republic. E-mail luce{at}medicon.cz

The aims of this study were to delineate the relative contribution of angiotensin II (ANG II) subtype 1A (AT_1A) and 1B (AT_1B) receptors to the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in mice, to examine if increased nitric oxide synthase (NOS) activity counteracts the vasoconstrictor influences of ANG II in 2K1C hypertensive mice, and to determine the role of ANG II type 2 (AT₂) receptors in 2K1C hypertension in mice. AT_1A ANG II receptor knockout (AT_1A-/-) and wild-type (AT_1A+/+) mice underwent clipping of the right renal artery. Systolic blood pressure (SBP) was significantly lower in AT_1A-/- compared with AT_1A+/+ mice, and neither clip placement nor AT₂ receptor blockade with PD 123319 (PD) altered SBP in AT_1A-/- mice. A significant and sustained rise in SBP from 119±5 to 163±6 mm Hg was observed in the 2K1C AT_1A+/+ mice from day 10 to day 26. Chronic PD infusion did not alter the course of hypertension in 2K1C/AT_1A+/+. Acute PD infusion did not alter mean arterial pressure (MAP) in AT_1A+/+, PD/AT_1A+/+, 2K1C/AT_1A+/+, PD/2K1C/AT_1A+/+, AT_1A-/-, PD/AT_1A-/-, and PD/2K1C/AT_1A-/- mice compared with basal levels. In contrast, acute PD infusion caused significant increases in MAP in 2K1C/AT_1A-/- mice. The subsequent acute NOS inhibition caused greater increases in MAP in 2K1C/AT_1A+/+ and PD/2K1C/AT_1A+/+ mice than in AT_1A+/+ and PD/AT_1A+/+ mice. These results support the essential role of AT_1A receptors in mediating 2K1C hypertension and support the hypothesis that augmented NO production serves as a counteracting system in this model of hypertension.

Key Words: mice • receptors, angiotensin II • hypertension, renovascular • nitric oxide synthase • nitric oxide

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