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(Circulation Research. 2000;86:1167.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Inability to Induce Hypertension in Normotensive Rat Expressing AT₁ Receptor Antisense

Alok S. Pachori, Hongwei Wang, Craig H. Gelband, Carlos M. Ferrario, Michael J. Katovich, Mohan K. Raizada

From the Hypertension and Vascular Disease Center (C.M.F.), Wake Forest University, Winston-Salem, NC, and the Departments of Physiology (H.-W.W., C.H.G., M.K.R.) and Pharmacodynamics (A.S.P., M.J.K.), University of Florida, Colleges of Medicine and Pharmacy, Gainesville, Fla.

Correspondence to Mohan K. Raizada, PhD, Department of Physiology, College of Medicine, University of Florida, Box 100274, Gainesville, FL 32610. E-mail mraizada{at}phys.med.ufl.edu

Abstract—Our previous studies have shown that neonatal delivery of angiotensin type 1 receptor antisense (AT₁R-AS) in a retroviral vector prevents spontaneously hypertensive rats from developing hypertension for life but has no effect on blood pressure (BP) in normotensive animals. Based on these results, we hypothesized that AT₁R-AS transduction in normotensive rats would protect them from developing experimental hypertension. The present study was designed to evaluate this hypothesis. A single intracardiac administration of AT₁R-AS by a retroviral-mediated delivery system (LNSV-AT₁R-AS) in 5-day-old normotensive Sprague-Dawley rats resulted in long-term expression of the AT₁R-AS without an effect on basal BP. However, angiotensin II (Ang II)–induced BP, dipsogenic responses, and renovascular contractility were significantly attenuated in the LNSV–AT₁R-AS–treated rats. Chronic infusion of low-dose Ang II (55 ng · kg^-1 · min^-1) in LNSV-alone–treated rats caused a modest increase in BP, profound increase in cardiac hypertrophy, and increased vascular contractility. In contrast, the LNSV-AT₁R-AS–treated rats were protected from developing these changes after Ang II infusion. These data establish that LNSV-AT₁R-AS pretreatment protects healthy rats from developing Ang II–dependent hypertension.

Key Words: angiotensin II • gene therapy • renin-angiotensin system • angiotensin type 1 receptor • hypertension

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