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(Hypertension. 1997;30:363.)
© 1997 American Heart Association, Inc.

Articles

Losartan Versus Gene Therapy

Chronic Control of High Blood Pressure in Spontaneously Hypertensive Rats

Di Lu; Mohan K. Raizada; Shridhar Iyer; Phyllis Reaves; Hong Yang; Michael J. Katovich

From the Department of Physiology, College of Medicine (D.L., M.K.R., P.R., H.Y.), and the Department of Pharmacodynamics, College of Pharmacy (S.I., M.J.K.), University of Florida, Gainesville.

Correspondence to Mohan K. Raizada, PhD, Professor and Associate Dean for Graduate Education, Department of Physiology, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610.

Abstract Interruption of the renin-angiotensin system by pharmacological manipulations attenuates high blood pressure (BP) in the spontaneously hypertensive rat (SHR). However, these agents, such as losartan, need to be administered daily to maintain effective BP control. Therefore, we have hypothesized that a genetic intervention in the expression of angiotensin type 1 receptor (AT₁R) should attenuate development of hypertension on a long-term basis in SHR. A retroviral-mediated AT₁R antisense cDNA gene delivery system (LNSV–AT₁R-AS) was used to test this hypothesis and to compare its BP-lowering effects with those of losartan. Introduction of LNSV–AT₁R-AS into 5-day-old Wistar-Kyoto rats and SHR resulted in a robust expression of AT₁R antisense (AS) within 3 days and persisted for at least 30 days. This expression was associated with a selective attenuation of high BP in SHR by 25 to 30 mm Hg. Although basal lowering of BP was exclusive to SHR, the angiotensin II (Ang II) pressor response was significantly reduced in all LNSV–AT₁R-AS–treated rats. The decreased response to Ang II was associated with a similar attenuation of Ang II–induced dipsogenic responses in both strains of rats. The BP-lowering effects of LNSV–AT₁R-AS treatment and losartan treatment were similar and primarily observed in SHR. However, the antihypertensive effect lasted less than 24 hours in losartan-treated SHR compared with 90 days in LNSV–AT₁R-AS–treated SHR. In addition, losartan was unable to further lower BP in LNSV–AT₁R-AS–treated SHR. Collectively, these results suggest that both losartan and LNSV–AT₁R-AS treatment produces an antihypertensive response selectively in SHR that is mediated by interruption of AT₁R function. However, a single, acute genetic treatment with LNSV–AT₁R-AS can result in long-term control of high BP at a similar level of effectiveness as losartan, without altering plasma Ang II levels.

Key Words: AT₁ receptor • hypertension • gene transfer • gene therapy • blood pressure • angiotensin II

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