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(Circulation. 2000;101:682.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Antisense Inhibition of ß₁-Adrenergic Receptor mRNA in a Single Dose Produces a Profound and Prolonged Reduction in High Blood Pressure in Spontaneously Hypertensive Rats

Yuan Clare Zhang, BS; Jonathan D. Bui, PhD; Leping Shen, BS; M. Ian Phillips, PhD, DSc

From the Department of Physiology, School of Medicine, University of Florida, Gainesville.

Correspondence to Dr M. Ian Phillips, Department of Physiology, School of Medicine, University of Florida, Box 100274, Gainesville, FL 32610. E-mail mip{at}phys.med.ufl.edu

Background—ß-Blockers are the first line of therapy for hypertension. However, they are associated with side effects because of central nervous system (CNS) effects and ß₂-adrenergic antagonism. To overcome these problems and provide a long-term ß₁-blockade, antisense oligonucleotides against rat ß₁-adrenergic receptor (ß₁-AR) mRNA (ß₁-AS-ODN) were designed and tested for the ability to inhibit cardiac ß₁-ARs as well as lower blood pressure in spontaneously hypertensive rats (SHRs).

Methods and Results—Radioligand binding assay showed that a single intravenous injection of ß₁-AS-ODN delivered in cationic liposomes significantly decreased cardiac ß₁-AR density by 30% to 50% for 18 days (P<0.01), with no effect on ß₂-ARs. This was accompanied by marked attenuation of ß₁-AR–mediated positive inotropic response in isolated perfused hearts in vitro (P<0.02) and in conscious SHRs monitored by telemetry in vivo (P<0.02). Furthermore, the blood pressure of SHRs was reduced for 20 days, with a 38 mm Hg maximum drop. Heart rate was not significantly decreased. Quantitative autoradiography was performed to assess ß₁-AS-ODN effects on the CNS, which demonstrated no changes in ß₁-ARs in brain, in contrast to a significant reduction in heart and kidney (P<0.05). For comparison with ß-blockers, the effects of atenolol on cardiovascular hemodynamics were examined, which lowered blood pressure for only 10 hours and elicited appreciable bradycardia in SHRs.

Conclusions—These results indicate that ß₁-AS-ODN, a novel approach to specific ß₁-blockade, has advantages over currently used ß-blockers in providing a profound and prolonged reduction in blood pressure without affecting heart rate, ß₂-ARs, and the CNS. Diminished cardiac contractility resulting from less ß₁-AR expression contributes to the antihypertensive effect.

Key Words: gene therapy • receptors, adrenergic, beta • hypertension • contractility

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