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(Hypertension. 2000;35:219.)
© 2000 American Heart Association, Inc.

Scientific Contributions

New ß-Blocker

Prolonged Reduction in High Blood Pressure With ß₁ Antisense Oligodeoxynucleotides

Yuan Clare Zhang; Birgitta Kimura; Leping Shen; M. Ian Phillips

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, 1600 SW Archer Rd, Gainesville, FL 32610. E-mail mip{at}phys.med.ufl.edu

Abstract—ß-Blockers are widely used for hypertension treatment but must be taken daily. We have developed a novel ß-blocker by targeting ß₁-adrenergic receptor (ß₁-AR) mRNA with antisense oligodeoxynucleotides (ß₁-AS-ODN). A single intravenous injection of ß₁-AS-ODN significantly reduced cardiac contractility and blood pressure (38±5 mm Hg, P<0.05) in spontaneously hypertensive rats for 3 weeks. In the present study, we improved the antihypertensive effect of ß₁-AS-ODN by delivery with the cationic liposomes DOTAP/DOPE and studied its impact on the peripheral renin-angiotensin system. Five charge ratios (±) of liposome/ODN from 0 to 3.5 were tested to deliver 0.5 mg/kg ß₁-AS-ODN intravenously in spontaneously hypertensive rats (n=30). On the basis of the magnitude and duration of hypotension, 2.5 was determined to be the optimal charge ratio, which decreased blood pressure by up to 35 mm Hg for 20 to 33 days (P<0.05). The effects were specific for ß₁-AR, because radioligand binding assay and quantitative autoradiography showed a 35% reduction in ß₁-AR levels in kidney but no change in ß₂-AR. ß₁-AS-ODN diminished the preprorenin mRNA levels in renal cortex by 37% 4 days after administration. This transient effect was followed by a delayed yet marked diminution of plasma renin activity and plasma angiotensin II levels on days 10 and 17 (P<0.01). The results show that ß₁-AS-ODN has an effective long-term antihypertensive effect up to 33 days with a single intravenous injection. The mechanism appears to be through reduced ß₁-AR number specifically and reduced cardiac contractility. The inhibition of the renin-angiotensin system is probably a second mechanism to produce the sustained antihypertensive effect of ß₁-AS-ODN.

Key Words: antisense • ß₁-adrenergic receptors • blood pressure • renin-angiotensin system • kidney

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