New beta-blocker: prolonged reduction in high blood pressure with beta(1) antisense oligodeoxynucleotides.

Abstract

beta-Blockers are widely used for hypertension treatment but must be taken daily. We have developed a novel beta-blocker by targeting beta(1)-adrenergic receptor (beta(1)-AR) mRNA with antisense oligodeoxynucleotides (beta(1)-AS-ODN). A single intravenous injection of beta(1)-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 beta(1)-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 beta(1)-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 beta(1)-AR, because radioligand binding assay and quantitative autoradiography showed a 35% reduction in beta(1)-AR levels in kidney but no change in beta(2)-AR. beta(1)-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 beta(1)-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 beta(1)-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 beta(1)-AS-ODN.