New β-Blocker

—β-Blockers are widely used for hypertension treatment but must be taken daily. We have developed a novel β-blocker by targeting β1 -adrenergic receptor (β1 -AR) mRNA with antisense oligodeoxynucleotides (β1 -AS-ODN). A single intravenous injection of β1 -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 β1 -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 β1 -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 β1 -AR, because radioligand binding assay and quantitative autoradiography showed a 35% reduction in β1 -AR levels in kidney but no change in β2 -AR. β1 -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 β1 -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 β1 -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 β1 -AS-ODN.