New beta-blocker - Prolonged reduction in high blood pressure with beta(1)antisense oligodeoxynucleotides

beta-Blockers are widely used for hypertension treatment but must be taken daily. We have developed a novel beta-blocker by targeting beta(1)-adrenerg ic receptor (beta(1)-AR) mRNA with antisense oligodeoxynucleotides (beta(1) -AS-ODN). A single intravenous injection of beta(1)-AS-ODN significantly re duced cardiac contractility and blood pressure (38+/-5 mm Hg, P<0.05) in sp ontaneously hypertensive rats for 3 weeks. In the present study, we improve d the antihypertensive effect of beta(1)-AS-ODN by delivery with the cation ic liposomes DOTAP/DOPE and studied its impact on the peripheral renin-angi otensin 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 hyp otension, 2.5 was determined to be the optimal charge ratio, which decrease d 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 quantit ative 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 mRN A levels in renal cortex by 37% 4 days after administration. This transient effect was followed by a delayed yet marked diminution of plasma renin act ivity and plasma angiotensin II levels on days 10 and 17 (P<0.01). The resu lts show that beta(1)-AS-ODN has an effective long-term antihypertensive ef fect up to 33 days with a single intravenous injection. The mechanism appea rs 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.