Antisense Inhibition of β1-Adrenergic Receptor mRNA in a Single Dose Produces a Profound and Prolonged Reduction in High Blood Pressure in Spontaneously Hypertensive Rats

Background —β-Blockers are the first line of therapy for hypertension. However, they are associated with side effects because of central nervous system (CNS) effects and β2 -adrenergic antagonism. To overcome these problems and provide a long-term β1 -blockade, antisense oligonucleotides against rat β1 -adrenergic receptor (β1 -AR) mRNA (β1 -AS-ODN) were designed and tested for the ability to inhibit cardiac β1 -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 β1 -AS-ODN delivered in cationic liposomes significantly decreased cardiac β1 -AR density by 30% to 50% for 18 days (P <0.01), with no effect on β2 -ARs. This was accompanied by marked attenuation of β1 -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 β1 -AS-ODN effects on the CNS, which demonstrated no changes in β1 -ARs in brain, in contrast to a significant reduction in heart and kidney (P <0.05). For comparison with β-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 β1 -AS-ODN, a novel approach to specific β1 -blockade, has advantages over currently used β-blockers in providing a profound and prolonged reduction in blood pressure without affecting heart rate, β2 -ARs, and the CNS. Diminished cardiac contractility resulting from less β1 -AR expression contributes to the antihypertensive effect.