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

Abstract

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 n 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.