Antisense Inhibition of b1-Adrenergic Receptor mRNA in a Single Dose Produces a Profound and Prolonged Reduction in High Blood Pressure in Spontaneously Hypertensive Rats

Background—b-Blockers are the first line of therapy for hypertension. However, they are associated with side effects because of central nervous system (CNS) effects and b2-adrenergic antagonism. To overcome these problems and provide a long-term b1-blockade, antisense oligonucleotides against rat b1-adrenergic receptor (b1-AR) mRNA (b1-AS-ODN) were designed and tested for the ability to inhibit cardiac b1-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 b1-AS-ODN delivered in cationic liposomes significantly decreased cardiac b1-AR density by 30% to 50% for 18 days (P,0.01), with no effect on b2-ARs. This was accompanied by marked attenuation of b1-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 b1-AS-ODN effects on the CNS, which demonstrated no changes in b1-ARs in brain, in contrast to a significant reduction in heart and kidney (P,0.05). For comparison with b-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 b1-AS-ODN, a novel approach to specific b1-blockade, has advantages over currently used b-blockers in providing a profound and prolonged reduction in blood pressure without affecting heart rate, b2-ARs, and the CNS. Diminished cardiac contractility resulting from less b1-AR expression contributes to the antihypertensive effect. (Circulation. 2000;101:682-688.)