title: Antisense inhibition of beta(1)-adrenergic receptor mRNA in a single dose produces a profound and prolonged reduction in high blood pressure in spontaneously hypertensive rats.
abstract: BACKGROUND
  beta-Blockers are the first line of therapy for hypertension. However, they are associated with side effects because of central nervous system (CNS) effects and beta(2)-adrenergic antagonism. To overcome these problems and provide a long-term beta(1)-blockade, antisense oligonucleotides against rat beta(1)-adrenergic receptor (beta(1)-AR) mRNA (beta(1)-AS-ODN) were designed and tested for the ability to inhibit cardiac beta(1)-ARs as well as lower blood pressure in spontaneously hypertensive rats (SHRs).
  
  
  RESULTS
  Radioligand binding assay showed that a single intravenous injection of beta(1)-AS-ODN delivered in cationic liposomes significantly decreased cardiac beta(1)-AR density by 30% to 50% for 18 days (P<0.01), with no effect on beta(2)-ARs. This was accompanied by marked attenuation of beta(1)-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 beta(1)-AS-ODN effects on the CNS, which demonstrated no changes in beta(1)-ARs in brain, in contrast to a significant reduction in heart and kidney (P<0.05). For comparison with beta-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 beta(1)-AS-ODN, a novel approach to specific beta(1)-blockade, has advantages over currently used beta-blockers in providing a profound and prolonged reduction in blood pressure without affecting heart rate, beta(2)-ARs, and the CNS. Diminished cardiac contractility resulting from less beta(1)-AR expression contributes to the antihypertensive effect.
authors.affiliation: Department of Physiology, School of Medicine, University of Florida, Gainesville 32610, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Zhang
authors.forename: J D
authors.initials: JD
authors.lastname: Bui
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: M I
authors.initials: MI
authors.lastname: Phillips
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D009200:Myocardial Contraction / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1