Reduced beta-adrenergic receptor activation decreases G-protein expression and beta-adrenergic receptor kinase activity in porcine heart

J Clin Invest. 1995 Mar;95(3):1271-80. doi: 10.1172/JCI117777.


To determine whether beta-adrenergic receptor agonist activation influences guanosine 5'-triphosphate-binding protein (G-protein) expression and beta-adrenergic receptor kinase activity in the heart, we examined the effects of chronic beta 1-adrenergic receptor antagonist treatment (bisoprolol, 0.2 mg/kg per d i.v., 35 d) on components of the myocardial beta-adrenergic receptor-G-protein-adenylyl cyclase pathway in porcine myocardium. Three novel alterations in cardiac adrenergic signaling associated with chronic reduction in beta-adrenergic receptor agonist activation were found. First, there was coordinate downregulation of Gi alpha 2 and Gs alpha mRNA and protein expression in the left ventricle; reduced G-protein content was also found in the right atrium. Second, in the left ventricle, there was a twofold increase in beta-adrenergic receptor-dependent stimulation of adenylyl cyclase and a persistent high affinity state of the beta-adrenergic receptor. Finally, there was a reduction in left ventricular beta-adrenergic receptor kinase activity, suggesting a previously unrecognized association between the degree of adrenergic activation and myocardial beta-adrenergic receptor kinase expression. The heart appears to adapt in response to chronic beta-adrenergic receptor antagonist administration in a manner that would be expected to offset reduced agonist stimulation. The mechanisms for achieving this extend beyond beta-adrenergic receptor upregulation and include alterations in G-protein expression, beta-adrenergic receptor-Gs interaction, and myocardial beta-adrenergic receptor kinase activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptation, Biological
  • Adenylyl Cyclases / analysis
  • Animals
  • Base Sequence
  • Binding, Competitive
  • Bisoprolol / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Down-Regulation
  • GTP-Binding Proteins / biosynthesis*
  • GTP-Binding Proteins / genetics
  • Glycopyrrolate / pharmacology
  • Heart / drug effects*
  • Heart Atria / drug effects
  • Heart Rate / drug effects
  • Heart Ventricles / drug effects
  • Isoproterenol / pharmacology
  • Membranes / enzymology
  • Molecular Sequence Data
  • Myocardium / enzymology
  • RNA, Messenger / analysis
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Swine
  • Up-Regulation
  • beta-Adrenergic Receptor Kinases


  • RNA, Messenger
  • Receptors, Adrenergic, beta
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Isoproterenol
  • Glycopyrrolate
  • Bisoprolol