(-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through beta2 -adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling

Naunyn Schmiedebergs Arch Pharmacol. 2007 Mar;375(1):11-28. doi: 10.1007/s00210-007-0138-x. Epub 2007 Feb 13.

Abstract

Activation of either coexisting beta1- or beta2 -adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium. Previous biochemical work with the beta2 -selective agonist zinterol is consistent with activation of the cascade beta2 -adrenoceptors-->Gsalpha-protein-->adenylyl cyclase-->cAMP-->protein kinase (PKA)-->phosphorylation of phospholamban, troponin I, and C-protein-->hastened relaxation of human atria from nonfailing hearts. However, in feline and rodent myocardium, catecholamines and zinterol usually do not hasten relaxation through activation of beta2 -adrenoceptors, presumably because of coupling of the receptors to Gi protein. It is unknown whether the endogenously occurring beta2 -adrenoceptor agonist adrenaline acts through the above cascade in human atrium and whether its mode of action could be changed in heart failure. We assessed the effects of (-)-adrenaline, mediated through beta2 -adrenoceptors (in the presence of CGP 20712A 300 nM to block beta1 -adrenoceptors), on contractility and relaxation of right atrial trabecula obtained from nonfailing and failing human hearts. Cyclic AMP levels were measured as well as phosphorylation of phospholamban, troponin I, and protein C with Western blots and the back-phosphorylation procedure. For comparison, beta1 -adrenoceptor-mediated effects of (-)-noradrenaline were investigated in the presence of ICI 118,551 (50 nM to block beta2 -adrenoceptors). The positive inotropic effects of both (-)-noradrenaline and (-)-adrenaline were accompanied by reductions in time to peak force and time to reach 50% relaxation. (-)-Adrenaline caused similar positive inotropic and lusitropic effects in atrial trabeculae from failing hearts. However, the inotropic potency, but not the lusitropic potency, of (-)-noradrenaline was reduced fourfold in atrial trabeculae from heart failure patients. Both (-)-adrenaline and (-)-noradrenaline enhanced cyclic AMP levels and produced phosphorylation of phospholamban, troponin I, and C-protein to a similar extent in atrial trabeculae from nonfailing hearts. The hastening of relaxation caused by (-)-adrenaline together with the PKA-catalyzed phosphorylation of the three proteins involved in relaxation, indicate coupling of beta2 -adrenoceptors to Gs protein. The phosphorylation of phospholamban at serine16 and threonine17 evoked by (-)-adrenaline through beta2 -adrenoceptors and by (-)-noradrenaline through beta1 -adrenoceptors was not different in atria from nonfailing and failing hearts. Activation of beta2 -adrenoceptors caused an increase in phosphorylase a activity in atrium from failing hearts further emphasizing the presence of the beta2 -adrenoceptor-Gsalpha-protein pathway in human heart. The positive inotropic and lusitropic potencies of (-)-adrenaline were conserved across Arg16Gly- and Gln27Glu-beta2 -adrenoceptor polymorphisms in the right atrium from patients undergoing coronary artery bypass surgery, chronically treated with beta1 -selective blockers. The persistent relaxant and biochemical effects of (-)-adrenaline through beta2 -adrenoceptors and of (-)-noradrenaline through beta1 -adrenoceptors in heart failure are inconsistent with an important role of coupling of beta2 -adrenoceptors with Gialpha-protein in human atrial myocardium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agonists / pharmacology
  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Antagonists / pharmacology
  • Adult
  • Aged
  • Atrial Appendage / drug effects
  • Atrial Appendage / physiology
  • Calcium-Binding Proteins / metabolism
  • Carrier Proteins / metabolism
  • Cyclic AMP / metabolism
  • Diastole / drug effects
  • Diastole / physiology
  • Epinephrine / chemistry
  • Epinephrine / pharmacology*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / physiology
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / physiology*
  • Genotype
  • Heart Failure / metabolism
  • Heart Failure / physiopathology*
  • Humans
  • In Vitro Techniques
  • Isoproterenol / pharmacology
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects
  • Myocardial Contraction / physiology*
  • Norepinephrine / pharmacology
  • Phosphorylase a / metabolism
  • Phosphorylation / drug effects
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / physiology*
  • Troponin I / metabolism

Substances

  • Adrenergic Agonists
  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Antagonists
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Receptors, Adrenergic, beta-2
  • Troponin I
  • myosin-binding protein C
  • phospholamban
  • Cyclic AMP
  • Phosphorylase a
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gs
  • Isoproterenol
  • Norepinephrine
  • Epinephrine