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(-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through β2-adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling

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Abstract

Activation of either coexisting β1- or β2-adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium. Previous biochemical work with the β2-selective agonist zinterol is consistent with activation of the cascade β2-adrenoceptors→Gsα-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 β2-adrenoceptors, presumably because of coupling of the receptors to Gi protein. It is unknown whether the endogenously occurring β2-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 β2-adrenoceptors (in the presence of CGP 20712A 300 nM to block β1-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, β1-adrenoceptor-mediated effects of (-)-noradrenaline were investigated in the presence of ICI 118,551 (50 nM to block β2-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 β2-adrenoceptors to Gs protein. The phosphorylation of phospholamban at serine16 and threonine17 evoked by (-)-adrenaline through β2-adrenoceptors and by (-)-noradrenaline through β1-adrenoceptors was not different in atria from nonfailing and failing hearts. Activation of β2-adrenoceptors caused an increase in phosphorylase a activity in atrium from failing hearts further emphasizing the presence of the β2-adrenoceptor–Gsα-protein pathway in human heart. The positive inotropic and lusitropic potencies of (-)-adrenaline were conserved across Arg16Gly- and Gln27Glu-β2-adrenoceptor polymorphisms in the right atrium from patients undergoing coronary artery bypass surgery, chronically treated with β1-selective blockers. The persistent relaxant and biochemical effects of (-)-adrenaline through β2-adrenoceptors and of (-)-noradrenaline through β1-adrenoceptors in heart failure are inconsistent with an important role of coupling of β2-adrenoceptors with Giα-protein in human atrial myocardium.

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Acknowledgements

PM thanks the National Health and Medical Research Council of Australia for support. AJK is grateful to the British Heart Foundation for support.

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Authors and Affiliations

  1. Department of Medicine, The University of Queensland, The Prince Charles Hospital, Chermside, Queensland, 4032, Australia

    Peter Molenaar, Santiyagu M. Savarimuthu, Lu Chen, Annalese B. T. Semmler, Anne Carle & Ian Yang

  2. Department of Pharmacology, The University of Melbourne, Parkville, Victoria, 3052, Australia

    Doreen Sarsero

  3. Department of Thoracic Medicine, The Prince Charles Hospital, Chermside, Queensland, 4032, Australia

    Ian Yang

  4. Max-Delbrück Center of Molecular Medicine, Cardiology, Berlin, Germany

    Sabine Bartel, Donate Vetter, Inge Beyerdörfer & Ernst-Georg Krause

  5. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK

    Alberto J. Kaumann

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  1. Peter Molenaar
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Molenaar, P., Savarimuthu, S.M., Sarsero, D. et al. (-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through β2-adrenoceptors in human atrial myocardium from nonfailing and failing hearts, consistent with Gs coupling but not with Gi coupling. Naunyn-Schmied Arch Pharmacol 375, 11–28 (2007). https://doi.org/10.1007/s00210-007-0138-x

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