(-)-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

Activation of either coexisting beta(1)- or beta(2)-adrenoceptors with noradrenaline or adrenaline, respectively, causes maximum increases of contractility of human atrial myocardium. Previous biochemical work with the beta(2)-selective agonist zinterol is consistent with activation of the cascade beta(2)-adrenoceptors -> Gs alpha-protein -> adenylyl cyclase -> cAMP -> protein kinase (PKA)-> phosphorylation of phospholamban, troponin 1, 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 beta 2-adrenoceptors, presumably because of coupling of the receptors to Gi protein. It is unknown whether the endogenously occurring beta(2)-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 beta(2)-adrenoceptors (in the presence of CGP 20712A 300 nM to block beta(1)-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 1, and protein C with Western blots and the back-phosphorylation procedure. For comparison, beta(1)-adrenoceptor-mediated effects of (-)-noradrenaline were investigated in the presence of ICI 118,551 (50 nM to block beta(2)-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 1, 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 beta(2)-adrenoceptors to Gs protein. The phosphorylation of phospholamban at serine16 and threonine17 evoked by (-)-adrenaline through beta(2)-adrenoceptors and by (-)-noradrenaline through beta(1)-adrenoceptors was not different in atria from nonfailing and failing hearts. Activation of beta(2)-adrenoceptors caused an increase in phosphorylase a activity in atrium from failing hearts further emphasizing the presence of the beta(2)-adrenoceptor-Gs alpha-protein pathway in human heart. The positive inotropic and lusitropic potencies of (-)-adrenaline were conserved. across Arg16Gly- and Gln27Glu-beta(2)-adrenoceptor polymorphisms in the right atrium from patients undergoing coronary artery bypass surgery, chronically treated with beta-selective blockers. The persistent relaxant and biochemical effects of (-)-adrenaline through beta(2)-adrenoceptors and of (-)-noradrenaline through beta(1)-adrenoceptors in heart failure are inconsistent with an important role of coupling of beta(2)-adrenoceptors with Gi alpha-protein in human atrial myocardium.