Function of cardiac β1- and β2-adrenoceptors of newborn piglets: Role of phosphodiesterases PDE3 and PDE4

The structures of porcine and human beta(2)-adrenoceptors differ but the repercussions for porcine cardiac function are unknown. We investigated the function of porcine beta(2)-adrenoceptors in 3 cardiac regions, sinoatrial node, left atrium and right ventricle of newborn piglets. Both (-)-noradrenaline and (-)-adrenaline caused sinoatrial tachycardia: 60 10% and 62 7% of the maximum response (E-max) to (-)-noradrenaline (-logEC(50)= 9.0) and (-)-adrenaline (-logEC(50)= 7.5) respectively, were resistant to antagonism by the p1-selective CGP20712A (2-hydroxy-5-[2-[[2-hydroxy-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide) (300 nM) but antagonized by beta(2)-selective ICI118551 (elythro(+/-)-[1-(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]3-[(1-methylethyl)amino]-2-butanol) (50 nM), consistent with mediation through 132-adrenoceptors. The phosphodiesterase3-selective inhibitor cilostamide and phosphodiesterase4-selective inhibitor rolipram did not affect catecholamine chronotropic potencies. Only small CGP20712A-resistant positive inotropic effects of ()adrenaline were detected in the left atria (13 2% of Errux) and ventricular trabeculae (14 5% of Ernax). The atrial inotropic responses to (-)-noradrenaline and (-)-adrenaline faded; fades were prevented by rolipram but not cilostamide or concurrent cilostamide + rolipram respectively. (-)-Noradrenaline (ICI118551 present) increased left atrial cAMP levels through 31-adrenoceptors that were markedly enhanced by rolipram but unaffected by cilostamide. Concurrent cilostamide + rolipram uncovered inotropic and cAMP responses to (-)-adrenaline (CGP20712A present). We conclude that sinoatria1132-adrenoceptors are more important than beta(1)-adrenoceptors in the mediation of tachycardia caused by both (-)-noradrenaline and (-)-adrenaline in the newborn piglet. beta(2)-adrenoceptors have only a minor role in the mediation of left atrial and ventricular inotropic effects of (-)adrenaline. Catecholamine-evoked tachycardia is not controlled by PDE3 or PDE4. PDE4, but not PDE3, controls the atrial inotropic and cAMP beta(1)-adrenoceptor-mediated responses to (-)-noradrenaline. Both PDE3 and PDE4 blunt left atrial inotropic and CAMP responses to (-)-adrenaline through beta(2)-adrenoceptors. (C) 2010 Elsevier BM. All rights reserved.