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

The structures of porcine and human β2-adrenoceptors differ but the repercussions for porcine cardiac function are unknown. We investigated the function of porcine β2-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 (Emax) to (−)-noradrenaline (− logEC50 = 9.0) and (−)-adrenaline (− logEC50 = 7.5) respectively, were resistant to antagonism by the β1-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 β2-selective ICI118551 (erythro(±)-[1-(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) (50 nM), consistent with mediation through β2-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 Emax) and ventricular trabeculae (14 ± 5% of Emax). 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 β1-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 sinoatrial β2-adrenoceptors are more important than β1-adrenoceptors in the mediation of tachycardia caused by both (−)-noradrenaline and (−)-adrenaline in the newborn piglet. β2-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 β1-adrenoceptor-mediated responses to (−)-noradrenaline. Both PDE3 and PDE4 blunt left atrial inotropic and cAMP responses to (−)-adrenaline through β2-adrenoceptors.