Function of cardiac beta1- and beta2-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 beta(1)-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 (erythro(+/-)-[1-(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) (50 nM), consistent with mediation through beta(2)-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 E(max)) and ventricular trabeculae (14+/-5% of E(max)). 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 beta(1)-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 beta(2)-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.
Galindo-Tovar
Alejandro
A
Department of Pharmacology, Medical School, University of Murcia, and Research Unit of the University Hospital Virgen de la Arrixaca, Murcia 30100, Spain.
Vargas
Maria Luisa
ML
Kaumann
Alberto J
AJ
D000322:Adrenergic Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology*; D004837:Epinephrine / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D009638:Norepinephrine / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D012849:Sinoatrial Node / Q000187:drug effects; D013552:Swine; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology*
D000322:Adrenergic Agonists; D000319:Adrenergic beta-Antagonists; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C021294:cilostamide; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D009638:Norepinephrine; D004837:Epinephrine