title: The effects of both noradrenaline and CGP12177, mediated through human beta1 -adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells.
abstract: (-)-Noradrenaline and (-)-CGP12177 activate beta(1)-adrenoceptors through a high (H)- and low-affinity (L) site, respectively. The positive inotropic effects of (-)-noradrenaline are blunted by phosphodiesterase4 (PDE4) but not PDE3, while both PDE isoenzymes, acting in concert, prevent the effects of (-)-CGP12177 through beta(1)-adrenoceptors in rat ventricle. We sought to unravel the role of PDE3 and PDE4 on signals through the H and L sites in human myocardium. The kinetics of matching positive inotropic effects of (-)-noradrenaline (20 nM) and (-)-CGP12177 (100 nM) were investigated on human atrial trabeculae in the absence and presence of the PDE3 inhibitor cilostamide (300 nM), PDE4 inhibitor rolipram (1 microM) or both. The influence of cilostamide and rolipram on agonist-evoked cyclic adenosine monophosphate (cAMP) increases were also compared in Chinese hamster ovary (CHO) cells expressing recombinant human beta1 -adrenoceptors. (-)-Noradrenaline and (-)-CGP12177 caused matching inotropic responses that faded during a 60-min time course. Cilostamide, but not rolipram, increased the positive inotropic effects and abolished the time dependent fade of both agonists. In CHO cells, rolipram, but not cilostamide, enhanced the cAMP signals caused by both (-)-noradrenaline and (-)-CGP12177. PDE3, but not PDE4, blunts the positive inotropic effects of both (-)-noradrenaline and (-)-CGP12177 through H and L sites, respectively, of human atrial beta1 -adrenoceptors. However, in CHO cells, PDE4 blunts the cAMP signals of both (-)-noradrenaline and (-)-CGP12177. Neither CHO cells nor the rat ventricle are appropriate models for the beta1 -adrenoceptor-evoked signalling to PDE3 observed in human atrium.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. ajk41@hermes.cam.ac.uk
authors.forename: Alberto
authors.initials: A
authors.lastname: Kaumann
authors.forename: Annalese B T
authors.initials: AB
authors.lastname: Semmler
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000368:Aged; D000818:Animals; D020517:Atrial Appendage / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007537:Isometric Contraction / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; D015363:Quinolones; D018342:Receptors, Adrenergic, beta-1; C021294:cilostamide; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D007545:Isoproterenol; C033394:CGP 12177; D009638:Norepinephrine