The effects of both noradrenaline and CGP12177, mediated through human beta(1)-adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells

Kaumann, Alberto, Semmler, Annalese B. T. and Molenaar, Peter (2007) The effects of both noradrenaline and CGP12177, mediated through human beta(1)-adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells. Naunyn-schmiedebergs Archives of Pharmacology, 375 2: 123-131. doi:10.1007/s00210-007-0140-3


Author Kaumann, Alberto
Semmler, Annalese B. T.
Molenaar, Peter
Title The effects of both noradrenaline and CGP12177, mediated through human beta(1)-adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells
Journal name Naunyn-schmiedebergs Archives of Pharmacology   Check publisher's open access policy
ISSN 0028-1298
1432-1912
Publication date 2007-04
Sub-type Article (original research)
DOI 10.1007/s00210-007-0140-3
Volume 375
Issue 2
Start page 123
End page 131
Total pages 9
Place of publication New York
Publisher Springer
Language eng
Subject 11 Medical and Health Sciences
300512 Pharmacology
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 mu M) 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 beta(1)-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 beta(1)-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 PI-adrenoceptor-evoked signalling to PDE3 observed in human atrium.
Keyword Pharmacology & Pharmacy
beta(1) -adrenoceptor sites
human atrium
CHOcell cAMP center dot (-)-noradrenaline center dot(-)-CGP12177
phosphodiesterase isoenzymes
Beta-adrenoceptor
Contractile-force
Human-heart
Adenylate-cyclase
Human Myocardium
Rat Ventricle
Receptors
Stimulation
Beta-2-adrenoceptors
Beta-1-adrenoceptor
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
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Created: Mon, 18 Feb 2008, 17:06:18 EST