Phosphodiesterase-4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (-)-adrenaline mediated through mouse cardiac beta(1)-adrenoceptors.
OBJECTIVE
beta(1) and beta(2)-adrenoceptors coexist in murine heart but beta(2)-adrenoceptor-mediated effects have not been detected in atrial and ventricular tissues, possibly due to marked phosphodiesterase (PDE) activity. We investigated the influence of the PDE3 inhibitor cilostamide and PDE4 inhibitor rolipram on the effects of (-)-adrenaline in three regions of murine heart.


METHODS
(-)-Adrenaline-evoked cardiostimulation was compared on sinoatrial beating rate, left atrial and right ventricular contractile force in isolated tissues from 129SvxC57B1/6 cross mice. Ventricular arrhythmic contractions were also assessed.


RESULTS
Both rolipram (1 microM) and cilostamide (300 nM) caused transient sinoatrial tachycardia but neither enhanced the chronotropic potency of (-)-adrenaline. Rolipram potentiated 19-fold (left atrium) and 7-fold (right ventricle) the inotropic effects of (-)-adrenaline. (-)-Adrenaline elicited concentration-dependent ventricular arrhythmias that were potentiated by rolipram. All effects of (-)-adrenaline were antagonized by the beta(1)-adrenoceptor-selective antagonist CGP20712A (300 nM). Cilostamide (300 nM) did not increase the chronotropic and inotropic potencies of (-)-adrenaline, but administered jointly with rolipram in the presence of CGP20712A, uncovered left atrial inotropic effects of (-)-adrenaline that were prevented by the beta(2)-adrenoceptor-selective antagonist ICI118551.


CONCLUSIONS
PDE4 blunts the beta(1)-adrenoceptor-mediated effects of (-)-adrenaline in left atrium and right ventricle but not in sinoatrial node. Both PDE3 and PDE4 reduce basal sinoatrial rate in a compartment distinct from the beta(1)-adrenoceptor compartment. PDE3 and PDE4, acting in concert, prevent left atrial beta(2)-adrenoceptor-mediated inotropy. PDE4 partially protects the right ventricle against (-)-adrenaline-evoked arrhythmias.
Galindo-Tovar
A
A
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Kaumann
A J
AJ
D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000633:toxicity*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004837:Epinephrine / Q000633:toxicity*; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D012849:Sinoatrial Node / Q000187:drug effects / Q000378:metabolism; D013616:Tachycardia, Sinus / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D007093:Imidazoles; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; D015363:Quinolones; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C021294:cilostamide; C026777:ICI 118551; C049763:CGP 20712A; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D007545:Isoproterenol; D004837:Epinephrine