title: Contractile responses to selective phosphodiesterase inhibitors following chronic beta-adrenoreceptor activation.
abstract: Contractile responses to phosphodiesterase (PDE) inhibitors are attenuated in heart failure, an effect limiting the clinical value of these agents. In this study, we sought to determine whether abnormalities in the beta-adrenoreceptor (beta-AR)-cyclic adenosine monophosphate (cAMP) signal transduction are sufficient to account for downregulation of PDE inhibitor-induced inotropic responses following chronic sympathetic activation. Sustained beta-AR activation produced by administration of isoproterenol (ISO) (50 microg kg(-1) day(-1) i.p. for 1 month) to rats resulted in cardiac hypertrophy, but did not affect baseline cardiac systolic function, as assessed in vivo by echocardiography and ex vivo under controlled loading conditions and heart rate (left ventricular systolic pressure-volume and stress-strain relations). Moreover, chronic ISO administration did not alter the baseline myocardial norepinephrine release or inotropic responses to incremental concentrations of Ca(2+) in isolated, perfused heart preparations. However, left ventricular contractile responses to ISO, the PDE III inhibitor amrinone, and the PDE IV inhibitor rolipram were attenuated following chronic beta-AR activation. Myocardial cAMP concentrations after stimulation with amrinone and rolipram were similar in ISO-treated and control rats. However, in ISO-treated rats, a marked decrease in contractile responsiveness to the cell-permeable, PDE-resistant cAMP analogue, 8-bromoadenosine cAMP, was noted. In conclusion, these data suggest that in cardiac disease, sustained beta-AR activation, without producing ventricular systolic dysfunction or enhanced myocardial norepinephrine release, is sufficient to account for the downregulation of contractile responses to PDE inhibitors. This effect appears to be largely mediated through abnormalities in signal transduction between cAMP and Ca(2+)-induced Ca(2+) release.
authors.affiliation: Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown 2193, Johannesburg, South Africa. osadchii@mail.ru
authors.forename: Oleg E
authors.initials: OE
authors.lastname: Osadchii
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Woodiwiss
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Norton
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D009929:Organ Size; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium; D009638:Norepinephrine