Inotropic responses to phosphodiesterase inhibitors in cardiac hypertrophy in rats.
In the present study we sought to determine whether reduced contractile responses to phosphodiesterase inhibitors occur in the face of chronic cardiac hypertrophy associated with beta-adrenergic inotropic downregulation. As compared to age-matched Wistar-Kyoto control rats, spontaneously hypertensive rats at 6-8 months of age exhibited a striking decrease in left ventricular inotropic responses induced by isoproterenol, a beta-adrenoceptor agonist, in isolated, isovolumically contracting heart preparations. Despite profound beta-adrenoceptor-mediated inotropic downregulation, similar contractile responses to the phosphodiesterase III selective inhibitors, amrinone and milrinone, the phosphodiesterase IV selective inhibitor, rolipram, and non-selective phosphodiesterase inhibitor, pentoxifylline, were detected in normal and hypertrophic heart preparations. Moreover, the inotropic potency of the cAMP analogue, 8-Br-cAMP, was increased in spontaneously hypertensive rats. These findings suggest that in chronic cardiac hypertrophy, contractile responses to phosphodiesterase inhibitors may be preserved despite marked reductions in inotropic responses to beta-adrenoceptor agonists.
Osadchii
Oleg
O
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown, Johannesburg 2193, South Africa. woodiwissaj@physiology.wits.ac.za
Norton
Gavin
G
Woodiwiss
Angela
A
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020889:Rolipram / Q000494:pharmacology
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000676:Amrinone; D020889:Rolipram; D007545:Isoproterenol; D010431:Pentoxifylline