Impaired regulation of cell communication by beta-adrenergic receptor activation in the failing heart.
We investigated the influence of beta-adrenergic receptor activation on the control of gap junctional conductance (gj) in the heart of cardiomyopathic hamsters (11 months old). We measured gj in isolated ventricular cell pairs using two voltage-clamp circuits. Administration of isoproterenol (10(-6) mol/L) to the bath had no effect on gj in myopathic cell pairs but increased gj by 45 +/- 3% (+/- SE) in normal hamsters. Moreover, forskolin (10(-7) mol/L), an activator of adenyl cyclase, did not change gj in myopathic cells but enhanced gj by 23 +/- 2.8% in controls. Similar results were obtained with isobutylmethylxanthine (10(-6) mol/L), a phosphodiesterase inhibitor. Dibutyryl-cAMP (10(-6) mol/L), however, increased gj of cardiomyopathic cell pairs by 58 +/- 2.1% within 2 minutes and enhanced gj in controls by 50 +/- 3.6%. The effect of dibutyryl-cAMP on gj of myopathic cells was suppressed by intracellular dialysis of an inhibitor of protein kinase A. These observations indicate that the regulation of gj by the beta-adrenergic receptor-G protein-adenyl cyclase signaling system is greatly impaired in the failing heart but the ability of cAMP to increase gj is still preserved.
De Mello
W C
WC
Department of Pharmacology, School of Medicine, University of Puerto Rico, San Juan 00936-5067, USA.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D009202:Cardiomyopathies / Q000503:physiopathology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D004553:Electric Conductivity; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values
D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine