title: The functional activity of inhibitory G protein (G(i)) is not increased in failing heart ventricle.
abstract: Beta-adrenergic receptor (βAR) inotropic effects are attenuated and muscarinic receptor-mediated inhibition thereof is enhanced in heart failure. We investigated if increased G(i) activity contributes to attenuated βAR-inotropic effects and potentiates muscarinic accentuated antagonism in failing rat ventricle. Contractility was measured in ventricular strips and adenylyl cyclase (AC) activity in ventricular membranes from rats with post-infarction heart failure (HF) or Sham-operated controls (Sham). The maximal βAR-mediated inotropic effect of isoproterenol was reduced by ~70% and basal, βAR- & forskolin-stimulated AC activity was significantly lower in HF vs. Sham. Carbachol-evoked antagonism of the βAR-mediated inotropic response was complete only in HF despite a ~40% reduction in the ability of carbachol to inhibit βAR-stimulated AC. However, neither the relative efficacy (contractility decreased by ~46%) nor the potency of carbachol to inhibit the βAR inotropic response differed between Sham and HF ventricle. Pertussis toxin (PTX) inactivation of G(i) did not increase the maximal βAR inotropic effect or the attenuated basal, βAR- & forskolin-stimulated AC activity in HF, but increased the potency of isoproterenol only in Sham (~0.5 log unit). In HF ventricle pretreated with PTX, simultaneous inhibition of phosphodiesterases 3,4 (PDE3,4) alone produced a larger inotropic response than isoproterenol in ventricle untreated with PTX (84% and 48% above basal respectively). In the absence of PTX, PDE3,4 inhibition evoked negligible inotropic effects in HF. These data are not consistent with the hypothesis that increased G(i) activity contributes to the reduced βAR-mediated inotropic response and AC activity in failing ventricle. The data, however, support the hypothesis that G(i), through chronic receptor independent inhibition of AC, together with PDE3,4 activity, is necessary to maintain a low basal level of contractility.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: R I
authors.initials: RI
authors.lastname: Hussain
authors.forename: J M
authors.initials: JM
authors.lastname: Aronsen
authors.forename: F
authors.initials: F
authors.lastname: Afzal
authors.forename: I
authors.initials: I
authors.lastname: Sjaastad
authors.forename: J-B
authors.initials: JB
authors.lastname: Osnes
authors.forename: T
authors.initials: T
authors.lastname: Skomedal
authors.forename: F O
authors.initials: FO
authors.lastname: Levy
authors.forename: K A
authors.initials: KA
authors.lastname: Krobert
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D037342:Pertussis Toxin / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology; D017725:Ventricular Pressure
chemical_list: D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D018721:Muscarinic Agonists; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D015363:Quinolones; C021294:cilostamide; D002217:Carbachol; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D020889:Rolipram; D007545:Isoproterenol