PMID- 23220156 OWN - NLM STAT- MEDLINE DCOM- 20130723 LR - 20220316 IS - 1095-8584 (Electronic) IS - 0022-2828 (Linking) VI - 56 DP - 2013 Mar TI - The functional activity of inhibitory G protein (G(i)) is not increased in failing heart ventricle. PG - 129-38 LID - S0022-2828(12)00420-8 [pii] LID - 10.1016/j.yjmcc.2012.11.015 [doi] AB - Beta-adrenergic receptor (betaAR) 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 betaAR-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 betaAR-mediated inotropic effect of isoproterenol was reduced by ~70% and basal, betaAR- & forskolin-stimulated AC activity was significantly lower in HF vs. Sham. Carbachol-evoked antagonism of the betaAR-mediated inotropic response was complete only in HF despite a ~40% reduction in the ability of carbachol to inhibit betaAR-stimulated AC. However, neither the relative efficacy (contractility decreased by ~46%) nor the potency of carbachol to inhibit the betaAR inotropic response differed between Sham and HF ventricle. Pertussis toxin (PTX) inactivation of G(i) did not increase the maximal betaAR inotropic effect or the attenuated basal, betaAR- & 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 betaAR-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. CI - Copyright (c) 2012 Elsevier Ltd. All rights reserved. FAU - Hussain, R I AU - Hussain RI AD - Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway. FAU - Aronsen, J M AU - Aronsen JM FAU - Afzal, F AU - Afzal F FAU - Sjaastad, I AU - Sjaastad I FAU - Osnes, J-B AU - Osnes JB FAU - Skomedal, T AU - Skomedal T FAU - Levy, F O AU - Levy FO FAU - Krobert, K A AU - Krobert KA LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121207 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (Adrenergic beta-Agonists) RN - 0 (Cardiotonic Agents) RN - 0 (Muscarinic Agonists) RN - 0 (Phosphodiesterase 3 Inhibitors) RN - 0 (Phosphodiesterase 4 Inhibitors) RN - 0 (Quinolones) RN - 45S5605Q18 (cilostamide) RN - 8Y164V895Y (Carbachol) RN - EC 2.4.2.31 (Pertussis Toxin) RN - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go) RN - EC 4.6.1.1 (Adenylyl Cyclases) RN - K676NL63N7 (Rolipram) RN - L628TT009W (Isoproterenol) SB - IM MH - Adenylyl Cyclases/metabolism MH - Adrenergic beta-Agonists/pharmacology MH - Animals MH - Carbachol/pharmacology MH - Cardiotonic Agents/pharmacology MH - GTP-Binding Protein alpha Subunits, Gi-Go/antagonists & inhibitors/*metabolism MH - Heart Failure/*metabolism/physiopathology MH - Heart Ventricles/drug effects/metabolism/*physiopathology MH - In Vitro Techniques MH - Isoproterenol/pharmacology MH - Male MH - Muscarinic Agonists/pharmacology MH - Myocardial Contraction/*drug effects MH - Myocardial Infarction/*metabolism/physiopathology MH - Pertussis Toxin/pharmacology MH - Phosphodiesterase 3 Inhibitors/pharmacology MH - Phosphodiesterase 4 Inhibitors/pharmacology MH - Quinolones/pharmacology MH - Rats MH - Rats, Wistar MH - Rolipram/pharmacology MH - Ventricular Pressure EDAT- 2012/12/12 06:00 MHDA- 2013/07/24 06:00 CRDT- 2012/12/11 06:00 PHST- 2012/06/21 00:00 [received] PHST- 2012/11/22 00:00 [revised] PHST- 2012/11/24 00:00 [accepted] PHST- 2012/12/11 06:00 [entrez] PHST- 2012/12/12 06:00 [pubmed] PHST- 2013/07/24 06:00 [medline] AID - S0022-2828(12)00420-8 [pii] AID - 10.1016/j.yjmcc.2012.11.015 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2013 Mar;56:129-38. doi: 10.1016/j.yjmcc.2012.11.015. Epub 2012 Dec 7.