title: Non-classical regulation of β1- and β 2-adrenoceptor-mediated inotropic responses in rat heart ventricle by the G protein Gi.
abstract: Studies suggest that increased activity of Gi contributes to the reduced β-adrenoceptor-mediated inotropic response (βAR-IR) in failing cardiomyocytes and that β2AR-IR but not β1AR-IR is blunted by dual coupling to Gs and Gi. We aimed to clarify the role of Gi upon the β1AR-IR and β2AR-IR in Sham and failing myocardium by directly measuring contractile force and cAMP accumulation. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation in cardiomyocytes from rats with post-infarction heart failure (HF) or sham operates (Sham). The β2AR-IR in Sham and HF was small and was amplified by simultaneously inhibiting phosphodiesterases 3 and 4 (PDE3&4). In HF, the inotropic response and cAMP accumulation evoked by β1AR- or β2AR-stimulation were reduced. Inactivation of Gi with pertussis toxin (PTX) did not restore the β1AR-IR or β2AR-IR in HF to Sham levels but did enhance the maximal β2AR-IR. PTX increased both β1AR- and β2AR-evoked cAMP accumulation more in Sham than that in HF, and HF levels approached those in untreated Sham. The potency of agonists at β1 and at β2ARs (only under PDE3&4 inhibition) was increased in HF and by PTX in both HF and Sham. Without PDE3&4 inhibition, PTX increased only the maximal β2AR-IR, not potency. We conclude that Gi regulates both β1AR- and β2AR-IR independent of receptor coupling with Gi. Gi together with PDE3&4 tonically restrict the β2AR-IR. Gi inhibition did not restore the βAR-IR in HF despite increasing cAMP levels, suggesting that the mechanism of impairment resides downstream to cAMP signalling.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Caroline Bull
authors.initials: CB
authors.lastname: Melsom
authors.forename: Rizwan Iqbal
authors.initials: RI
authors.lastname: Hussain
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Ørstavik
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Tor
authors.initials: T
authors.lastname: Skomedal
authors.forename: Jan-Bjørn
authors.initials: JB
authors.lastname: Osnes
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Kurt Allen
authors.initials: KA
authors.lastname: Krobert
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go