title: Selective beta1-adrenoceptor blockade enhances the activity of the stimulatory G-protein in human atrial myocardium.
abstract: 1. Chronic selective beta1-adrenoceptor (beta1AR) blocker treatment enhances the sensitivity of beta2-adrenoceptor (beta2AR) in human heart (Hall et al., 1990; 1991). To clarify the mechanism of the cross-sensitization between beta1AR and beta2AR, we determined whether the stimulatory G-protein (G(s)alpha) function is increased in atria from beta1AR-blocker treated patients compared with non-beta-blocked patients, and investigated whether this change is caused by an alteration of post-translational modification of Gsalpha protein. 2. G(s)alpha function was determined by reconstitution of human atrial G(s)alpha into S49 cyc- cell membranes. In the reconstitution system, GTPgammaS stimulated cyclic AMP generation in a dose-dependent manner. Upon 10(-4) M GTPgammaS stimulation, G(s)alpha activity in the beta1AR-blocker, atenolol, treated group (78.2+/-10. 3 pmol cyclic AMP mg(-1) min(-1) 10(-3)) was 65% higher than that in non-beta-blocked patients (47.3+/-6.3 pmol cyclic AMP mg(-1) min(-1) 10(-3), n=15, P=0.02). 3. Isoelectric point (pI) valu G(s)alpha were measured by two dimensional gel electrophoresis (2D-E) and the amount of each isoform quantified by image analysis of a Western blot of the gel using specific antibody. Multiple isoforms of G(s)alpha were detected by 2D-E with different pI values. There were no significant differences between the groups of patients in either pI values or the proportions of the acidic isoforms of G(s)alpha to the main basic form (n=12, P>0.05). 4. The results suggest that chronic beta1AR-blockade enhances Gsalpha function in human atrium, and this may account in part for the hypersensitivity of beta2AR and other Gs-coupled receptors during beta1AR-blockade. The increased G(s)alpha function is unlikely to be caused directly by blockade of protein kinase A phosphorylation of G(s)alpha protein.
authors.affiliation: Clinical Pharmacology Unit, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 2QQ.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Plumpton
authors.forename: M J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000368:Aged; D001262:Atenolol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006325:Heart Atria / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007526:Isoelectric Point; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D014407:Tumor Cells, Cultured
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D020033:Protein Isoforms; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001262:Atenolol; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases