title: Autoantibodies against cardiac β(1)-adrenoceptor do not affect the low-affinity state β(1)-adrenoceptor-mediated inotropy in rat cardiomyocytes.
abstract: Circulating autoantibodies directed against the 2nd extracellular loop (EL-2) of β(1)-adrenoceptors (β(1)-AABs) have been detected in the serum of patients with various cardiovascular pathologies. β(1)-AABs induce agonistic, positive inotropic effects via β(1)-adrenoceptors (β(1)ARs). In the mammalian heart, β(1)-AR can exist in 2 distinct activated configurations (the so-called high- and low-affinity states). The aim of the present study was to investigate whether the action of β(1)-AAB is dependent on the affinity state of β(1)AR in isolated ventricular cardiomyocytes of adult Wistar rats. Immunoglobulin G (IgG) containing β(1)-AAB obtained from animals immunized with a peptide corresponding to the EL-2 of human β(1)-AR, caused a dose-dependent increase in cell shortening. Isoproterenol-induced inotropy was significantly reduced in cardiomyocytes that had been preincubated with IgG containing β(1)-AAB and in cardiomyocytes isolated from immunized rats. The negative effects of preincubation with IgG containing β(1)-AAB on the response to isoproterenol was inhibited in the presence of bisoprolol. CGP 12177A and pindolol-induced inotropy was not affected by IgG preincubation or immunization. No detectable inotropic effect of cell shortening was obtained with IgG containing β(1)-AAB in the presence of propranolol and 3-isobutyl-1-methylxanthine. The present study demonstrates that β(1)-AABs have no agonist/antagonist-like effects upon low-affinity state β(1)-ARs. This result indicates that β(1)-AABs recognize and stabilize the high-affinity state, but are unable to stabilize and (or) induce the low-affinity state receptor.
authors.affiliation: L'Université Nantes Angers Le Mans (LUNAM) - Oniris, Atlanpole-La Chantrerie, Nantes, France.
authors.forename: Mohammed Amine
authors.initials: MA
authors.lastname: Abdelkrim
authors.forename: Mohamed Yassine
authors.initials: MY
authors.lastname: Mallem
authors.forename: Gérard
authors.initials: G
authors.lastname: Chatagnon
authors.forename: Marc
authors.initials: M
authors.lastname: Gogny
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Desfontis
authors.forename: Jacques
authors.initials: J
authors.lastname: Noireaud
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology*; D017298:Bisoprolol / Q000494:pharmacology; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D001323:Autoantibodies; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D011433:Propranolol; D010869:Pindolol; D007545:Isoproterenol; C033394:CGP 12177; D015056:1-Methyl-3-isobutylxanthine; D017298:Bisoprolol