title: Negative inotropic effects of isoprenaline on isolated left atrial assays from aged transgenic mice with cardiac over-expression of human beta(2)-adrenoceptors.
abstract: The action of isoprenaline has been evaluated in an isolated, left atrial assay, from aged transgenic mice with cardiac-specific over-expression of the beta(2)-adrenoceptor. In the assay, isoprenaline produced a negative inotropic concentration-response curve that was not altered by incubation with CGP-20712A (1 microM), a beta(1)-adrenoceptor antagonist. However, after incubation with ICI-118,551 (300 nM), a selective beta(2)-adrenoceptor antagonist, isoprenaline produced a positive inotropic concentration-effect curve that was located to the left of the negative inotropic curve. This suggests that the negative inotropic effect was mediated by a homogenous population of negatively-coupled beta(2)-adrenoceptors. In the presence of CGP-20712A (300 nM), the positive curve was shifted to the right, suggesting that the positive inotropic effect was mediated, at least in part, by beta(1)-adrenoceptors. These results differ substantially from those previously obtained in young transgenic mice. An outline of an explanatory model, based on a concept of over-expressed receptors 'stealing' G-proteins, is suggested.
authors.affiliation: Department of Analytical Pharmacology, Guy's King's & St. Thomas' School of Medicine & Dentistry, 123 Coldharbour Lane, London SE5 9NU, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Prendergast
authors.forename: N P
authors.initials: NP
authors.lastname: Shankley
authors.forename: J W
authors.initials: JW
authors.lastname: Black
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D016275:Atrial Function; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D007093:Imidazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; C049763:CGP 20712A; D007545:Isoproterenol