Published online before print May 6, 2002, doi: 10.1161/01.CIR.0000017187.61348.95
(Circulation. 2002;105:2497.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Specific ß2AR Blocker ICI 118,551 Actively Decreases Contraction Through a Gi-Coupled Form of the ß2AR in Myocytes From Failing Human Heart
From the National Heart and Lung Institute, Imperial College School of Medicine, London, UK; Department of Experimental Surgery (W.J.K.), Duke University Medical Center, Durham, NC; Institute of Pharmacology (T.R., T.E.), University of Erlangen, Germany; and Institut fur Pharmakologie und Toxikologie (U.R., J.F.H.), Universitat Carl Gustav Carus, Dresden, Germany.
Correspondence to Dr Sian E. Harding, National Heart and Lung Institute, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Dovehouse St, London SW3 6LY, UK. E-mail sian.harding{at}ic.ac.uk
Background— We have observed direct (noncatecholamine-blocking) negative inotropic effects of the selective ß2-adrenoceptor (AR) antagonist ICI 118,551 in myocytes from failing human ventricle. In this study we characterize the effect in parallel in human myocytes and in myocytes from animal models where ß2ARs or Gi proteins are overexpressed.
Methods and Results— Enzymatically isolated, superfused ventricular myocytes were exposed to ßAR agonists and antagonists/inverse agonists, and contraction amplitude was measured. ICI 118,551 decreased contraction in ventricular myocytes from failing human hearts by 45.3±4.1% (n=20 hearts/31 myocytes, P<0.001) but had little effect in nonfailing hearts (4.9±4%, n=5 myocytes/3 hearts). Effects were significantly larger in patients classified as end-stage. Transgenic mice with high ß2AR number and increased Gi levels had normal basal contractility but showed a similar negative inotropic response to ICI 118,551. Overexpression of human ß2AR in rabbit myocytes using adenovirus potentiated the negative inotropic effect of ICI 118,551. In human, rabbit, and mouse myocytes, the negative inotropic effects were blocked after treatment of cells with pertussis toxin to inactivate Gi, and overexpression of Gi
2 induced the effect de novo in normal rat myocytes.
Conclusions— We hypothesize that ICI 118,551 binding directs the ß2AR to a Gi-coupled form and away from the Gs-coupled form (ligand-directed trafficking). ICI 118,551 effectively acts as an agonist at the Gi-coupled ß2AR, producing a direct negative inotropic effect. Conditions where ß2ARs are present and Gi is raised (failing human heart, TGß2 mouse heart) predispose to the appearance of the negative inotropic effect.
Key Words: myocytes • receptors, adrenergic, beta • contractility • heart failure
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