Published Online
on May 6, 2002

A more recent version of this article appeared on May 28, 2002

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Submitted on December 28, 2001
Revised on March 14, 2002
Accepted on March 20, 2002

Specific ß₂AR Blocker ICI 118,551 Actively Decreases Contraction Through a G_i-Coupled Form of the ß₂AR in Myocytes From Failing Human Heart

Haibin Gong PhD, Hong Sun MD, Walter J. Koch PhD, Thomas Rau MD, Thomas Eschenhagen PhD, Ursula Ravens PhD, Jürgen F. Heubach PhD, Dawn L. Adamson MB, BS, and Sian E. Harding PhD^*

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.

^* To whom correspondence should be addressed. 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 G_i 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 G_i 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 G_i, and overexpression of G_i2 induced the effect de novo in normal rat myocytes.

Conclusions—We hypothesize that ICI 118,551 binding directs the ß₂AR to a G_i-coupled form and away from the G_s-coupled form (ligand-directed trafficking). ICI 118,551 effectively acts as an agonist at the G_i-coupled ß₂AR, producing a direct negative inotropic effect. Conditions where ß₂ARs are present and G_i 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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