Specific beta(2)AR blocker ICI 118,551 actively decreases contraction through a G(i)-coupled form of the beta(2)AR in myocytes from failing human heart.
BACKGROUND
We have observed direct (noncatecholamine-blocking) negative inotropic effects of the selective beta(2)-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 beta(2)ARs or G(i) proteins are overexpressed.


RESULTS
Enzymatically isolated, superfused ventricular myocytes were exposed to betaAR 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 beta(2)AR number and increased G(i) levels had normal basal contractility but showed a similar negative inotropic response to ICI 118,551. Overexpression of human beta(2)AR 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(i)alpha(2) induced the effect de novo in normal rat myocytes.


CONCLUSIONS
We hypothesize that ICI 118,551 binding directs the beta(2)AR 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 beta(2)AR, producing a direct negative inotropic effect. Conditions where beta(2)ARs are present and G(i) is raised (failing human heart, TGbeta(2) mouse heart) predispose to the appearance of the negative inotropic effect.
Gong
Haibin
H
National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
Sun
Hong
H
Koch
Walter J
WJ
Rau
Thomas
T
Eschenhagen
Thomas
T
Ravens
Ursula
U
Heubach
Jürgen F
JF
Adamson
Dawn L
DL
Harding
Sian E
SE
D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D037342:Pertussis Toxin; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D012720:Severity of Illness Index; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D010566:Virulence Factors, Bordetella; C026777:ICI 118551; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go