(Circulation. 2001;103:1649.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Upregulation of ß3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium
From the Department of Medicine, Unit of Pharmacology and Therapeutics, University of Louvain Medical School (S.M., O.F., J.-L.B.), Brussels, Belgium; INSERM U533, Physiopathologie et Pharmacologie Cellulaires et Moléculaires (J.-N.T., C.G.) and Faculté des Sciences et Techniques (C.G.), Nantes, France; and Department of Pathology, Brigham and Women’s Hospital, and Physiology Program, Harvard School of Public Health (L.K.), Boston, Mass.
Correspondence to Jean-Luc Balligand, Department of Medicine, Unit of Pharmacology and Therapeutics, FATH 5349, University of Louvain Medical School, 53 avenue Mounier, B1200 Brussels, Belgium, e-mail Balligand{at}mint.ucl.ac.be; or Chantal Gauthier, INSERM U533, Physiopathologie et Pharmacologie Cellulaires et Moléculaires, 44093 Nantes, France,
Background—Contrary to ß1- and ß2-adrenoceptors, ß3-adrenoceptors mediate a negative inotropic effect in human ventricular muscle. To assess their functional role in heart failure, our purpose was to compare the expression and contractile effect of ß3-adrenoceptors in nonfailing and failing human hearts.
Methods and Results—We
analyzed left ventricular samples from 29 failing (16 ischemic and 13
dilated cardiomyopathic) hearts (ejection fraction 18.6±2%) and 25
nonfailing (including 12 innervated) explanted hearts (ejection
fraction 64.2±3%). ß3-Adrenoceptor proteins
were identified by immunohistochemistry in ventricular cardiomyocytes
from nonfailing and failing hearts. Contrary to
ß1-adrenoceptor mRNA, Western blot analysis of
ß3-adrenoceptor proteins showed a 2- to 3-fold
increase in failing compared with nonfailing hearts. A similar increase
was observed for G
i-2 proteins that couple
ß3-adrenoceptors to their negative inotropic
effect. Contractile tension was measured in electrically stimulated
myocardial samples ex vivo. In failing hearts, the positive inotropic
effect of the nonspecific amine isoprenaline was reduced by 75%
compared with that observed in nonfailing hearts. By contrast, the
negative inotropic effect of ß3-preferential
agonists was only mildly reduced.
Conclusions—Opposite changes occur in ß1- and ß3-adrenoceptor abundance in the failing left ventricle, with an imbalance between their inotropic influences that may underlie the functional degradation of the human failing heart.
Key Words: receptors, adrenergic, beta • heart failure • catecholamines • contractility • nitric oxide synthase
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