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CLINICAL RESEARCH: CARDIAC PHARMACOLOGY

Nebivolol, a Vasodilating Selective β₁-Blocker, Is a β₃-Adrenoceptor Agonist in the Nonfailing Transplanted Human Heart

Bertrand Rozec, MD, PhD^_*,,,,||, Mortéza Erfanian, BS^_*,,,, Karine Laurent, BS^_*,,,, Jean-Noël Trochu, MD, PhD^_*,,, and Chantal Gauthier, PhD^_*,,,,_*

^_* INSERM, UMR915, l'institut du thorax, Nantes, France
CNRS, ERL3147, Nantes, France
Université de Nantes, Nantes, France
CHU Nantes, l'institut du thorax, Nantes, France
^|| Department of Anaesthesiology, CHU Nantes, Nantes, France

Manuscript received May 27, 2008; revised manuscript received November 20, 2008, accepted November 24, 2008.

^_* Reprint requests and correspondence: Dr. Chantal Gauthier, INSERM UMR915, l'institut du thorax, Faculty of Medicine, 1, Rue Gaston Veil, BP 53508, 44035 Nantes, France (Email: chantal.gauthier{at}nantes.inserm.fr).

Objectives: The present study was to assess whether nebivolol could activate β₃-adrenergic receptors (ARs) in the human heart.

Background: Nebivolol is a third-generation β-blocker used in the treatment of heart failure. It associates selective β₁-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of β₃-ARs, but no data are available in the heart.

Methods: The effect of nebivolol (0.1 nmol/l to 10 µmol/l) upon the developed peak tension was tested in endomyocardial biopsies from human nonrejecting transplanted hearts. Tension was recorded at steady state using a mechanoelectric force transducer.

Results: Nebivolol induced a concentration-dependent decrease in peak tension (maximum effect obtained at 10 µmol/l: –55 ± 4%, n = 6), which was similar to that obtained with a preferential β₃-AR agonist, BRL 37344 (maximum effect obtained at 1 µmol/l: –45 ± 2%, n = 12). The nebivolol effect was not modified by 10 µmol/l nadolol, a β_1,2-AR antagonist, but was significantly reduced in the presence of 1 µmol/l L-748,337, a selective β₃-AR antagonist, and after pre-treatment with 100 µmol/l N^G-monomethyl-L-arginine, an NOS inhibitor.

Conclusions: Our study demonstrated that nebivolol activated β₃-AR in the human ventricle. The NO-dependent negative inotropic effect of nebivolol associated with its vasodilating properties previously described in human microcoronary arteries could improve the energetic balance in heart. Those effects could explain the improvement of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as previously described in clinical trials.

Key Words: nebivolol • β-adrenergic receptor • human heart • contractility • nitric oxide

Abbreviations and Acronyms   AR = adrenergic receptor   eNOS = endothelial nitric oxide synthase   L-NMMA = NG-monomethyl-L-arginine   NO = nitric oxide   NOS = nitric oxide synthase

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