Nebivolol, a vasodilating selective beta(1)-blocker, is a beta(3)-adrenoceptor agonist in the nonfailing transplanted human heart.
OBJECTIVE
The present study was to assess whether nebivolol could activate beta(3)-adrenergic receptors (ARs) in the human heart.


BACKGROUND
Nebivolol is a third-generation beta-blocker used in the treatment of heart failure. It associates selective beta(1)-adrenergic antagonist properties with endothelial and nitric oxide (NO)-dependent vasodilation. Several studies reported that this vasodilation could result from an activation of beta(3)-ARs, but no data are available in the heart.


METHODS
The effect of nebivolol (0.1 nmol/l to 10 micromol/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 micromol/l: -55 +/- 4%, n = 6), which was similar to that obtained with a preferential beta(3)-AR agonist, BRL 37344 (maximum effect obtained at 1 micromol/l: -45 +/- 2%, n = 12). The nebivolol effect was not modified by 10 micromol/l nadolol, a beta(1,2)-AR antagonist, but was significantly reduced in the presence of 1 micromol/l L-748,337, a selective beta(3)-AR antagonist, and after pre-treatment with 100 micromol/l N(G)-monomethyl-L-arginine, an NOS inhibitor.


CONCLUSIONS
Our study demonstrated that nebivolol activated beta(3)-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.
Rozec
Bertrand
B
INSERM, UMR, l'institut du thorax, Nantes, France.
Erfanian
Mortéza
M
Laurent
Karine
K
Trochu
Jean-Noël
JN
Gauthier
Chantal
C
D058671:Adrenergic beta-1 Receptor Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D001706:Biopsy; D002316:Cardiotonic Agents / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D000068577:Nebivolol; D019001:Nitric Oxide Synthase / Q000187:drug effects; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D058671:Adrenergic beta-1 Receptor Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D002316:Cardiotonic Agents; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; D014665:Vasodilator Agents; D000068577:Nebivolol; C057368:BRL 37344; D019001:Nitric Oxide Synthase