Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol.
BACKGROUND
The therapeutic effects of nonspecific beta-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective beta1-adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial beta3-adrenoreceptors in human coronary microarteries that mediate endothelium- and NO-dependent relaxation and hypothesized that nebivolol activates these beta3-adrenoreceptors.


RESULTS
Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 micromol/L, -86+/-6% of prostaglandin F2alpha contraction); this was sensitive to NO synthase (NOS) inhibition, unaffected by the beta(1-2)-blocker nadolol, and prevented by the beta(1-2-3)-blocker bupranolol (P<0.05; n=3 to 8). Importantly, nebivolol failed to relax microarteries from beta3-adrenoreceptor-deficient mice. Nebivolol (10 micromol/L) also relaxed human coronary microvessels (-71+/-5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to beta(1-2)-blockade (all P<0.05). In a mouse aortic ring assay of neoangiogenesis, nebivolol induced neocapillary tube formation in rings from wild-type but not beta3-adrenoreceptor- or endothelial NOS-deficient mice. In cultured endothelial cells, 10 micromol/L nebivolol increased NO release by 200% as measured by electron paramagnetic spin trapping, which was also reversed by NOS inhibition. In parallel, endothelial NOS was dephosphorylated on threonine(495), and fura-2 calcium fluorescence increased by 91.8+/-23.7%; this effect was unaffected by beta(1-2)-blockade but abrogated by beta(1-2-3)-blockade (all P<0.05).


CONCLUSIONS
Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial beta3-adrenoreceptors to release NO and promote neoangiogenesis. These properties may prove particularly beneficial for the treatment of ischemic and cardiac failure diseases through preservation of coronary reserve.
Dessy
Chantal
C
Université Catholique de Louvain Medical School, Brussels, Belgium.
Saliez
Julie
J
Ghisdal
Philippe
P
Daneau
Géraldine
G
Lobysheva
Irina I
II
Frérart
Françoise
F
Belge
Catharina
C
Jnaoui
Karima
K
Noirhomme
Philippe
P
Feron
Olivier
O
Balligand
Jean-Luc
JL
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D000068577:Nebivolol; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D009566:Nitrates; D009573:Nitrites; D022702:Receptors, Adrenergic, beta-3; D000068577:Nebivolol; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D002118:Calcium