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Vol. 292, Issue 2, 698-703, February 2000
Laboratory of Microvascular and Cardiovascular Pharmacology,
Department of Preclinical and Clinical Pharmacology, University of
Florence, Florence, Italy (A.P., S.F., S.A., A.F., F.L.); and
Microcirculation Research Institute and Department of Medical
Physiology, Texas A & M University System Health Science Center,
College Station, Texas (H.J.G.).
Nebivolol is a recently developed 
-blocker provided with
vasodilator properties. Because the mechanism of the putative
endothelium-dependent effect of this -adrenoceptor blocker has not
been completely elucidated, the aim of this study was to investigate
the effects of nebivolol on an isolated resistance vascular bed and on
cell messengers and constitutive nitric-oxide synthase activity (cNOS) in endothelial cells. Experiments were carried out using the rat mesenteric vascular bed and cultured bovine coronary postcapillary venular endothelial cells from bovine heart (CVEC). In
mesenteric vascular bed preconstricted by 30 µM noradrenaline and 0.3 µM U46619, dl-nebivolol induced a
concentration-dependent relaxing effect at concentrations between 3 and
30 µM; this effect was changed to a concentration-dependent
vasoconstrictor response either in endothelium-denuded preparations or
in intact preparations pretreated with 100 µM
N
-nitro-L-arginine methyl
ester plus 3 µM indomethacin. The vasorelaxant effect of
dl-nebivolol in preconstricted preparations was
completely blocked by pretreatment either with the phospholipase C
inhibitor U73122 (1 µM) or with the endoplasmic reticulum
Ca2+-ATPase inhibitor thapsigargin (1 µM) for 30 min. The
cellular level of the inositol trisphosphate metabolite inositol
monophosphate in coronary postcapillary venular endothelial cells was
not affected by dl-nebivolol in the concentration range
100 nM to 1 µM, but it was concentration dependently increased after
exposure for 15 min to 10 and 30 µM
dl-nebivolol. The activity of cNOS was almost doubled
after a 5-min exposure to 10 µM dl-nebivolol and was
significantly impaired by thapsigargin and
N-nitro-L-arginine methyl
ester treatment, although it was unaffected by
N-nitro-D-arginine methyl
ester. These findings demonstrate that nebivolol, in micromolar
concentrations, induces vasorelaxation through activation of inositol
phosphate metabolism and stimulation of cNOS activity in endothelial cells.
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