Nebivolol inhibits vascular smooth muscle cell proliferation by mechanisms involving nitric oxide but not cyclic GMP.
The objective of this study was to elucidate the mechanisms by which nebivolol, a cardio-selective beta-adrenergic receptor antagonist, inhibits rat aortic smooth muscle cell (RASMC) proliferation. Nebivolol was compared with DETA-NO and S-nitroso-N-acetylpenicillamine (SNAP), two nitric oxide (NO) donor agents, and alpha-difluoromethylornithine (DFMO), a known inhibitor of ornithine decarboxylase (ODC). All four test agents inhibited RASMC proliferation in a concentration-dependent manner, with nebivolol being the most potent (IC(50) = 4.5 microM), whereas atenolol, another relatively selective beta(1)-blocker, was inactive. DFMO, nebivolol, and DETA-NO interfered with cell proliferation in a cell-density-dependent manner, the lower the cell density the greater the inhibition of cell proliferation. The cytostatic effects of nebivolol and DETA-NO were completely independent of cyclic GMP, as neither ODQ (cytosolic guanylyl cyclase inhibitor) nor zaprinast (cyclic GMP phosphodiesterase inhibitor) affected the antiproliferative action of nebivolol or DETA-NO. The cytostatic effects of nebivolol, SNAP, and DFMO were largely prevented by the addition of excess putrescine, but not ornithine, to cell cultures. Moreover, nebivolol caused a marked reduction in the intracellular levels of putrescine, spermidine, and spermine. Like DFMO, nebivolol and DETA-NO interfered with the G(1)-phase to S-phase cell cycle transition in RASMC. These observations confirm previous findings that DFMO and NO interfere with RASMC proliferation by inhibiting ODC and polyamine production and provide evidence that nebivolol works by the same mechanism.
Ignarro
Louis J
LJ
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90095-1735, USA. lignarro@mednet.ucla.edu
Sisodia
Manisha
M
Trinh
Kim
K
Bedrood
Sahar
S
Wu
Guoyao
G
Wei
Liu Hua
LH
Buga
Georgette M
GM
D000818:Animals; D001011:Aorta / Q000166:cytology; D001578:Benzopyrans / Q000494:pharmacology*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats
D001578:Benzopyrans; D004983:Ethanolamines; D000068577:Nebivolol; D009569:Nitric Oxide; D006152:Cyclic GMP