Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells.
OBJECTIVE
Secondary failure due to late restenosis continues to occur in 30-50% of individuals after PTCA. beta-Blockers play an important role in the treatment of CAD. The aim of this study was to investigate the effects of the new beta-blocker nebivolol on cell proliferation of human coronary smooth muscle cells (haCSMCs) and endothelial cells (haECs) in comparison to traditional beta-blockers.


METHODS
The effect of nebivolol and other beta-blockers on proliferation of HaECs and HaCSMCs was analyzed by bromodeoxyuridine incorporation. Apoptosis was measured by determination of hypodiploid DNA in both cell types. Additionally, in HaECs NO formation, endothelin-1 transcription and secretion were determined.


RESULTS
Incubation for 1, 2, 4, 7 or 14 days resulted in a concentration- and time-dependent reduction of proliferation up to 80% in HaECs and HaCSMCs. beta-Blockers such as propranolol, metoprolol or bisoprolol did not exert this effect. Nebivolol inhibited accelerated haCSMC proliferation even in the presence of growth factors such as TGFbeta(1) and PDGF-BB. Nebivolol concentration-dependently induced a moderate apoptosis (10(-5) mol/l: 23%) and a decrease of haCSMCs in the S-phase by 66%. HaECs showed comparable results. During nebivolol incubation NO formation of HaCEs increased, while endothelin-1 transcription and secretion were suppressed.


CONCLUSIONS
Whereas classical beta-blockers do not affect cell growth, only nebivolol inhibits haCSMC or haEC proliferation and induces a moderate rate of apoptosis. Furthermore, in HaCEs NO formation increases and endothelin-1 secretion decreases suggesting that nebivolol may represent a beta-blocker with great promises in CAD therapy.
Brehm
B R
BR
Department of Cardiology, University of Tübingen, Otfried-Müllerstrasse 10, 72076, Tübingen, Germany. bernard_brehm@compuserve.com
Wolf
S C
SC
Bertsch
D
D
Klaussner
M
M
Wesselborg
S
S
Schüler
S
S
Schulze-Osthoff
K
K
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077214:Becaplermin; D001578:Benzopyrans / Q000494:pharmacology*; D017298:Bisoprolol / Q000494:pharmacology; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D019332:Endothelin-1; D016232:Endothelins; D004983:Ethanolamines; D010982:Platelet-Derived Growth Factor; D011498:Protein Precursors; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A; D000068577:Nebivolol; D000077214:Becaplermin; D009569:Nitric Oxide; D011433:Propranolol; D008790:Metoprolol; D017298:Bisoprolol