Effects of carvedilol on oxidative stress in human endothelial cells and healthy volunteers.
OBJECTIVE
Carvedilol is a nonselective beta- and alpha(1)-receptor antagonist with additional antioxidant properties in vitro. In this study, we assessed the antioxidative potential of carvedilol in cell culture and in antihypertensive doses in healthy men.


METHODS
In vitro, human cultured endothelial cells were treated with native low-density lipoprotein (LDL), oxidized LDL or tumor necrosis factor (TNF)alpha in the absence and in the presence of carvedilol (40 micro M); 8-iso-prostaglandin (PG)F(2alpha), as parameter of oxidative stress, was determined in the supernatants. In a double-blind, randomized, cross-over study, 17 healthy men received 25 mg carvedilol b.i.d., 100 mg metoprolol b.i.d. or placebo for 6 days. After each treatment, systemic oxidative stress was assessed by measuring urinary excretion of 8-iso-PGF(2alpha) and 2,3-dinor-5,6-dihydro-8-iso-PGF(2alpha), and the plasma concentration of 3-nitrotyrosine by means of gas chromatography-tandem mass spectrometry. In addition, thiobarbituric acid-reactive substances (TBARS) in plasma were assessed using spectrophotometry.


RESULTS
Native LDL and oxidized LDL induced 8-iso-PGF(2alpha) production in endothelial cells. Carvedilol significantly reduced this effect (e.g., for oxidized LDL: 2.66+/-0.22 pg vs 1.46+/-0.14 pg 8-iso-PGF(2alpha) per micro g protein, P<0.05). In healthy volunteers, carvedilol and metoprolol markedly decreased blood pressure and heart rate, but had no statistically significant effect on any indicator of oxidative stress measured. Remarkably, a trend toward reduction of urinary isoprostanes and 3-nitrotyrosine in plasma by both active treatments was observed, suggesting a non-specific antioxidative effect by beta blockade.


CONCLUSIONS
In vitro, the antioxidative potential of carvedilol was confirmed. In healthy men, antihypertensive doses of carvedilol exert no specific inhibition of oxidative stress.
Institute of Clinical Pharmacology, Medizinische Hochschule Hannover, 30623 Hannover, Germany.
Stefanie A
SA
Fahlbusch
Dimitrios
D
Tsikas
Christina
C
Mehls
Frank-Mathias
FM
Gutzki
Rainer H
RH
Böger
Jürgen C
JC
Frölich
Dirk O
DO
Stichtenoth
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D018592:Cross-Over Studies; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism; D004311:Double-Blind Method; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D028421:Isoprostanes / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
C411579:2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2(alpha); D018674:Adrenergic Antagonists; D000975:Antioxidants; C103832:BM 910228; D002227:Carbazoles; D028421:Isoprostanes; D008077:Lipoproteins, LDL; D011412:Propanolamines; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D000077261:Carvedilol; C002744:3-nitrotyrosine; D014443:Tyrosine; D015237:Dinoprost; D008790:Metoprolol; D015232:Dinoprostone; C011987:8-isoprostaglandin E2