Carvedilol, a new antihypertensive agent, prevents lipid peroxidation and oxidative injury to endothelial cells.
The protective effects of carvedilol, a new beta-adrenergic receptor blocker and vasodilating antihypertensive agent, against oxygen free radical-mediated injury were studied in cultured bovine endothelial cells and compared with five other beta-blockers. Carvedilol dose-dependently inhibited oxygen radical-induced lipid peroxidation (50% inhibition at 2.6 mumol/L) and glutathione depletion (50% inhibition at 1.8 mumol/L) in the cells. Under the same conditions, other beta-blockers--propranolol, labetalol, pindolol, atenolol, and celiprolol--had only mild or no effect. Moreover, carvedilol protected against oxygen radical--mediated cell damage, as assessed by cellular lactate dehydrogenase release, with a 50% inhibition at 4.1 mumol/L and increased the cell survival in a dose-dependent manner, whereas other beta-blockers had mild or no effects. Pretreatment of the cells with carvedilol for 7 days significantly enhanced the protective effects of carvedilol. Using 2-methyl-2-nitrosopropane as a trapping agent, the spin adduct in cell lipids was monitored by electron paramagnetic resonance. Carvedilol dose-dependently decreased the intensity of the free radical signals, indicating its free radical-scavenging ability. The prevention of oxidative injury to endothelial cells might potentially contribute to the clinical beneficial effects of carvedilol as an antihypertensive agent.
Yue
T L
TL
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Mckenna
P J
PJ
Gu
J L
JL
Cheng
H Y
HY
Ruffolo
R R
RR
Feuerstein
G Z
GZ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers; D005609:Free Radicals; D005978:Glutathione / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011341:Probucol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000009:adverse effects
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002227:Carbazoles; D016166:Free Radical Scavengers; D005609:Free Radicals; D011412:Propanolamines; D017382:Reactive Oxygen Species; D000077261:Carvedilol; D009529:Nicardipine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D011341:Probucol