PROTECTIVE EFFECTS OF THE THIOPHOSPHATE AMIFOSTINE (WR-2721) AND A LAZAROID (U83836E) ON LIPID-PEROXIDATION IN ENDOTHELIAL-CELLS DURING HYPOXIA REOXYGENATION/
K. Mertsch et al., PROTECTIVE EFFECTS OF THE THIOPHOSPHATE AMIFOSTINE (WR-2721) AND A LAZAROID (U83836E) ON LIPID-PEROXIDATION IN ENDOTHELIAL-CELLS DURING HYPOXIA REOXYGENATION/, Biochemical pharmacology, 56(8), 1998, pp. 945-954
Little is known about pharmacological interventions with thiophosphate
s or lazaroids in endothelial cells injured by hypoxia/reoxygenation w
ith respect to membrane lipid peroxidation (LPO) caused by reactive ox
ygen species. Therefore, a cell line of bovine aortic endothelial cell
s was studied after 120-min hypoxia followed by 30-min reoxygenation,
resulting in moderate and predominantly reversible injury (energy depr
ession/cytosolic Ca2+-accumulation during hypoxia, which almost normal
ized during reoxygenation; membrane blebs, an increasing amount of lys
osomes, vacuolization, lipofuscin formation, alterations in mitochondr
ia size, some lyzed cells). 18.9 +/- 4.3% of the cells died. Radical i
nduced LPO measured as malondialdehyde continuously increased to 2.18
+/-: 0.17 nmol/mg of protein after reoxygenation vs control (0.41 +/-
0.13, P < 0.05). Simultaneously, the content of 4-hydroxynonenal, a no
vel indicator of LPO, increased from 0.02 +/- 0.01 to 0.11 +/- 0.02 nm
ol/mg of protein (P < 0.01). The results support the assumption that r
eoxygenation injury is accompanied by an increase in membrane LPO, cau
sing structural and functional disturbances in the monolayer. The thio
phosphate WR 2721 [S-2-(3-aminopropylamino) ethylphosphorothioic acid]
and the lazaroid U83836E {(-)-2-[[4-(2,6-di-1-pyrrolidinyl 4-pyrimidi
nyl)-1-piperazinyl] 4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol
(dihydrochloride)} were effective scavengers of (OH)-O-., being more
efficient than trolox C (6-hydroxy-2,5,7,8-tetramethylchroman-2-carbon
acid) used as standard (EC50: 12, 5 and 15 mu M, respectively, measur
ed by electron spin resonance spectroscopy). One mM WR 2721, 10 mu M U
83836E, and 5 mu M trolox C reduced formation of malondialdehyde durin
g hypoxia/reoxygenation to 53 +/- 7, 51 +/- 10 and 48 +/- 6%, respecti
vely (P < 0.05 each, versus control). In general, WR 2721 and U83836E
prevent radical-induced membrane LPO in a model of endothelial cells i
njured by hypoxia/reoxygenation. The use of these two agents is a new
approach to protect the endothelium against oxidative stress. (C) 1998
Elsevier Science Inc.