Protective effect of ebselen on constrictive hepatic vasculature: prevention of alcohol-induced effects on portal pressure in perfused livers.
The effect of an organoselenium compound, ebselen [2-phenyl-1,2-benzisoselenazol-3-(2H)-one], on ethanol-induced liver damage through perturbation of microcirculation was investigated in perfused livers from fed rats. Infusion of ethanol at concentrations > or = 25 mM into the portal vein increased portal pressure in a concentration-dependent manner. Release of lactate dehydrogenase (LDH) into the effluent perfusate was minimal at 30 min; thereafter LDH release began to increase gradually until the end of the experiment (60 min after the onset of ethanol infusion) and was dependent on ethanol concentration. Simultaneous infusion of ebselen at a concentration of 10 or 30 microM with ethanol reduced significantly this ethanol-induced increase in portal pressure by 50 to 75% (P < .05) and LDH release by 70% (P < .05). When endothelin-1 or phenylephrine was infused into the liver, portal pressure was increased, reaching maximal levels (50 +/- 17 and 46 +/- 7 mm of H2O, respectively) and then decreasing gradually. Ebselen reduced the maximal increase in portal pressure induced by endothelin-1 (18 +/- 2 mm of H2O) by 64% (P < .05). In addition, ebselen decreased the maximal levels of portal pressure induced by phenylephrine (8 +/- 1 mm of H2O) by 83% (P < .05). These data indicate that ebselen has a vasodilative effect on constriction of hepatic vasculature and diminishes ethanol-induced hepatic damage by offsetting ethanol-induced increase in portal pressure. Thus, ebselen may prove useful for treatment of alcoholic liver injury via improvement of microcirculatory disturbances.
First Department of Medicine, Osaka University Medical School, Japan.
M
M
Oshita
Y
Y
Takei
S
S
Kawano
H
H
Fusamoto
T
T
Kamada
D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity*; D054833:Isoindoles; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010477:Perfusion; D010656:Phenylephrine / Q000494:pharmacology; D017082:Portal Pressure / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
D001393:Azoles; D016232:Endothelins; D054833:Isoindoles; D016566:Organoselenium Compounds; D010656:Phenylephrine; D000431:Ethanol; C042986:ebselen; D007770:L-Lactate Dehydrogenase