Hydroperoxide metabolism in rat liver. K+ channel activation, cell volume changes and eicosanoid formation.
Addition of t-butylhydroperoxide (0.2 mM) to isolated perfused rat liver led to a net K+ release of 7.2 +/- 0.2 mumol/g within 8 min and a net K+ reuptake of 6.6 +/- 0.4 mumol/g following withdrawal of the hydroperoxide, in line with earlier findings by Sies et al. [Sies, H., Gerstenecker, C., Summer, K. H., Menzel, H. & Flohé, R. (1974) in Glutathione (Flohé, L., Benöhr, C., Sies, H., Waller, H. D., eds) pp. 261-276, G. Thieme Publ. Stuttgart]. Net K+ release roughly paralleled the amount of GSSG released from the liver under the influence of the hydroperoxide. The t-butylhydroperoxide-induced K+ efflux was inhibited by approximately 70% in the presence of Ba2+ (1 mM), by 30% in Ca(2+)-free perfusions and was decreased by 50-60% when the intracellular Ca2+ stores were simultaneously depleted by repeated additions of phenylephrine. t-Butylhydroperoxide-induced K+ efflux was accompanied by a decrease of the intracellular water space by 58 +/- 14 microliter/g (n = 4), corresponding to a 10% cell shrinkage. The effect of t-butylhydroperoxide on cell volume was inhibited by 70-80% in the presence of Ba2+. In isolated rat hepatocytes treatment with t-butylhydroperoxide led to a slight hyperpolarization of the membrane at concentrations of 100 nM, but marked hyperpolarization occurred at t-butylhydroperoxide concentrations above 10 microM. t-Butylhydroperoxide (0.2 mM) transiently increased the portal-perfusion pressure by 3.3 +/- 0.6 cm H2O (n = 18), due to a slight stimulation of prostaglandin-D2 release under the influence of the hydroperoxide. In the presence of Ba2+ (1 mM), t-butylhydroperoxide increased the perfusion pressure by 12.7 +/- 1.2 cm H2O (n = 9) and produced an approximately tenfold increase of prostaglandin-D2 and thromboxane-B2 release. Under these conditions, glucose output from the liver rose from 0.9 +/- 0.03 to 2.9 +/- 0.7 mumol.g-1.min-1 (n = 4) with a time course roughly resembling that of portal-pressure increase and prostaglandin-D2 overflow. These effects were largely abolished in the presence of ibuprofen or the thromboxane-receptor-antagonist BM 13.177. The t-butylhydroperoxide effects on perfusion pressure, glucose and eicosanoid output were also enhanced in the presence of insulin or during hypotonic exposure; i.e. conditions known to swell hepatocytes, but not during hyperosmotic exposure. The data suggest that t-butylhydroperoxide induces liver-cell shrinkage and hyperpolarization of the plasma membrane due to activation of Ba(2+)-sensitive K+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)
Hallbrucker
C
C
Medizinische Universitätsklinik Freiburg, Federal Republic of Germany.
Ritter
M
M
Lang
F
F
Gerok
W
W
Häussinger
D
D
D000818:Animals; D001464:Barium / Q000494:pharmacology; D015777:Eicosanoids / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009994:Osmolar Concentration; D010477:Perfusion; D010545:Peroxides / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011312:Pressure; D015230:Prostaglandin D2 / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000096:biosynthesis; D020122:tert-Butylhydroperoxide
D015777:Eicosanoids; D010545:Peroxides; D015221:Potassium Channels; D001464:Barium; D013929:Thromboxane B2; D020122:tert-Butylhydroperoxide; D011188:Potassium; D015230:Prostaglandin D2