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Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365
The aim of this study was to determine if the
effect of prostaglandin E2
(PGE2) on hepatic oxygen uptake
was affected by oxygen tension. Livers from fed female Sprague-Dawley
rats were perfused at normal or high flow rates (4 or 8 ml · g
1 · min
1)
to vary local oxygen tension within the liver lobule. During perfusion
at normal flow rates, PGE2 (5 µM) infusion increased oxygen uptake by about 50 µmol · g
1 · h
1;
however, when livers were perfused at high flow rates, the increase was
nearly twice as large. Simultaneously, glucose output was increased
rapidly by about 50%, whereas glycolysis was decreased about 60%.
When flow rate was held constant, increases in oxygen uptake due to
PGE2 were proportional to oxygen
delivery. Infusion of PGE2 into
livers perfused at normal flow rates increased state 3 rates of oxygen uptake of subsequently isolated
mitochondria by about 25%; however, rates were increased 50-75%
in mitochondria isolated from livers perfused at high flow rates. Thus
it is concluded that PGE2
stimulates oxygen uptake via mechanisms regulated by oxygen tension in
perfused rat liver. High flow rates also increased basal rates of
oxygen uptake: this increase was prevented by inactivation of Kupffer
cells with GdCl3. In addition,
conditioned medium from Kupffer cells incubated at high oxygen tension
(75% oxygen) stimulated oxygen uptake of isolated parenchymal cells by
>30% and elevated PGE2
production about twofold compared with Kupffer cells exposed to normal
air-saturated buffer (21% oxygen). These effects were blocked
completely by both indomethacin and nisoldipine. These data support the
hypothesis that oxygen stimulates Kupffer cells to release mediators
such as PGE2 which elevate oxygen
consumption in parenchymal cells, possibly by mechanisms involving
cyclooxygenase and calcium channels.
Kupffer cells; eicosanoids; hypermetabolic state
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