Pentoxifylline prevention of altered hepatocyte calcium regulation during hemorrhagic shock/resuscitation.
OBJECTIVE
To evaluate the effect of pentoxifylline on altered hepatocyte calcium regulation and hepatocyte oxidant injury after hemorrhagic shock.


METHODS
Prospective, randomized, controlled study.


METHODS
University research laboratory.


METHODS
Anesthetized, male Sprague-Dawley rats, weighing 220 to 300 g.


METHODS
Hemorrhagic shock was induced by bleeding rats to a mean arterial blood pressure of 40 mm Hg for 60 min. Rats were then resuscitated with 60% of shed blood and three-fold the bleed out volume of lactated Ringer's solution without and with pentoxifylline (50 mg/kg body weight). After hepatocyte isolation by portal collagenase perfusion, the rate of hepatocyte calcium influx (Ca2+in) in the absence and presence of epinephrine (100 nM), both cellular Ca2+ uptake (Ca2+up) and membrane Ca2+ flux (Ca2+flux) were determined, using 45Ca2+ incubation techniques. Hepatocyte lipid peroxidation was fluorometrically determined by thiobarbituric acid-reactive substances.


RESULTS
Pentoxifylline inhibited the significant increase of hepatocyte Ca2+in, Ca2+up, and Ca2+flux observed in untreated rats subjected to hemorrhage/resuscitation. In shocked rats, pentoxifylline restored the impaired epinephrine-induced Ca2+ influx response and prevented increased hepatocyte lipid peroxidation.


CONCLUSIONS
The protective effects of pentoxifylline could be attributed to its known anti-inflammatory properties reducing excessive in vivo stimulation of hepatocytes by Ca2+ agonistic mediators and attenuating oxygen radical-related disturbances of transmembrane Ca2+ transport mechanisms. Since altered cellular Ca2+ regulation is a key event of cellular dysfunction, resuscitation with pentoxifylline after hemorrhagic shock/resuscitation may provide an adjuvant therapeutic tool to prevent postischemic hepatic failure.
Silomon
M
M
Department of Anesthesiology, University of Saarland, Homburg/Saar, Germany.
Pizanis
A
A
Larsen
R
R
Rose
S
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D017392:Thiobarbituric Acid Reactive Substances
D000893:Anti-Inflammatory Agents; D017392:Thiobarbituric Acid Reactive Substances; D005978:Glutathione; D010431:Pentoxifylline; D002118:Calcium; D004837:Epinephrine