Abstract
To evaluate the effect of pentoxifylline on altered hepatocyte calcium regulation and hepatocyte oxidant injury after hemorrhagic shock. Prospective, randomized, controlled study. University research laboratory. Anesthetized, male Sprague-Dawley rats, weighing 220 to 300 g. 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. 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. 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.
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