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, Design: Prospective, randomized, controlled study, Setting: University research laboratory, Subjects: Anesthetized, male Sprague-Dawley rats, weighing 220 to 300 g, Interventions: 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 (Ca-in(2+)) in the absence and presence of epinephrine (100 nM), both cellular Ca2+ uptake (Ca-up(2+)) and membrane Ca2+ flux (Ca-flux(2+)) were determined, using Ca-45(2+) incubation techniques, Hepatocyte lipid peroxidation was fluorometrically determined by thiobarbituric acid-reactive substances, Measurements and Main Results: Pentoxifylline inhibited the significant increase of hepatocyte Ca-in(2+), Ca-up(2+), and Ca-flux(2+) 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 media tors and attenuating oxygen radical related disturbances of trans membrane 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.