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Heparin Fragments Effects in Liver Injury Secondary to Liver Ischemia/Reperfusion (I/R)
ÊNio R. Vasques^*1, José Eduardo M. Cunha¹, ANA Maria M. Coelho¹, EMíLio E. Abdo¹, Sandra N. Sampietre¹, Helena B. Nader², Ivarne S. Tersariol², Eleazar Chaib¹, Luiz Augusto C. D'Albuquerque^1
1GASTROENTEROLOGY, FMUSP, São Paulo, Brazil; ²MOLECULAR BIOLOGY, UNIFESP, SÃO PAULO, Brazil

Background: Ischemia and reperfusion (I/R) is an essential phenomena in tissue damage in pathological conditions such as acute myocardial infarction, liver surgery and organ transplantation. Intracellular calcium concentrations are determining factors in cell death induced by I/R. It is estimated that 60% of the calcium entering into the cell is regulated by the sodium calcium exchanger (Na-Ca exg). In calcium overload situations the exchanger can operates extrusion of intracellular calcium excess. Therefore, if the intracellular calcium homeostasis is related to cell death in the presence of calcium overload, drugs acting on the Na-Ca exg could be a strategy to minimize hepatocellular injury. Some heparin fragments such as Trissulfated Disaccharide (TD) act on the Na-Ca exg inhibiting the exchange inhibitory peptide (XIP), which inhibits the cytoplasmic calcium extrusion, and consequently decreases the intracellular calcium overload. XIP inhibition is applicable as a possible new strategy to minimize hepatotoxicity secondary to the ischemia/reperfusion injury due to calcium overload.
Objective: To evaluate the effects of TD administration in liver injury secondary to the ischemia/reperfusion in rats.
Methods: Wistar male rats, kept under mechanical ventilation, underwent partial liver ischemia induced by 60 min. pedicle clamping of medium and left anterior lateral segments. Animals were divided into 2 groups: Control Group (n=12): rats receiving saline solution 10 minutes before reperfusion, TD Group (n=12): rats receiving TD in a dosage of 0.2 mg/kg IV, 10 minutes before reperfusion The volume administered of each drug was 0.4 ml. Four hours after reperfusion, blood was collected for determinations of AST and ALT. Liver tissue samples were assembled for mitochondrial oxidation and phosphorylation and malondialdehyde (MDA) content. Pulmonary vascular permeability was also determined.
Results: Four hours after liver reperfusion AST and ALT serum level increases in TD Group animals were significantly lower than in Control Group (p<0.05).
Significant reductions of liver MDA content and ofmitochondrial dysfunction were observed in TD Group when compared to Control Group (p<0.05). No differences in pulmonary vascular permeability were observed between the two groups.
Conclusion: TD maintains liver mitochondrial function and increases liver tolerance to I/R injury. These effects require further evaluation before the introduction of this drug in the clinical setting.

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