| Research Abstract |
Although intraoperative ischemia/hypoxia-reperfusion/reoxygenation of the liver generally occurs under general anesthesia, little is known about the direct effect of volatile anesthetic agents on hepatic injury due to this phenomenon. The effect of volatile anesthetics on ischemia/hypoxia-reperfusion injury was studied using isolated liver perfusion.
The liver was isolated from 24h-fasted, male Sprague-Dawley rats and perfused through the portal vein with a modified Krebs-Ringer bicarbonate solution in a recirculating perfusion-aeration system. Ischemia was induced by reducing the bascline perfusion pressure from 1.2 to 0.2 kPa followed by reperfusion to baseline level. Hypoxic perfusion was produced by decreasing the oxygen concentration in the gas mixture from 95% to 10% followed by reoxygenation at 95% oxygen. Viability of the liver was assessed by lactate dehydrogenase (LDH) release from the liver. To determine the effect of volatile anesthetics on the extracellular generation of su
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peroxide in the liver, the reduction of ferricytochrome c with or without superoxide dismutase was measured.
Ischemia was evident by reduced oxygen delivery to the liver, and caused an increase in lactate production. Reperfusion caused a transient increase in lactate uptake and a significant increase in LDH release. Halothane, isoflurane and sevoflurane significantly attenuated LDH release during reperfusion. The suppression of LDH release was evident even when isoflurane was administered mainly during reperfusion period, but not when it was administered mainly during ischemia. These results indicate that volatile anesthetics may protect the fasted liver from carly, neutrophil-independent, ischemia reperfusion injury by acting during the reperfusion phase.
LDH release was transiently but dramatically increased by reoxygenation and significantly attenuated by 1 and 2 minimum alvcolar concentrations of isoflurane. Suppression of Kupffer cells with gadolinium chloride also attenuated the LDH release. Isoflurane significantly reduced the superoxide generation on reperfusion. These results show that isoflurane protected the liver from early reoxygenation injury presumably mediated by Kupffer cells. The mechanisms of the inhibitory effect of isoflurane on the injury may involve suppression of extracellular superoxide generation during reoxygenation.
Isolated rat livers with cell free perfusion were exposed to various periods of ischemia-reperfusion or hypoxia-reoxygenation. Hepatic oxygen consumption and alanine aminotransferase leakage from liver were determined during perfusion. The gene expression of heat shock protein 70, a major stress protein, of the liver was analyzed by Nothern blotting after perfusion. The expression of heat shock protein 70 mRNA augmented as the reperfusion period increased. The expression level after graded ischemia or hypoxia significantly correlated with the calculated hepatic oxygen bebt (r^2=0.737, p<0.001, n=21). These results suggest that accumulation of heat shock protein 70 mRNA reflects the severity of ischemia-reperfuion and hypoxia-reoxygenation injuries, and that stress response in reperfusion can be triggered without formed elements of blood.
Altcrations in intracellular calcium homeostasis have been implicated in ischemia-reperfusion injuries. The effects of volatile anesthetics on the hemodynamic and metabolic alterations induced by the calcium ionophore A23187 were studied using isolated liver perfusion in fasted rats. Halothane, isoflurane and sevoflurane maintained basal hepatic flow, reduced oxygen consumption, and transiently enhanced net lactate production. All anesthetics significantly attenuated the decreases in hepatic flow and oxygen consumption after the administration of A23187. Volatile anesthetics may attenuate the hepatic vasoconstriction and oxygen debt induced by intracellular calcium overload. Less
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