Mitsuhiro Terasaki

Hemodynamics and Hepatic Energy Metabolism in Canine Model of Acute Hepatic Venous Occlusion with Mesocaval Shunt

The relationship between portal hemodynamics and the energy metabolism of the liver with acute hepatic venous occlusion (HVO) was investigated by assessing the changes in the hepatic blood flow, arterial blood ketone body ratio (AKBR) and adenylate energy charge potential (ECP) of the liver tissue in canine model. Acute HVO was induced by the ligation of both the supra- and infrahepatic inferior vena cava (IVC) over the protruding ends of a heparin-coated polyethylene cannula inserted into the IVC. All dogs with only HVO (n = 5) died within 30 min. HVO dogs with additional mesocaval (MC) shunt (n = 10) survived longer than 7 days, during which time their AKBR were maintained in the normal range (over 1.0). ECP was also maintained above the normal level (over 0.850) during the 28-day period. Along with increasing portal pressure caused by the narrowing of the shunt anastomosis, the hepatic blood flow decrease gradually, resulting in a sudden decrease in AKBR and ECP when the portal pressure increased over 11 mm Hg. It is suggested that the normalization of portal pressure is one of the most important factors for maintaining the hepatic energy metabolism and that MC shunt is an effective therapy for maintaining the function of the liver with HVO, as long as portal pressure can be kept within normal range.

Clinical application of arterialization of portal vein in living related donor partial liver transplantation

Arterialization of the portal vein was employed during hepatic arterial reconstruction in our first few clinical experiences of partial liver transplantation using liver grafts obtained from living related donors. This procedure reduced the time required for revascularization of the grafts to about 25 min, and could in fact reduce the ischemic phase of the grafts. Repeated practice of the clinical transplantation technique has shortened the time needed to complete vascular reconstruction, eliminating the need for this procedure in most of our subsequent cases. In many clinical cases, however, there may be emergency situations which require vascular reconstruction, resulting in a prolongation of ischemic phase and the deterioration of the cellular viability of the graft. In such situations, arterialization of the portal vein can be a useful way to prevent the prolongation of the ischemic phase and to rescue the graft.

Evaluation of the Protective Effect of a Novel Prostacyclin Analog on Mesenteric Circulation following Warm Ischemia

The protective effect of a novel prostacyclin (PGI2) analog, OP-2507, on mesenteric circulation was investigated in a canine warm ischemia model. In 20 mongrel dogs, the entire portion of the intestine supplied by the superior mesenteric artery (SMA) and drained by the superior mesenteric vein (SMV) was completely isolated, maintaining the blood and lymph vessels intact. Sixty or 120 min of complete warm ischemia (WI) of the intestine was induced by clamping SMA and SMV, followed by reperfusion for 120 min. Animals were divided into five groups (each n = 4): group 1, sham operation; group 2, 60 min WI; group 3, 120 min WI; group 4, 60 min WI with PGI2 analog administration; group 5, 120 min WI with PGI2 analog administration. The analog was administered at a rate of 6 micrograms.kg-1.h-1 immediately after laparotomy until the end of the observation period. Mean arterial pressure, SMA blood flow (SMABF), SMV pressure were monitored and total mesenteric vascular resistance (TMVR) was calculated. To evaluate the endothelial activation, endothelin, which is secreted from the endothelium under hypoxic stress, was assayed from blood samples of SMV. None of the animals showed significant changes in mean arterial pressure. In groups 2 and 3, SMABF decreased significantly to less than 60% of preoperative value (15 ml.kg-1.min-1) and TMVR significantly increased from 8.1 and 7.3 mm Hg.ml-1.kg.min before WI to 14.0 and 16.4 mm Hg.ml-1.kg.min after 120 min reperfusion, respectively, resulting in delayed hypoperfusion. In contrast, in groups 4 and 5, SMABF increased to over 100% of preoperative level, while TMVR declined from 7.8 and 8.4 mm Hg.ml-1.kg.min before WI to 6.2 and 6.3 mm Hg.ml-1.kg.min after 120 min reperfusion. After 60 min reperfusion, SMABF and TMVR showed a significant difference between the treated and nontreated groups. Only in group 3, high endothelin concentrations (over 20 pg/ml) were observed even after 120 min reperfusion. It was concluded that the PGI2 analog was able to suppress the endothelial activation and the disturbance of mesenteric circulation caused by WI and reperfusion.

Preserved mitochondrial function by allopurinol despite deteriorated hemodynamics in warm ischemia-damaged canine liver

SummaryTo investigate the pathophysiology of warm ischemia (WI) of the liver, the changes in hemodynamics and energy metabolism were studied during and after 60-min complete WI induced by total hepatic vascular exclusion (HVE) in the canine model. Hepatic arterial blood flow after WI was maintained at 76% of the pre-ischemic level, while portal blood flow was only 27% of the pre-ischemic level associated with increased portal vein pressure, which was twice the pre-ischemic level, resulting in a decrease of total hepatic blood flow to 46% of the pre-ischemic level. Concentration of tissue lipid peroxide increased after WI. Arterial blood ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state, could not recover to the pre-ischemic level after termination of WI. However, when 100 mg/kg of allopurinol (xanthine oxidase inhibitor) was administered intravenously 10 min prior to initiating WI, AKBR was restored to the pre-ischemic level at 30 min after WI in spite of the fact that allopurinol administration to one group produced no remarkable changes in the hepatic hemodynamics compared with the group without allopurinol treatment. Concentration of adenine nucleotides was significantly higher for the treated group at the end of and after WI than for the group without allopurinol treatment and was maintained at a higher level even after WI. Lipid peroxide production was suppressed. Electron microscopic examination revealed that allopurinol treatment could not prevent mitochondrial swelling. It is suggested that WI causes injury primarily to the portal sinusoidal circulation, resulting in portal congestion concomitant with high portal pressure after the release of WI. Allopurinol could prevent the deterioration of mitochondrial ATP metabolism, and was able to inhibit lipid peroxide production, resulting in the rapid recovery of mitochondrial redox state in spite of the fact that it produced no amelioration of hepatic hemodynamics and morphological alterations.

Effects of Transjugular Intrahepatic Portosystemic Shunts on Hepatic Metabolic Function Determined with Serial Monitoring of Arterial Ketone Bodies

PURPOSE To investigate the effects of transjugular intrahepatic portosystemic shunt (TIPS) on hepatic metabolic function by measuring serial arterial ketone body ratio (acetoacetate/-hydroxybutyrate; AKBR). MATERIAL AND METHODS The arterial blood of 30 TIPS patients was assayed before TIPS, 30 minutes after TIPS, and 24 hours after TIPS for acetoacetate, beta-hydroxybutyrate, and glucose. The authors compared the AKBR values to clinical outcome stratified by Child class, emergent versus elective TIPS, and before-TIPS AKBR value < or = 0.5 versus before-TIPS AKBR value > 0.5. RESULTS A significant change was noted between the AKBR values obtained before TIPS and values 30 minutes after TIPS (0.76 +/- 0.09 vs 0.61 +/- 0.05, P < .05) and between 30 minutes and 24 hours after TIPS (0.81 +/- 0.10, P < .001), but not between the value obtained before TIPS and that obtained 24 hours after TIPS. The 30-day mortality rate in emergency TIPS patients was 50% compared to 7% in the elective TIPS patients (P < .01). The pre-TIPS AKBR values were significantly suppressed in the emergency TIPS patients compared to the elective TIPS patients (0.56 +/- 0.04 vs 0.99 +/- 0.17, P < .005). The 30-day mortality rate in patients with a pre-TIPS AKBR value < or = 0.5 was 75%, which was significantly higher than the 14% rate in patients with a pre-TIPS AKBR value > 0.5 (P < .01). CONCLUSION A low pre-TIPS AKBR may be predictive of poor outcome after TIPS. Furthermore, AKBR may be of value in determining the timing for performing an elective TIPS.

Advantageous effect of low-molecular-weight heparin administration on hepatic mitochondrial redox state

The effect of low-molecular-weight heparin (LMWH) on hepatic mitochondrial metabolism was compared with that of unfractionated heparin (UH) after the intravenous administration of these two kinds of heparin to normal rabbits. The magnitude of decrease in blood triglyceride levels 5 min after administration of UH (200 U/kg) was significantly greater than after LMWH (200 U/kg). Free fatty acid levels in the blood were significantly higher after this dose of UH than after LMWH. Blood total ketone body levels (acetoacetate+3-hydroxybutyrate) 15 min after injection of 50 U/kg of UH were significantly higher than those after a dose of 50 U/kg of LMWH, and levels after 200 U/kg of UH were significantly higher than those after 200 U/kg of LMWH at 15, 30, 45 and 60 min. Enhanced ketogenesis was not noted after LMWH at any of the doses, or after UH at 3 U/kg. Arterial ketone body ratio (AKBR; acetoacetate/3-hydroxybutyrate), which reflects the hepatic mitochondrial oxidation-reduction state (NAD+/NADH), was maintained above 1.0 in all groups except in the U-200 group, while AKBR in that group was significantly decreased to 0.99±0.14 at 30 min, and further decreased to 0.80±0.08 at 60 min. These results indicate that LMWH has less effect on lipolysis than UH and does not enhance ketogenesis, resulting in less deterioration of mitochondrial redox state.

A new experimental model of specific liver hypoxia using membrane oxygenator

The present study introduces a new experimental canine model of hepatic arterial deoxygenation using a membrane oxygenator to investigate the influence of hepatic arterial hypoxia on hepatic hemodynamics and energy metabolism. Eighteen mongrel dogs weighing 10 kg each were randomly divided into three groups: group A served as a control (118.0±9.0 mmHg of hepatic arterial O2 content), group B as a moderately deoxygenated group (40 mmHg of hepatic arterial O2 content), and group C as a severely deoxygenated group (25 mmHg of hepatic arterial O2 content). Deoxygenation was achieved by perfusion of a gas mixture of O2 and N2 through the membrane oxygenator, which was interposed between the femoral artery and the proper hepatic artery, for 60 min. In group C, hypoxia decreased the mean systemic arterial blood pressure and hepatic arterial blood flow. Arterial blood ketone body ratio (AKBR=acetoacetate/3-hydroxybutyrate), which reflects the hepatic mitochondrial redox state, rapidly decreased prior to the significant increase of glutamate oxaloacetate transminase, glutamate pyruvate transminase, and lactate dehydrogenase after the initiation of hypoxia. Hepatic arterial deoxygenation to 25 mmHg for 60 min induced injury to hepatic hemodynamics, resulting in the deterioration of systemic hemodynamics even after the termination of liver hypoxia. This in vivo temporal hepatic arterial hypoxic model without alteration of inflow volume might be useful for investigating the mechanism of hypoxic injury and the critical point of liver hypoxia on hepatic and/or systemic hemodynamics and liver viability.