Calcium channel blocker and renal mitochondrial function in warm renal ischemia. (1/125)

OBJECTIVE: Ions, particularly calcium ions, play an important role in ischemia-reperfusion cell injury. In this study, we investigated the action of verapamil on the mitochondrial function of kidneys submitted to ischemia without blood reperfusion in order to study isolated early and late ischemic effects. MATERIALS AND METHODS: 44 rats were submitted to bilateral warm renal ischemia for 30 minutes. The kidneys were then immediately reperfused with saline or Euro-Collins (EC) solution, with and without previous administration of 0.35 mg/kg of verapamil. Mitochondrial function was assessed at the end of renal perfusion and after 24 hours of cold preservation. RESULTS: In kidneys perfused with saline, verapamil allowed a significant early preservation of state III mitochondrial respiration, a result that was no longer evident after 24 hours. In kidneys perfused with EC solution, verapamil did not change state III for either early or late evaluations. Comparison of the groups showed that the results obtained for kidneys perfused with EC were always superior to those obtained for the saline group, except for the initial analysis of kidneys treated with saline and verapamil, which showed results similar to those obtained with EC perfusion alone. CONCLUSION: Administration of verapamil before warm ischemia provides partial and short-lasting functional protection of the mitochondrial function in kidneys perfused with sodium rich saline. With Euro-Collins solution, verapamil did not show any additional beneficial effect. This fact permits us to conclude that protective action is effective only under conditions that facilitate increased sodium uptake and/or potassium loss.  (+info)

Major effects of delayed graft function and cold ischaemia time on renal allograft survival. (2/125)

BACKGROUND: There is mounting evidence from experimental and clinical studies that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death, and that these may affect transplant outcome. The aim of this study is to investigate the influence of donor factors on renal allograft outcome in a homogeneous cohort of 518 patients transplanted in a single centre over a 9 year period. METHODS: Endpoints of the study were delayed graft function (DGF), acute rejection (AR), 1 year graft survival and long-term survival of those grafts that reached 1 year. Multivariate analysis was performed to determine factors that may have influenced the graft outcome indicators. RESULTS: DGF was the major predictor of graft failure overall with cold ischaemia time (CIT) as an important independent factor. The level of histocompatibility did not influence graft survival. DGF was the major factor affecting 1 year graft survival (P<0.0005) with effects persisting beyond 1 year. DGF was significantly influenced by CIT, donor age, female kidney into male recipient and donor creatinine (P<0.05). Other donor factors and factors associated with donor management were not risk factors for DGF, rejection episodes or graft survival. The risk factors for a number of AR episodes were HLA-DR mismatch and DGF (P<0.005). When grafts surviving for 1 year were considered, only CIT, recipient age and creatinine at 1 year (P<0.05) were found to affect graft survival significantly. CONCLUSIONS: The results of this analysis of well-matched transplant recipients show that CIT and DGF are the most important predictors of poor short and long-term graft survival. Therefore, in order to improve the long-term survival of renal allografts efforts should focus on limiting CIT and the damage that occurs during this period and on improving our understanding of DGF.  (+info)

Glycine intravenous donor preconditioning is superior to glycine supplementation to low-potassium dextran flush preservation and improves graft function in a large animal lung transplantation model after 24 hours of cold ischemia. (3/125)

OBJECTIVES: The potential role of glycine in combination with standard lung preservation with low-potassium dextran solution in lung ischemia-reperfusion injury has not been investigated in a preclinical porcine transplant model. METHODS: In a control group (n = 6), donor lungs were flushed with 1 liter of low-potassium dextran solution. In a second group (LPD-glyc, n = 6), low-potassium dextran solution was supplemented with 3.75 g of glycine. In a third group (IV-glyc, n = 6), donor preconditioning was performed by intravenous administration of 3.75 g glycine 1 hour before low-potassium dextran preservation. Grafts were stored in low-potassium dextran at 4 degrees C for 24 hours. Posttransplant graft function was assessed throughout a 7-hour observation period. RESULTS: In the control group, 2 recipients died of right-sided heart failure caused by severe ischemia-reperfusion injury. All animals of the glycine groups survived the entire observation period. Pulmonary vascular resistance remained significantly (P < .01) lower in both glycine groups when compared with controls. At the end of the observation period pulmonary vascular resistance in the control group was higher (P < .01) compared with the glycine groups (1310 +/- 319 dyn x sec x cm(-5) vs 879 +/- 127 dyn x sec x cm(-5) [LPD-glyc] vs 663 +/- 191 dyn x sec x cm(-5) [IV-glyc]). Changes of lung tissue water content were lower in the IV-glyc group compared with the LPD-control (P < .01) and LPD-glyc lungs (P < .05). Oxygenation (PO2/FiO2) was higher in the IV-glyc group compared with the LPD-glyc and control lungs (445 +/- 110 mm Hg vs 388 +/- 124 mm Hg [P < .01] vs 341 +/- 224 mm Hg [P < .001], respectively). DISCUSSION: Modification of low-potassium dextran solution with glycine or donor preconditioning ameliorates ischemia-reperfusion injury in lung transplantation. This intriguing approach merits further evaluation with respect to the mechanisms involved and may improve results in clinical lung preservation.  (+info)

In situ demonstration of improvement of liver mitochondria function by melatonin after cold ischemia. (4/125)

In a previous investigation, reperfusion with a melatonin-containing medium was demonstrated to enhance bile production and tissue ATP levels in rat livers, cold-preserved with University of Wisconsin (UW) or Celsior solutions, with respect to melatonin-free reperfusion; lipid peroxidation products in the perfusate were not influenced by the indole. This was ascribed to an increased efficiency of the hepatocyte mitochondria induced by melatonin. Reactive oxygen species (ROS) normally leak from the electron transfer chain in mitochondria and excessive ROS production is presumed to mediate ischemia-reperfusion (I/R) damage. A histochemical reaction was used to demonstrate ROS on the same model. Compared to the lobular zonation of ROS in control livers, the stained area of cold-preserved livers reperfused without melatonin was restricted to a narrow portal region, in keeping with the much lower ATP content. When reperfusion was performed with melatonin, the liver morphology was improved and the ROS reaction in hepatocytes more intense, though not reaching the control liver pattern. Sinusoidal cells were poorly-stained in both cases. In conclusion, with this different approach, melatonin was confirmed to improve mitochondrial performance and to discriminate parenchymal from sinusoidal cell behavior. Our observations confirm that melatonin mitigates I/R injury and support its potential in liver transplantation.  (+info)

Cardioprotective effects of tetrahydrobiopterin in cold heart preservation after cardiac arrest. (5/125)

BACKGROUND: It has recently been shown that tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), reduces ischemia-reperfusion myocardial injury. The aim of this study was to determine if supplementation with BH4 after cardiac arrest followed by cold heart preservation would exert a cardioprotective effect against ischemia-reperfusion injury. MATERIALS AND METHODS: Isolated perfused rat hearts were subjected to 4 degrees C cold ischemia and reperfusion. Hearts were treated with cold cardioplegic solution with or without BH4 just before ischemia and during the first 5 min of reperfusion period. Effects of BH4 on left ventricular function, myocardial contents of high-energy phosphates, and nitrite plus nitrate were measured in the perfusate, before ischemia and after reperfusion. Moreover, the effect of BH4 on the cold-heart preservation followed by normothermic (37 degrees C) ischemia was determined. RESULTS: BH4 improved the contractile and metabolic abnormalities in reperfused cold preserved hearts that were subjected to normothermic ischemia. Furthermore, BH4 significantly alleviated ischemic contracture during ischemia, and restored the diminished perfusate levels of nitrite plus nitrate after reperfusion. CONCLUSION: These results demonstrated that BH4 reduces ischemia-reperfusion injury in cold heart preservation. The cardioprotective effect of BH4 implies that BH4 could be a novel and effective therapeutic option in the preservation treatment of donor heart after cardiac arrest.  (+info)

Mediators of rat ischemic hepatic preconditioning after cold preservation identified by microarray analysis. (6/125)

Hepatic ischemia-reperfusion injury associated with liver transplantation is an as yet unresolved problem in clinical practice. Preconditioning protects the liver against the deleterious effects of ischemia, although the mechanism underlying this preconditioning is still unclear. To profile gene expression patterns involved in hepatic ischemic preconditioning, we analyzed the changes in gene expression in rat livers by DNA microarray analysis. Approximately 116 genes were found to have altered gene expression after 8 hours of cold ischemia. Moreover, the expression of 218 genes was modified by classic preconditioning followed by the same ischemia process. Given the importance of the effects of ischemic preconditioning (IP) in minimizing the liver damage induced by sustained ischemia before reperfusion, this study analyzed the putative genes involved in the beneficial role of IP in liver grafts undergoing cold ischemia before its implantation in the recipient (IP+I). Great differences were found in the gene expression pattern of ischemic preconditioning + long cold ischemia (IP+I) group when compared with the long cold ischemia alone condition (I), which could explain the protective regulatory mechanisms that take place after preconditioning. Twenty-six genes that were downregulated in cold ischemia were found upregulated after preconditioning preceding a long cold ischemia period. These would be genes activated or maintained by preconditioning. Heat shock protein genes and 3-hydroxy-3-methylglutaryl-coenzyme A reductase are among the most markedly induced transcripts.  (+info)

Prolonging warm ischemia reduces the cold preservation limits of liver grafts in swine. (7/125)

BACKGROUND: The critical shortage of transplantable organs necessitates utilization of unconventional donors. But the safe time limits of cold preservation of liver grafts subjected to warm ischemia (WI) for up to 30 minutes from non-heart-beating-donors (NHBDs) has not been delineated. In this study, we investigated how the limits of cold ischemia (CI) in University of Wisconsin (UW) solution are changed in liver grafts subjected to WI from 10 to 30 minutes. METHODS: A simple porcine NHBD liver transplantation (LT) model was developed. In donors, livers were subjected to 10, 20 or 30 minutes of WI and subsequent different times of CI in UW solution. Animals were divided into three groups (WI 10 min, WI 20 min, WI 30 min, n=13 in each group) and nine subgroups (from CI 6 h to CI 28 h). One-week survival rates of recipients, hepatic function, liver energy metabolism, grafted liver microcirculation and pathological observations of the liver were compared. RESULTS: In the WI 10 min group, the one-week survival rate of the CI 20 h subgroup was significantly higher than in the other two subgroups (CI 24 h and CI 28 h) (P<0.05). Furthermore, the CI 20 h subgroup had a lower level of alanine aminotransferase (ALT), less pathological damage, a higher concentration of adenosine triphosphate (ATP) and microcirculatory blood flow in the grafted livers at 1 hour after reperfusion than the other two subgroups. The same trends were also found in the other two groups (WI 20 min and WI 30 min) and their subgroups. CONCLUSIONS: The cold preservation limits of the liver grafts shortened from 20 to 12 to 6 hours when WI time was prolonged from 10 to 20 to 30 minutes. Only the liver grafts within these time limits could be safely transplanted.  (+info)

Novel short-term hypothermic oxygenated perfusion (HOPE) system prevents injury in rat liver graft from non-heart beating donor. (8/125)

OBJECTIVE: To assess a machine perfusion system in rescuing liver grafts from non-heart-beating donors (NHBD). SUMMARY BACKGROUND DATA: The introduction of extracorporeal liver perfusion systems in the clinical routine depends on feasibility. Conceivably, perfusion could be performed during recipient preparation. We investigated whether a novel rat liver machine perfusion applied after in situ ischemia and cold storage can rescue NHBD liver grafts. METHODS: We induced cardiac arrest in male Brown Norway rats by phrenotomy and ligation of the subcardial aorta. We studied 2 experimental groups: 45 minutes of warm in situ ischemia + 5 hours cold storage versus 45 minutes of warm in situ ischemia + 5 hours cold storage followed by 1 hour hypothermic oxygenated extracorporeal perfusion (HOPE). In both groups, livers were reperfused in a closed sanguineous isolated liver perfusion device for 3 hours at 37 degrees C. To test the benefit of HOPE on survival, we performed orthotopic liver transplantation in both experimental groups. RESULTS: After cold storage and reperfusion, NHBD livers showed necrosis of hepatocytes, increased release of AST, and decreased bile flow. HOPE improved NHBD livers significantly with a reduction of necrosis, less AST release, and increased bile flow. ATP was severely depleted in cold-stored NHBD livers but restored in livers treated by HOPE. After orthotopic liver transplantation, grafts treated by HOPE demonstrated a significant extension on animal survival. CONCLUSIONS: We demonstrate a beneficial effect of HOPE by preventing reperfusion injury in a clinically relevant NHBD model.  (+info)

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