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3-nitrotyrosine. This potent radical is the product of the rapid reaction of NO with oxygen radicals like superoxide and it has been associated with protein oxidation, lipid peroxidation and DNA strand breakage. It is surprising that we could not find any significant differences between treated and untreated groups in both wild type and knockout animals, and this is puzzling since it does not fit with our hypothesis related to the uncoupling of the nNOS. We would have expected significantly less nitrotyrosine formation in grafts of animals showing little microcirculatory derangements but this was not the case. However, since the results so far achieved indicate the prevention of nNOS uncoupling as the most plausible explanation for the observed protective effects of BH4 treatment we suppose shortcomings of the performed analyses related primarily to the pancreatic tissue full of active enzymes degrading proteins and to a certain point to the semiquantitative character of the analyses to be a cause of these discrepant observations. We can also not exclude that the selection of an earlier time point would have revealed differences between treated and untreated groups, since the major amount of oxidative burst is expected to occur immediately after reperfusion. In the light of the most important readouts, which are the prevention of microvascular derangements and the long-term survival of the recipients, both, the histopathological as well as immunohistochemical findings at the chosen time points, are probably of minor importance in this study. Surprisingly, the highly significant results observed in in vivo microcirculation analysis and in survival analysis are not supported by serum amylase and serum lipase levels in the recipient. The increase of serum amylase as well as lipase levels is widely accepted to indicate acinar cell necroses and subsequent tissue damage in pancreatic organs. This is regularly observed during acute pancreatitis as well as MedChemExpress SB366791 following pancreas transplantation. In our study, both parameters were elevated following 4 h reperfusion, showing however no differences between untreated and treated groups, independently of their genotype. This indicates that the knock out of the neuronal NOS isoform could not prevent a certain degree of early reperfusion-associated pancreatitis. We assume that the observed discrepancy between high pancreas enzyme levels in the serum and intact microcirculation in nNOS 2/2 graft recipients is related to the time point chosen for this analysis, probably too early to detect any differences. This fits very well with a clinical observation in pancreas recipients where microcirculatory derangements observed by in vivo orthogonal polarized spectral imaging during the first 30 minutes of graft reperfusion did not correlate with amylase/lipase levels in the nNOS and Graft Reperfusion serum during the first 48 h following reperfusion. A significant inverse correlation could only be detected as late as from day 3 on post transplantation. We suppose therefore that later time points would probably have shown a settling of the pancreatitis parameters in animals surviving the entire observation period. However, comparison between different groups in this model is possible only up to 48 h72 h following transplantation due to non-survivors, and this time point would still have probably been PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19691550 too early to show any differences. In PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19690573 conclusion, this study clearly shows for the first time that the neuronal isof

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Author: GTPase atpase