Analogs of cyclic nucleotides in rat liver preservation.
Analogs of cyclic nucleotides in rat liver preservation.
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DOI：
10.1097/00007890-199810150-00006
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发表时间：
1998-10
期刊：
影响因子：
6.2
通讯作者：
T. Maeda;N. Murase;V. Subbotin;T. Sakamoto;T. Yamada;M. Terakura;S. Todo
中科院分区：
文献类型：
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作者：
T. Maeda;N. Murase;V. Subbotin;T. Sakamoto;T. Yamada;M. Terakura;S. Todo
环核苷酸介导几种血管扩张剂的细胞内信号转导。除了其血管舒张作用之外，已知cAMP还保护内皮细胞并抑制枯否细胞活化。另一方面，cGMP有效地改善白细胞和血小板的粘附。我们测试了两种环核苷酸类似物（8溴环磷酸腺苷[8br-cAMP]和8溴环磷酸鸟苷[8br-cGMP]）在大鼠肝脏保存中的作用。方法在实验1中，在存活研究中，将单独的类似物（0.1-1.0 mM）加入到威斯康星州大学（UW）溶液中。在实验2中，供体和受体也用8br-cAMP或8br-cGMP处理，测试以下三组：组1=对照;组2=向供体、UW溶液和受体施用8br-cAMP;组3=向供体、UW溶液和受体施用8br-cGMP。实验3采用联合处理：第4组：供体给予8br-cGMP和UW溶液，受体给予cAMP;第5组：供体给予8br-cAMP和UW溶液，受体给予8br-cGMP。为了阐明每种核苷酸的作用，测试了另外两组：第6组=向供体和UW溶液施用8br-cAMP;第7组=向受体施用8br-cGMP。在实验4中，在再灌注后的几个时间点处死组1、5、6和7中的大鼠，并检查移植物血流量百分比（%BF）、积聚的中性粒细胞数目、血浆肿瘤坏死因子-α和白细胞介素-1水平以及血清丙氨酸氨基转移酶水平。结果在实验1和2中，未观察到对动物存活的显著影响。在实验3中，仅在组5中观察到动物存活率显著增加（100%，7/7，P=0.0004 vs.组1：16.7%，2/12）。与第1组相比，第5组在再灌注早期（15和30 min）未观察到%BF的改善。另一方面，第5组的%BF在后期（6 h）显著更高，与当时观察到的中性粒细胞蓄积减少一致。肿瘤坏死因子-α的产生和血清丙氨酸氨基转移酶水平也降低了这种治疗。在组织学上，在第1组中观察到的出血和节段性坏死在第5组中得到完全预防。结论：我们的结论是，与cAMP和cGMP的管理，移植物的恢复导致成功的移植受体，这两个类似物协同作用，在对抗保存和再灌注损伤，而不改善移植物的血流在再灌注早期阶段。这种作用是由于它们调节中性粒细胞活化和隔离。
BACKGROUND Cyclic nucleotides mediate intracellular signal transduction of several vasodilators. In addition to its vascular relaxant effects, cAMP is known to protect endothelial cells and to suppress Kupffer cell activation. On the other hand, cGMP potently ameliorates adhesion of leukocytes and platelets. We tested the effects of two analogs of cyclic nucleotides (8bromo cyclic adenosine monophosphate [8br-cAMP] and 8bromo cyclic guanosine monophosphate [8br-cGMP]) in rat liver preservation. METHODS In experiment 1, either analog (0.1-1.0 mM) alone was added to University of Wisconsin (UW) solution in a survival study. In experiment 2, donors and recipients were also treated with 8br-cAMP or 8br-cGMP, with the following three groups tested: group 1=control; group 2=administration of 8br-cAMP to donors, UW solution, and recipients; group 3=administration of 8br-cGMP to donors, UW solution, and recipients. Experiment 3 tested combined treatments: group 4=administration of 8br-cGMP to donors and UW solution, and cAMP to recipients; group 5=administration of 8br-cAMP to donors and UW solution, and 8br-cGMP to recipients. To elucidate the roles of each nucleotide, two further groups were tested: group 6=administration of 8br-cAMP to donors and UW solution; group 7=administration of 8br-cGMP to recipients. In experiment 4, rats in groups 1, 5, 6, and 7 were killed at several time points after reperfusion, and percent graft blood flow (%BF), number of accumulated neutrophils, plasma levels of tumor necrosis factor-alpha and interleukin-1, and serum alanine aminotransferase levels were examined. RESULTS In experiments 1 and 2, no significant effect was observed on animal survival. In experiment 3, a significant increase in animal survival was observed only in group 5 (100%, 7/7, P=0.0004 vs. group 1: 16.7%, 2/12). In group 5, no improvement of %BF was observed during the early phase of reperfusion (15 and 30 min) compared with that in group 1. On the other hand, the %BF of group 5 was significantly higher in the later phase (6 hr), consistent with the decrease in accumulation of neutrophils observed then. Production of tumor necrosis factor-alpha and serum alanine aminotransferase levels were also reduced with this treatment. Histologically, the bleeding and segmental necrosis, observed in group 1, were completely prevented in group 5. CONCLUSIONS We conclude that restoration of grafts with cAMP and administration of cGMP to recipients led to successful transplantation, and that the two analogs acted synergistically in opposing preservation and reperfusion injury without improvement of graft blood flow during the early phase of reperfusion. The effect was due to their regulation of neutrophil activation and sequestration.