The role of protein kinase A in anaerobic energy production during liver storage

Thomas A. Churchill, Beatrice M. Wu, David F. Mercer, Norman M. Kneteman

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Background/Aim: During cold liver storage in University of Wisconsin solution, glycolysis is inhibited by declining intracellular pH and a reduction in glycogen phosphorylase activity. The current study investigated the effects of a histidine-buffered, modified University of Wisconsin solution with cyclic-AMP analogue plus phosphodiesterase inhibitors to optimize both pH and PK A-mediated limits on glycolytic energy production. Methods: In an isolated rodent-liver system, dioctanoyl-cAMP was supplemented with each phosphodiesterase inhibitor (isobutylmethylxanthine, papaverine, Ro 20-1724, dipyridamole). Once the most efficacious combination was determined, a separate group of livers was cold-stored for 24 h and then reperfused at 37°C to examine regeneration of high energy adenylates. Results: Lactate accumulation in the histidine-lactobionate-raffinose group was 8.7 μmol/g; net increases were greater with all four phosphodiesterase inhibitors with dioctanoyl-cAMP; dipyridamole resulted in a maximum increase of 16.7 μmol/g. ATP was consistently higher in all treatment groups with phosphodiesterase inhibitors throughout 24 h; even after 10-24 h, levels with dipyridamole- treatment were 250-280% higher than with University of Wisconsin (p<0.05). Assessment of glycogen phosphorylase activity in the dipyridamole-treatment group indicated that increased glycolytic activity over the first 4 h was a direct consequence of elevated enzyme levels. However, between 410 h, phosphofructokinase underwent a phosphorylation, leading to an inhibition at this point in glycolysis. Upon reperfusion, the higher ATP/ADP and ADP/AMP ratios found with phosphodiesterase inhibitor treatment suggested that adenylate regeneration was superior with dipyridamole+dioctanoyl-cAMP. Conclusion: Dipyridamole plus dioctanoyl-cAMP treatment achieved increased glycogenolysis throughout 24 h storage by maintaining glycogen phosphorylase in a phosphorylated (active) state; however, a PK A-mediated phosphorylation (inhibition) of phosphofructokinase resulted in decreased glycolytic ATP production between 4-10 h.

Original languageEnglish (US)
Pages (from-to)473-480
Number of pages8
JournalJournal of Hepatology
Volume32
Issue number3
DOIs
Publication statusPublished - Mar 2000

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Keywords

  • Cyclic-AMP
  • Glycolysis
  • Hepatic energetics
  • Liver preservation
  • Phosphodiesterase inhibitors
  • Protein kinase A

ASJC Scopus subject areas

  • Hepatology

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