Addition of adenosine monophosphate-activated protein kinase activators to University of Wisconsin solution: a way of protecting rat steatotic livers.
This study investigates how the addition of trimetazidine (TMZ) and aminoimidazole-4-carboxamide ribonucleoside (AICAR) to University of Wisconsin (UW) solution protects steatotic livers. Steatotic and nonsteatotic livers were preserved for 24 hours at 4 degrees C in UW and UW with TMZ and AICAR (separately or in combination) and then perfused ex vivo for 2 hours at 37 degrees C. Adenosine monophosphate-activated protein kinase (AMPK) or nitric oxide (NO) synthesis inhibition in livers preserved in UW with TMZ was also investigated. Hepatic injury and function (transaminases, bile production, and sulfobromophthalein clearance) and factors potentially involved in the susceptibility of steatotic livers to ischemia-reperfusion (I/R), including vascular resistance, mitochondrial damage, adenosine triphosphate depletion, and oxidative stress were evaluated. AMPK, NO synthase (NOS), nitrate, and nitrite levels were also determined. The addition of TMZ and AICAR (separately or in combination) to UW reduced hepatic injury, improved functionality, and protected against the mechanisms responsible for the vulnerability of steatotic livers to I/R. Like AICAR, TMZ increased AMPK, constitutive NOS, and nitrates and nitrites, and conversely, AMPK or NO synthesis inhibition abolished the benefits of TMZ. In conclusion, TMZ, by means of AMPK, increased NO, thus protecting steatotic livers against their vulnerability to I/R injury. TMZ and AICAR may constitute new additives to UW solution in steatotic liver preservation, whereas a combination of both seems unnecessary.
Ben Mosbah
Ismail
I
Experimental Hepatic Ischemia-Reperfusion Unit, Instituto de Investigaciones Biomédicas de Barcelona, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Cientificas, Spain.
Massip-Salcedo
Marta
M
Fernández-Monteiro
Izabel
I
Xaus
Carme
C
Bartrons
Ramon
R
Boillot
Olivier
O
Roselló-Catafau
Joan
J
Peralta
Carmen
C
D055372:AMP-Activated Protein Kinases; D000227:Adenine Nucleotides / Q000378:metabolism; D000241:Adenosine / Q000627:therapeutic use; D000493:Allopurinol / Q000627:therapeutic use; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D020536:Enzyme Activators / Q000627:therapeutic use*; D005234:Fatty Liver / Q000517:prevention & control*; D005978:Glutathione / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008099:Liver / Q000201:enzymology / Q000502:physiology; D008930:Mitochondria, Liver / Q000502:physiology; D009097:Multienzyme Complexes / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019188:Organ Preservation Solutions / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011887:Raffinose / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000517:prevention & control; D012265:Ribonucleotides / Q000627:therapeutic use*; D014292:Trimetazidine / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000502:physiology
D000227:Adenine Nucleotides; D020536:Enzyme Activators; D007328:Insulin; D009097:Multienzyme Complexes; D019188:Organ Preservation Solutions; D012265:Ribonucleotides; C055206:University of Wisconsin-lactobionate solution; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D000493:Allopurinol; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose; D014292:Trimetazidine