title: Cyclic adenosine 3',5'-monophosphate in rat steatotic liver transplantation.
abstract: Numerous steatotic livers are discarded as unsuitable for transplantation (TR) because of their poor tolerance of ischemia/reperfusion (I/R). Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents protect against I/R injury both in nonsteatotic livers that have been removed from non-heart-beating donors and subjected to warm ischemia or cold ischemia (CIS) and in perfused, isolated livers. Ischemic preconditioning (PC), which is based on brief periods of I/R, protects steatotic liver grafts, but the mechanism that is responsible is poorly understood. This study examines the role of cAMP in the vulnerability shown by steatotic livers to TR-associated I/R injury and the benefits of PC in this situation. Steatotic livers with or without PC were transplanted into Zucker rats. The hepatic levels of cAMP were measured and altered pharmacologically. Our results indicate that the cAMP levels in the nonsteatotic liver grafts were similar to those found in a sham group. However, high cAMP levels were observed in steatotic liver grafts. The blockage of cAMP generation by adenylate cyclase inhibitor pre-treatment or PC had the following results: reduced hepatic injury and increased survival of steatotic graft recipients; greater preservation of adenosine triphosphate (ATP) and reduced lactate accumulation throughout CI. This blockade of cAMP by a nitric oxide-dependent mechanism protected steatotic liver grafts against oxidative stress and microvascular disorders after reperfusion. In conclusion, cAMP blocking-based strategies could protect patients against the inherent risk of steatotic liver failure after TR.
authors.affiliation: Esther Koplowitz Center, August Pi i Sunyer Institute for Biomedical Research, Barcelona, Spain.
authors.forename: Monica B
authors.initials: MB
authors.lastname: Jimenez-Castro
authors.forename: Arani
authors.initials: A
authors.lastname: Casillas-Ramirez
authors.forename: Marta
authors.initials: M
authors.lastname: Massip-Salcedo
authors.forename: Maria
authors.initials: M
authors.lastname: Elias-Miro
authors.forename: Anna
authors.initials: A
authors.lastname: Serafin
authors.forename: Antoni
authors.initials: A
authors.lastname: Rimola
authors.forename: Juan
authors.initials: J
authors.lastname: Rodes
authors.forename: Carmen
authors.initials: C
authors.lastname: Peralta
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D005234:Fatty Liver / Q000473:pathology / Q000628:therapy*; D006720:Homozygote; D006820:Hyaluronic Acid / Q000737:chemistry; D007511:Ischemia / Q000473:pathology; D019194:Ischemic Preconditioning; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation / Q000379:methods*; D018384:Oxidative Stress; D051381:Rats; D011924:Rats, Zucker; D013997:Time Factors; D000637:Transaminases / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C002744:3-nitrotyrosine; D014443:Tyrosine; D006820:Hyaluronic Acid; D000242:Cyclic AMP; D000637:Transaminases