Adrenomedullin ameliorates ischemia reperfusion injury in rat livers.
Adrenomedullin (ADM) is a novel potent vasodilatory peptide that was isolated from human pheochromocytoma cells in 1993. It consists of 52 amino acids with 1 intramolecular disulfide bond and a C-terminal amide structure. The vasodilatory effect of ADM is mediated by the activation of secondary messengers, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that are induced by nitric oxide (NO). The objective of the present study was to ascertain the protective effect of ADM against ischemia/reperfusion (I/R) injury on isolated perfused rat liver (IPRL) model after 60 min of warm ischemic preservation and identify the pathways involved. Administration of ADM in the perfusate during initial perfusion and in the preserving fluid during reperfusion after preservation augmented portal flow by 1.3-fold (p < 0.01), increased bile production by 2.3-fold (p < 0.01), reduced the release of lactate dehydrogenase (LDH) to 0.73-fold (p < 0.05), increased oxygen consumption by 1.28-fold (p < 0.01), and augmented tissue cAMP by 1.8-fold (p < 0.05) those observed in the absence of ADM. However, ADM administration did not increase tissue cGMP and the uptake of hyaluronio acid, which are the functions of endothelial cells. Histological examination revealed that ADM administration resulted in an improvement in the structural changes induced by the I/R insult; however, it could not prevent the destruction of the sinusoidal endothelial cells. These results indicated that the ADM-mediated increased portal flow in the liver under an I/R insult is not induced by the NO-cGMP pathway but by the activation of cAMP.
Sakurai
Tsunenori
T
Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
D053607:Adrenomedullin / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011168:Portal System / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism*
D009566:Nitrates; D053607:Adrenomedullin; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase