ABSTRACT
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.
Subject(s)
Adrenomedullin/pharmacology , Liver/blood supply , Reperfusion Injury/metabolism , Adrenomedullin/metabolism , Animals , Bile/metabolism , Cyclic AMP/metabolism , In Vitro Techniques , L-Lactate Dehydrogenase/metabolism , Liver/pathology , Male , Nitrates/metabolism , Oxygen Consumption/drug effects , Portal System/drug effects , Rats , Rats, Inbred LewABSTRACT
BACKGROUND: A Rho-ROCK signal system induces vascular contraction and neutrophil migration, both of which are characteristic features found with ischemia and reperfusion injury of the liver. We tested our hypothesis that a novel ROCK I inhibitor, Y-27632, attenuates hepatic ischemia and reperfusion injury. METHODS: Rats underwent 70% partial hepatic ischemia for 120 minutes and subsequent reperfusion. Y-27632 of 10mg/kg was given orally 1 hour before ischemia, while distilled water was given to the control animals. One week animal survival, systemic hemodynamics, hepatic tissue blood flow, liver function tests, plasma endothelin-1, serum hyaluronic acid levels, myeloperoxidase activity and malondialdehyde level in liver tissue, membrane attack complex-1 and intracellular adhesion molecule-1 staining, and histological architecture were analyzed. RESULTS: Y-27632 prolonged 1-week animal survival from 25% of untreated animals to 75% accompanied with significant amelioration of hepatic tissue blood flow, liver function tests and histological architecture without any adverse effects on systemic hemodynamics. In addition, plasma endothelin-1 and serum hyaluronic acid levels decreased markedly compared to the control, concomitant with remarkable suppression of membrane attack complex-1 stain positive neutrophils infiltration, myeloperoxidase activity and malondialdehyde level. CONCLUSION: Present study suggests that activation of a Rho-ROCK signal system is associated with ischemia and reperfusion injury of the liver, and that Y-27632 may be an attractive agent for application in major liver resection using temporary inflow occlusion and hepatic preservation.
