Background and aims: Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure. Methods: Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals. Results: This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET A ) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow. Conclusions: This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET A receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET A is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.

Cholecystokinin (CCK) has been suggested to be both pro-nociceptive and anti-opioid by actions on pain modulatory cells within the RVM. One consequence of activation of RVM CCK2 receptors may be enhanced spinal nociceptive transmission but how this might occur, especially in states of pathological pain is unknown. Here, in vivo microdialysis was used to demonstrate that levels of RVM CCK increased by approximately 2-fold following ligation of L5/L6 spinal nerves (SNL). Microinjection of CCK into the RVM of naïve rats elicited hypersensitivity to tactile stimulation of the hindpaw. Additionally, RVM CCK elicited a time-related increase in PGE2 measured in cerebrospinal fluid from the lumbar spinal cord. The peak increase in spinal PGE2 was approximately 5-fold and was observed at approximately 80-min post-RVM CCK, a time coincident with maximal RVM CCK-induced mechanical hypersensitivity. Spinal administration of naproxen, a non-selective COX-inhibitor, significantly attenuated RVM CCK-induced hindpaw tactile hypersensitivity. RVM-CCK also resulted in a 2-fold increase in spinal 5-HIAA, a 5-HT metabolite, as compared to controls, and mechanical hypersensitivity that was attenuated by spinal application of ondansetron, a 5-HT3 antagonist. The present studies suggest that chronic nerve injury can result in activation of descending facilitatory mechanisms that may promote hyperalgesia via ultimate release of PGE2 and 5-HT in the spinal cord.

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