Cirrhosis and endotoxin decrease urea synthesis in rats

Aim: In patients with cirrhosis, endotoxemia is frequent and the vitally important capacity for urea synthesis is impaired. The patients' mortality of infection is markedly increased, which could be related to adverse metabolic effects of endotoxins. The effects of endotoxins on in vivo urea synthesis and on urea cycle genes during cirrhosis are unknown. Methods: We examined the effects of a low dose of 0.5 mg/kg ip lipopolysaccharide (LPS) on the basal urea nitrogen synthesis rate (UNSR), the capacity of urea nitrogen synthesis (CUNS), liver tissue mRNA levels of urea cycle enzyme genes, and on the metabolic liver function measured by the galactose elimination capacity (GEC) in rats with cirrhosis induced by bile duct ligation and in control animals. Results: LPS and cirrhosis + LPS decreased UNSR by 40% (P < 0.05). Cirrhosis and LPS each tended to decrease CUNS and cirrhosis + LPS decreased CUNS by 40% (P < 0.05). Cirrhosis and LPS each decreased the mRNA level of the gene for the flux-generating urea cycle enzyme carbamoyl phosphate synthetase (CPS) and the mRNA for the rate-limiting urea cycle enzyme arginine succinate synthetase (ASS) (P < 0.05). Cirrhosis + LPS left the mRNA level of CPS unchanged and decreased that of ASS (P < 0.05). The GEC did not differ among the study groups. Conclusion: Endotoxemia in rats with experimental cirrhosis markedly impaired the ability of the animals' livers to synthesize urea, suggesting a pathophysiological mechanism underlying the severe consequences of endotoxemia in human cirrhosis.