Effect of the Cyclo-Oxygenase Inhibitor Fenbufen on Muscle and Liver Protein Metabolism, Muscle Glutamine and Plasma Insulin in Endotoxaemic Rats

1. The effect of fenbufen (γ-oxo-[1,1′-biphenyl]-4-butanoic acid), a known cyclo-oxygenase inhibitor, on the changes in muscle and liver protein metabolism in response to Escherichia coli endotoxin has been investigated in the rat. 2. Young male rats were fed a purified diet [18% (w/w) casein], with or without fenbufen (1.2 g/kg of diet). Groups of animals were injected with either endotoxin (LPS; Escherichia coli lipopolysaccharide 0.127 B8; 3 mg/kg body weight) or saline. Rectal temperature and food intake were measured over the following 24 h period, after which time measurements were made of muscle and liver protein content and synthesis in vivo, muscle protein degradation as the difference between protein synthesis and growth rates, muscle glutamine concentration and plasma insulin. 3. Fenbufen treatment alone tended to lower rectal temperature. It also reduced plasma insulin, slightly reduced food intake and slowed growth and muscle protein turnover, although muscle glutamine concentrations were unchanged. The slower protein synthesis mainly reflected reduced translational activity, which was consistent with the reduced insulin concentration. 4. LPS treatment increased rectal temperature by 1.6°C, and this was abolished by fenbufen, indicating that the dose of the drug was sufficient to block prostaglandin production in the hypothalamus. 5. LPS treatment induced similar losses in body weight and muscle protein in both control and fenbufen groups, despite a 50% lower food intake in the LPS plus fenbufen group compared with the LPS-only group. The loss of muscle protein in both groups reflected reduced protein synthesis and increased protein degradation. LPS treatment alone induced elevated plasma insulin, but fenbufen blocked this response and the insulin levels remained depressed. Muscle glutamine concentration fell in both LPS-treated groups, suggesting that the depression of protein synthesis and the development of the insulin resistance might be linked to the loss of intracellular glutamine. 6. LPS induced a relative increase in hepatic protein content, and total protein synthesis (by approximately 40%); fenbufen had no influence on these responses. 7. It is concluded that whereas treatment with fenbufen has marked effects on plasma insulin concentration, it has no influence on muscle and liver protein metabolism during endotoxaemia. Alternative mechanisms to those involving prostaglandins as mediators of the catabolic response of muscle are discussed, including those involving the glutamine transporter.