THE ENDOTHELIN RECEPTOR ANTAGONIST BOSENTAN RESTORES GUT OXYGEN DELIVERY AND REVERSES INTESTINAL MUCOSAL ACIDOSIS IN PORCINE ENDOTOXIN-SHOCK

Background-Endothelin-1, the most potent vasoconstrictor known, is pro duced in septic states and may be involved in the pathophysiology of t he deteriorated splanchnic circulation seen in septic shock. Aims-To e lucidate the capability of bosentan, a non-peptide mixed endothelin re ceptor antagonist, to attenuate splanchnic blood flow disturbances and counteract intestinal mucosal acidosis in endotoxic shock. Methods-In 16 anaesthetised pigs, central and regional haemodynamics were monito red by thermodilution and ultrasonic flow probes, respectively. A tono meter in the ileum was used for measurement of mucosal pH. Onset of en dotoxin challenge was followed by bosentan administration (to eight pi gs) two hours later. Results-Endotoxin infusion reduced cardiac index and systemic oxygen delivery; bosentan restored these parameters. The reduced mean arterial blood pressure and renal blood flow remained una ffected by bosentan. The profound reduction in gut oxygen delivery in response to endotoxin was completely abolished by bosentan. Bosentan s ignificantly improved the notably deteriorated intestinal mucosal pH a nd mucosal-arterial PCO2 gap. The mucosal-portal vein PCO2, gap, used to monitor the mucosa in relation to the gut as a whole (including the spleen and pancreas), was also greatly increased by endotoxaemia and significantly reversed by bosentan. Conclusion-Bosentan completely res tored the profound endotoxin induced reductions in systemic and gut ox ygen delivery with a concomitant reversal of intestinal mucosal acidos is. Results suggest that endothelin is involved in the pronounced perf usion disturbances seen in the gut in endotoxic shock. Bosentan may pr ove useful in reducing gut ischaemia in septic shock.