1 The non-selective endothelin (ET) receptor antagonist bosentan has been shown to restore systemic and gut oxygen delivery and reverse intestinal mucosal acidosis in porcine endotoxin shock. 2 To further elucidate the speci®c role of the ET A as opposed to the ET B receptor and their e ects in the splanchnic region a non-selective (ET MIX ra) A-182086 and selective ET A (ET A ra) PD155080 and ET B (ET B ra) A-192621 receptor antagonists were administered, separately or simultaneously (ET A+B ra) 2 h after onset of endotoxin shock. These four groups were compared to a control group receiving only endotoxin and vehicle. 3 Thirty-nine pigs were anaesthetized and catheterized for measurement of central and regional haemodynamics. A tonometer in the distal ileum was used for measurement of mucosal PCO 2 . Blood gases and plasma ET-1-LI levels as well as histological samples from the gut were assessed. Intervention was started 2 h after onset of endotoxemia and the experiments were terminated after 5 h. 4 Endotoxin-induced changes in systemic, gut oxygen delivery and portal hepatic vascular resistance and systemic acidosis were e ectively counteracted by both ET A+B ra and ET MIX ra. ET A ra administration was not e ective while ET B ra proved to be fatal as all animals in this group died prior to full time of the experiment. While both ET A+B ra and ET MIX ra improved gut oxygen delivery only the latter attenuated the profound endotoxin-induced ileal mucosal acidosis. 5 The lethal e ect seen from selective ET B receptor antagonism in the current study may be due to increased ET A receptor activity as plasma levels of ET-1 is increased several fold by blocking the ET B receptor and thereby the plasma-ET-1-clearing function. Furthermore, a loss of endothelial ET B receptor vasodilating properties may also have contributed to the lethal course in the ET B ra group 6 The ®ndings in this study suggest that ET is involved in the profound endotoxin-induced disturbances in splanchnic homeostasis in porcine endotoxaemia. Furthermore, antagonism of both ET A and ET B receptors is necessary to e ectively counteract these changes.

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