Differentiated effects on splanchnic homeostasis by selective and non-selective endothelin receptor antagonism in porcine endotoxaemia

Abstract

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 specific role of the ET(A) as opposed to the ET(B) receptor and their effects 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 PCO2. 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 effectively counteracted by both ET(A + B)ra and ET(MIX)ra. ET(A)ra administration was not effective 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 effect seen from selective ET(B) receptor antagonism in the current study may be due to increased ET 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 findings 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 effectively counteract these changes.