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 ETA as opposed to the ETB receptor and their effects in the splanchnic region a non-selective (ET(MIX)ra) A-182086 and selective ETA (ET(A)ra) PD155080 and ETB (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 an 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 ETB receptor antagonism in the current study may be due to increased ETA receptor activity as plasma levels of ET-1 is increased several fold by blocking the ETB receptor and thereby the plasma-ET-1-clearing function. Furthermore, a loss of endothelial ETB 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 ETA and ETB receptors is necessary to effectively counteract these changes.