Effects on haemodynamics by selective endothelin ET B receptor and combined endothelin ET A/ET B receptor antagonism during endotoxin shock

Abstract

The endothelin system is highly activated during endotoxin and septic shock. To investigate this matter the selective non-peptide endothelin ET B receptor antagonist A-192621 ([2 R-(2α,3β,4α)]-4-(1,3-benzodioxol-5-yl)-1-[2-[2,6-diethylphenyl)amino]-2-oxoethyl]-2-(4-propoxy-phenyl)-3-pyrrolidinecarboxylic acid) was administered alone and in combination with the selective non-peptide endothelin ET A receptor antagonist PD 155080 (sodium 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl)-4-oxobut-2-enoate) during established porcine endotoxin shock. Cardiopulmonary vascular function, metabolic parameters and plasma endothelin-1-like immunoreactivity levels were compared to a control group only receiving endotoxin. Administration of A-192621 alone resulted in cardiovascular collapse and death whereas combining A-192621 with PD 155080 abolished endotoxin induced pulmonary hypertension, enhanced cardiac performance and improved systemic oxygen delivery and acid–base balance. The beneficial effects of mixed endothelin ET A/ET B receptor antagonisms on the pulmonary and cardiovascular systems may result from blockage of constrictive endothelin receptors in and pulmonary circulation, reduced afterload and a direct inotropic effect. Possible mechanisms for the devastating effects by selective endothelin ET B receptor antagonism include increased endothelin ET A receptor-mediated vasoconstriction due to lack of endothelin ET B receptormediated vasodilation and decreased endothelin clearance from endothelin ET B receptor blockade. In conclusion, selective endothelin ET B receptor antagonism is deleterious whereas combined endothelin ET A and ET B receptor antagonism has favourable effects on haemodynamics, suggesting participation of the endothelin system in cardiopulmonary dysfunction during endotoxin shock.