Effects on haemodynamics by selective endothelin ETB receptor and combinedendothelin ETA/ETB receptor antagonism during endotoxin shock

The endothelin system is highly activated during endotoxin and septic shock . To investigate this matter the selective non-peptide endothelin ETB recep tor antagonist A-192621 ([2R-(2 alpha,3 beta,4 alpha)]-4-(1,3-benzodioxol-5 -yl)-1-[2-[2,6-diethylpehenyl)amino]-2oxoethyl]-2- (4-propoxy-phenyl)-3-pyr rolidinecarboxylic acid) was administered alone and in combination with the selective non-peptide endothelin ETA receptor antagonist PD 155080 (sodium 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl)-4-oxobut-2-enoate) d uring established porcine endotoxin shock. Cardiopulmonary vascular functio n, metabolic parameters and plasma endothelin-l-like immunoreactivity level s wen compared to a control group only receiving endotoxin. Administration of A-192621 alone resulted in cardiovascular collapse and death whereas com bining A-192631 with PD 155080 abolished endotoxin induced pulmonary hypert ension, enhanced cardiac performance and improved systemic oxygen delivery and acid-base balance. The beneficial effects of mixed endothelin ETA/ETB r eceptor antagonisms on the pulmonary and cardiovascular systems may result from blockage of constrictive endothelin receptors in and pulmonary circula tion, reduced afterload and a direct inotropic effect. Possible mechanisms for the devastating effects by selective endothelin ETB receptor antagonism include increased endothelin ETA receptor-mediated vasoconstriction due to lack of endothelin ETB receptormediated vasodilation and decreased endothe lin clearance from endothelin ETB receptor blockade. In conclusion; selecti ve endothelin ETB receptor antagonism is deleterious whereas combined endot helin ETA and ETB receptor antagonism has favourable effects on haemodynami cs. suggesting participation of the endothelin system in cardiopulmonary dy sfunction during endotoxin shock. (C) 1999 Elsevier Science B.V. All rights reserved.