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 ([2R-(2alpha,3beta, 4alpha)]-4-(1,3-benzodioxol-5-yl)-1-[2-[2, 6-diethylphenyl)amino]-2-oxoethyl]-2-(4-propoxy-phenyl)-3-py rrolidine
carboxylic 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-enoat e) 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.