a-192621 and Shock--Septic

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.

Topics: Animals; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endotoxins; Female; Hemodynamics; Hemoglobins; Hydrogen-Ion Concentration; Male; Pulmonary Circulation; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Shock, Septic; Swine