Role of endothelin ETA receptors in sepsis-induced mortality, vascular leakage, and tissue injury in rats.
The role of endothelin ETA receptors in sepsis-induced mortality and edema formation was evaluated with a selective antagonist ABT-627 [2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)amino carbonylmethyl)-pyrrolidine-3-carboxylic acid]. Sprague-Dawley rats received saline (control group), Escherichia coli endotoxin (10 mg/kg, sepsis group) or infusion of ABT-627 prior and immediately after saline and endotoxin injection. Mortality, edema formation (wet/dry ratios), and multiple tissue injury (indicated by serum concentrations of creatinine, urea, bilirubin, creatine kinase, lactate dehydrogenase, and aspartate aminotransferase) were monitored within 5 h. Endotoxin injection elicited 64% mortality, significantly augmented edema formation in liver, heart, lung, and kidney, and raised serum levels of tissue injury markers. Pretreatment with ABT-627 completely reversed endotoxin-induced mortality, significantly attenuated wet/dry ratios of the heart, liver, and kidney, but not lungs, and reduced serum levels of creatine kinase, creatinine, aspartate aminotransferase, and lactate dehydrogenase, but not that of urea and bilirubin. These results suggest that endothelin ETA receptors play a significant role in promoting mortality, edema formation (except in the lungs), and tissue injury in animals with severe sepsis.
Albertini
Mariangela
M
Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Sezione di Biochimica e Fisiologia, Università degli Studi di Milano, Italy.
Clement
Maria Giovanna
MG
Hussain
Sabah N A
SN
D000818:Animals; D000077868:Atrasentan; D004195:Disease Models, Animal; D004487:Edema / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D065130:Endothelin A Receptor Antagonists; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000378:metabolism*
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan