Endothelin receptor blockade attenuates lipopolysaccharide-induced pulmonary nitric oxide production.
Increased nitric oxide (NO) synthesis by the inducible nitric oxide synthase (iNOS) has been shown to contribute to the development of acute lung injury and delayed hypotension in animals injected with bacterial lipopolysaccharides (LPS). Recent evidence indicates that endothelin-1 (ET-1) is also elevated in septic humans and in animals. To assess the contribution of ETs to LPS-induced pulmonary NO production and iNOS expression, we used P1/fl, a 22 amino acid peptide, to selectively antagonize endothelin-A receptors. Anesthetized, mechanically ventilated rats were injected with either saline or LPS (E. coli endotoxin, 20 mg/kg) and studied for 5 h. Two other groups of rats were pretreated 15 min earlier with P1/fl peptide (20 microg/kg). Unlike saline-treated rats, rats injected with LPS showed a progressive decline in arterial pressure and a significant rise in plasma ET concentration and serum nitrite-nitrate level. In the lungs, LPS injection elicited a several-fold rise in lung iNOS activity and exhaled NO concentration and increased lung wet/dry ratio significantly. Pretreatment with P1/fl peptide eliminated the decline in arterial pressure, the rise in lung wet/dry ratio, lung NOS activity, and iNOS protein expression and significantly attenuated the increase in pulmonary exhaled NO production but had no effect on plasma ET concentration. We conclude that activation of ET-A receptors by rising ET-1 concentration enhances NO production and iNOS expression in the respiratory and vascular systems and contributes to both LPS-induced hypotension and acute lung injury.
Fujii
Y
Y
Critical Care Division, Department of Medicine, Royal Victoria Hospital and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Magder
S
S
Cernacek
P
P
Goldberg
P
P
Guo
Y
Y
Hussain
S N
SN
D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004926:Escherichia coli / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*
C109027:ETR-p1-f1 antisense peptide; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D010455:Peptides; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase