Endothelin receptor blockade attenuates lipopolysaccharide-induced pulmonary nitric oxide production

Increased nitric oxide (NO) synthesis by the Inducible nitric oxide synthas e (iNOS) has been shown to contribute to the development of acute long inju ry and delayed hypotension in animals injected with bacterial lipopolysacch arides (LPS). Recent evidence indicates that endothelin-1 (ET-1) is also el evated in septic humans and in animals. To assess the contribution of ETs t o LPS-induced pulmonary NO production and iNOS expression, we used P1/fl, a 22 amino acid peptide, to selectively antagonize endothelin-A receptors. A nesthetized, 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 mu g/kg), Unl ike saline-treated rats, rats injected with LPS showed a progressive declin e in arterial pressure and a significant rise in plasma ET concentration an d serum nitrite-nitrate lever. In the lungs, LPS injection elicited a sever al-fold rise in lung iNOS activity and exhaled NO concentration and increas ed lung wet/dry ratio significantly. Pretreatment with P1/fl peptide elimin ated 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 respirato ry and vascular systems and contributes to both LPS-induced hypotension and acute lung injury.