phosphoramidon and Hemorrhage

The role of phosphoramidon-sensitive endothelin converting enzyme in the release of endogenous endothelin-1 was investigated in anesthetized rats. Intravenous infusion of phosphoramidon 0.3 mg/kg/min did not suppress the release of endothelin-1 stimulated by hemorrhage or cytokines. Elevation of endothelin-1 in rats subjected to hypoxia was not modified by phosphoramidon (0.1 or 0.3 mg/kg/min for 2 h). A high dose of phosphoramidon (10 mg/kg i.v. +0.1 mg/kg/min) significantly potentiated the hypoxia-induced increases in plasma endothelin-1 levels. Increases in endothelin-1 release caused by bilateral nephrectomy were further enhanced by hypoxia. It is concluded that the release of endogenous endothelin-1 release stimulated by hemorrhage, cytokines and hypoxia is resistant to inhibition by phosphoramidon, and at high doses, phosphoramidon potentiates hemorrhage- and hypoxia-induced increases in endothelin-1 levels, most likely by preventing its degradation.

Topics: Animals; Aspartic Acid Endopeptidases; Blood Pressure; Cytokines; Dose-Response Relationship, Drug; Endothelin-Converting Enzymes; Endothelins; Endotoxins; Glycopeptides; Hemorrhage; Hypoxia; Infusions, Intravenous; Interleukin-1; Male; Metalloendopeptidases; Nephrectomy; Rats; Tumor Necrosis Factor-alpha