PHOSPHORAMIDON DOES NOT INHIBIT ENDOGENOUS ENDOTHELIN-1 RELEASE STIMULATED BY HEMORRHAGE, CYTOKINES AND HYPOXIA IN RATS

The role of phosphoramidon-sensitive endothelin converting enzyme in t he release of endogenous endothelin-1 was investigated in anesthetized rats. Intravenous infusion of phosphoramidon 0.3 mg/kg/min did not su ppress the release of endothelin-1 stimulated by hemorrhage or cytokin es. Elevation of endothelin-1 in rats subjected to hypoxia was not mod ified 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 potentiat ed the hypoxia-induced increases in plasma endothelin-1 levels. Increa ses in endothelin-1 release caused by bilateral nephrectomy were furth er 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, phosp horamidon potentiates hemorrhage- and hypoxia-induced increases in end othelin-1 levels, most likely by preventing its degradation.