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 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.
Vemulapalli
S
S
Schering-Plough Research Institute, Kenilworth, NJ 07033.
Chiu
P J
PJ
Griscti
K
K
Brown
A
A
Kurowski
S
S
Sybertz
E J
EJ
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000097:blood*; D004731:Endotoxins / Q000494:pharmacology; D006020:Glycopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D006470:Hemorrhage / Q000097:blood* / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood* / Q000503:physiopathology; D007262:Infusions, Intravenous; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases; D009392:Nephrectomy; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D016232:Endothelins; D004731:Endotoxins; D006020:Glycopeptides; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon