In vivo characterization of a phosphoramidon-sensitive endothelin-converting enzyme in the rat.
Experiments were conducted to characterize the nature of a phosphoramidon-sensitive endothelin-converting enzyme in vivo by evaluating the pressor response to a bolus intravenous (i.v.) injection of endothelin family peptides following administration of phosphoramidon in anesthetized Sprague-Dawley rats. Phosphoramidon given i.v. at 10 mg/kg completely prevented the pressor response to human big endothelin-1-(1-38) (big ET-1). The EC50 for phosphoramidon was determined to be in the range of 1 to 3 mg/kg. The pressor response to big ET-1 60 min after phosphoramidon injection was attenuated by roughly 60% indicating a long inhibitory half-life. Very high doses of big ET-1 (> 20 mg/kg) were capable of over-riding the effect of phosphoramidon and produced characteristic pressor responses suggesting that the inhibition by phosphoramidon can be considered competitive in nature. Human big endothelin-3-(1-41) (big ET-3) produced significant increases in arterial pressure although with less potency and efficacy compared to big ET-1. The pressor response to big ET-3 was also inhibited by phosphoramidon. Phosphoramidon does not act indirectly by interfering with ET-1 receptor-mediated actions since the inhibitor has no effect on the in vivo pressor response to ET-1 and does not antagonize [125I]ET-1 receptor binding or constrictor responses in vitro. These results are consistent with the idea that a phosphoramidon-sensitive endothelin-converting enzyme is capable of cleaving both big ET-1 and big ET-3 to the active peptides in the rat.
Pollock
D M
DM
Abbott Laboratories, Abbott Park, IL 60064.
Divish
B J
BJ
Milicic
I
I
Novosad
E I
EI
Burres
N S
NS
Opgenorth
T J
TJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011311:Pressoreceptors / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D006020:Glycopeptides; D017466:Receptors, Endothelin; D015260:Neprilysin; C008890:phosphoramidon