Endothelin-1 (1-31) is an intermediate in the production of endothelin-1 after big endothelin-1 administration in vivo.
The precursor of endothelin-1, big endothelin-1, can be hydrolyzed by chymase to generate endothelin-1 (1-31) in vitro. In the present study, we explored the processes involved in the production of endothelin-1 (1-31) as well as its pharmacodynamic characteristics in the rabbit in vivo. Endothelin-1 (1-31) (1 nmol/kg, injected into the left cardiac ventricle) induced a monophasic increase of mean arterial blood pressure similarly to big endothelin-1 (1-38), whereas endothelin-1 induces a biphasic response. Phosphoramidon, a dual neutral endopeptidase and endothelin-converting enzyme inhibitor, blocked both pressor responses to endothelin-1 (1-31) and big endothelin-1 but not those afforded by endothelin-1. Thiorphan, a neutral endopeptidase inhibitor, markedly inhibited the response to endothelin-1 (1-31) but only weakly reduced that of big endothelin-1. In contrast, CGS 35066, an endothelin-converting enzyme inhibitor, was significantly more efficient against the pressor response to big endothelin-1 than to endothelin-1 (1-31). Furthermore, injection of big endothelin-1 concomitantly with phosphoramidon induced an increase in endothelin-1 (1-31) plasma levels. Finally, intracardiac-administered endothelin-1 (1-31) induced an increase of endothelin-1 plasma levels, which are markedly reduced by phosphoramidon and thiorphan but not by CGS 35066. Our results thus demonstrate that endothelin-1 (1-31) is an alternate intermediate in the production of endothelin-1 after big endothelin-1 administration in the rabbit in vivo.
Fecteau
Marie-Hélène
MH
Department of Pharmacology, Medical School, Université de Sherbrooke, 3001 12th Ave N, Sherbrooke, Québec, J1H 5N4, Canada.
Honoré
Jean-Claude
JC
Plante
Mirco
M
Labonté
Julie
J
Rae
Giles A
GA
D'Orléans-Juste
Pedro
P
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006352:Heart Ventricles; D007267:Injections; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000096:biosynthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D017466:Receptors, Endothelin / Q000378:metabolism; D015244:Thiorphan / Q000494:pharmacology
D001572:Benzofurans; C404932:CGS 35066; D019332:Endothelin-1; D006020:Glycopeptides; D063065:Organophosphonates; D010446:Peptide Fragments; D011480:Protease Inhibitors; D017466:Receptors, Endothelin; C114932:endothelin-1 (1-31); D015244:Thiorphan; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon