Human big endothelin releases prostacyclin in vivo and in vitro through a phosphoramidon-sensitive conversion to endothelin-1.
Human big endothelin (big ET) and endothelin-1 (ET-1) induce similar increases in left ventricular systolic pressure in the anesthetized rabbit. Unlike ET-1, human big ET does not induce an initial transient hypotension. Human big ET (3 nmol/kg) inhibits ADP-induced platelet aggregation ex vivo by 60% whereas ET-1 at 1 nmol/kg inhibits platelet aggregation by more than 80%. The C-terminal fragment, big ET[22-38] (3 nmol/kg), has no antiaggregatory properties. Inhibition of ex vivo platelet aggregation by human big ET and ET-1 was not seen in rabbits pretreated with indomethacin (5 mg/kg). Human big ET (10(-7) M) or ET-1 (2.5 x 10(-9)-10(-8) M) induced the release of prostacyclin (PGI2) from rabbit, guinea pig, and rat lungs. Phosphoramidon (50 microM, infused 45 min prior to and during administration of peptides) inhibited the prostanoid-releasing properties of human big ET without affecting the release induced by ET-1. Intravascular administration of human big ET (1 nmol/kg) significantly increased the circulating levels of immunoreactive ET-1 (ir-ET-1) for 30 min whereas administration of ET-1 at the same concentration increased the plasma level of ir-ET-1 for 5 min only. Our results suggest that human big ET is converted to ET-1 in the rabbit in vivo. We further suggest that to induce the release of prostanoids in perfused lungs, human big ET needs to be converted to ET-1 by a phosphoramidon-sensitive endothelin-converting enzyme (ECE).
D'Orléans-Juste
P
P
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Lidbury
P S
PS
Telemaque
S
S
Warner
T D
TD
Vane
J R
JR
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology* / Q000502:physiology; D011464:Epoprostenol / Q000378:metabolism*; D006020:Glycopeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D010975:Platelet Aggregation Inhibitors; D011498:Protein Precursors; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon