The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes.
Human polymorphonuclear leukocytes (PMNs) converted human big endothelin (bET; 2 microM) to an endothelin-1 (ET-1) like contractile factor, as assessed by bioassay. The generation of this ET-1 like activity was rapid (minutes), time-dependent and more pronounced in non-activated cells, suggesting a partial degradation by activated PMNs. Phosphoramidon (54 micrograms/ml) inhibited the formation of this contractile factor, whereas phenylmethylsulfonylfluoride (PMSF; 25 micrograms/ml), pepstatin A (1 microgram/ml) or epoxysuccinyl-L-leucylamido-(guanidino)butane (E-64; 10 micrograms/ml) did not. Incubations of activated PMNs with PMSF significantly potentiated the generation of ET-1 like activity and selectively inhibited the degradation of [125I]ET-1 by activated PMNs. These findings indicate that human PMNs contain and/or release neutral proteases, which can both rapidly produce and degrade ET-1, an observation which may have important (patho)physiologic implications.
Sessa
W C
WC
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Kaw
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S
Hecker
M
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Vane
J R
JR
D000818:Animals; D016232:Endothelins / Q000096:biosynthesis* / Q000097:blood / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007601:Jugular Veins / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010436:Pepstatins / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits
D016232:Endothelins; D006020:Glycopeptides; D010436:Pepstatins; D011480:Protease Inhibitors; C014195:Streptomyces pepsin inhibitor; D010664:Phenylmethylsulfonyl Fluoride; D009240:N-Formylmethionine Leucyl-Phenylalanine; D007930:Leucine; C024974:E 64; C008890:phosphoramidon; C031375:pepstatin