Alternative pathway to endothelin-converting enzyme for the synthesis of endothelin in human blood vessels.
We have investigated whether a chymostatin-sensitive enzyme, such as chymase, contributes to the production of vasoconstrictor endothelin peptides from exogenous big endothelin- 1 in endothelium-denuded human umbilical vein. Big endothelin-1 contracted veins with a pD2 = 7.75 +/- 0.08 (n = 23) and was five times less potent than endothelin-1 (pD2 = 8.43 +/- 0.11, n = 10). The selective endothelin-converting enzyme inhibitor, PD159790, (30 microM, n = 17) produced a significant (P < 0.005), threefold rightward shift of the big endothelin-1 concentration-response curve with no reduction in maximum response. A further shift was obtained with 100 microM PD159790 (n = 6), with a significant decrease in the maximum response from 84.0 +/- 5.3%KCl to 34.2 +/- 6.7%KCl (P < 0.005). Chymostatin (30 microM) had no effect on the big endothelin-1 response, however, the inhibitory effect of 100 microM chymostatin was significant (P < 0.005). Unlike PD159790, chymostatin did not significantly modify the maximum response to big endothelin-1. The combination of 30 microM PD159790 and 100 microM chymostatin was more effective than either inhibitor alone. Our data suggest a role for both endothelin-converting enzyme and a chymostatin-sensitive enzyme, such as chymase, in the conversion of big endothelin-1 to constrictor endothelin peptides in human umbilical vein smooth muscle. In cardiovascular diseases in which endothelin-converting enzyme activity is increased, inhibition of both enzymes may be required for effective therapeutic intervention.
Maguire
Janet
J
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. jjm1003@medschl.cam.ac.uk
Davenport
Anthony P
AP
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D066298:In Vitro Techniques; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects / Q000201:enzymology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019332:Endothelin-1; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D014662:Vasoconstrictor Agents; D011189:Potassium Chloride; C002101:chymostatin; D053818:Chymases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes