Aggregation of human polymorphonuclear leukocytes by endothelin: role of platelet-activating factor.
The mechanisms by which endothelin-1 (ET-1) acts on polymorphonuclear leukocytes (PMN) are insufficiently known. In this study, we assessed the hypotheses that ET-1 is a PMN-aggregating agent, and that platelet-activating factor (PAF) is the principal mediator of ET-1-induced PMN aggregation. ET-1 induced dose-related PMN aggregation, which started 1 min after ET-1 exposure. Two different specific PAF receptor antagonists blocked the effect of ET-1 on PMN aggregation. In addition, ET-1 induced a significant increase in the production of PAF by PMN after 2 to 5 min of ET-1 incubation. ET-1 induced PAF release from PMN rather than accumulation. This PAF production was dependent on intra- and extracellular Ca2+. In this regard, the PAF receptor antagonists significantly blunted the ET-1-induced peak in cytosolic free Ca2+ ([Ca2+]i). Our results, therefore, indicate that ET-1 is effective in causing aggregation of human PMN and that its action appears to be mediated by PAF production via a Ca(2+)-dependent mechanism.
Gómez-Garre
D
D
Laboratorio de Nefrología, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spain.
Guerra
M
M
González
E
E
López-Farré
A
A
Riesco
A
A
Caramelo
C
C
Escanero
J
J
Egido
J
J
D001381:Azepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002449:Cell Aggregation / Q000187:drug effects*; D002499:Centrifugation, Density Gradient; D003600:Cytosol / Q000378:metabolism; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D046934:Ginkgolides; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D004224:Diterpenes; D016232:Endothelins; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D009240:N-Formylmethionine Leucyl-Phenylalanine; C045856:ginkgolide B; D002118:Calcium