Modulation of human neutrophil chemotaxis by the endothelin-B receptor agonist sarafotoxin S6c.
At low concentrations (4 x 10(-9) M) sarafotoxin S6c, a selective agonist of the ETB receptor, caused a slight but significant chemotactic enhancement of neutrophil migration. In contrast with stimulation by endothelins, stimulation of migration by sarafotoxin was only mediated by the ETB receptor because BQ123, a selective antagonist of the ETA receptor, had no effect on the enhancement. At higher concentrations (10(-8) M and higher) sarafotoxin inhibited neutrophil migration stimulated by chemotactic activators. It thus appears that the ETB receptor mediates the inhibition of migration by high concentrations of sarafotoxin. The degree of inhibition by sarafotoxin was dependent on the type of activator; especially IL-8 activated migration was strongly inhibited. Extracellular calcium had little effect on stimulation or inhibition by sarafotoxin, in contrast with endothelins. In a very small concentration range (4 x 10(-8) M) sarafotoxin caused an increase of cytoplasmic free calcium; higher concentrations of sarafotoxin had no effect on cytoplasmic calcium, nor did they affect calcium changes caused by fMet-Leu-Phe (fMLP). IRL1038, a selective antagonist of the ETB receptor, equally gave a small potentiation at low concentrations, and inhibited agonist-activated chemotaxis at higher concentrations, suggesting that occupation of the ETB receptor by either agonist or antagonist results in a modulation of migration.
Elferink
J G
JG
Department of Medical Biochemistry, University of Leiden, The Netherlands.
de Koster
B M
BM
D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000633:toxicity; D010972:Platelet Activating Factor / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000819:agonists*; D014662:Vasoconstrictor Agents / Q000633:toxicity*; D014757:Viper Venoms / Q000633:toxicity*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D016209:Interleukin-8; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010972:Platelet Activating Factor; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium