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 ET(B) 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 ET(B) receptor because BQ123, a selective antagonist of the ET(A) 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 ET(B) 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 ET(B) receptor, equally gave a small potentiation at low concentrations, and inhibited agonist-activated chemotaxis at higher concentrations, suggesting that occupation of the ET(B) receptor by either agonist or antagonist results in a modulation of migration.