Stimulation and inhibition of neutrophil chemotaxis by endothelin-3

Depending on the concentration, endothelin-3 (ET-3) has activating or inhibitory effects on neutrophil migration. At concentrations below 10 nM, neutrophil migration was stimulated by ET-3. The stimulating effect of ET-3 was mainly chemotactic, in contrast with that of ET-1, which was mainly chemokinetic. Concentrations of ET-3 lower than 10 nM potentiated chemotaxis activated by fMet-Leu-Phe (fMLP), whereas concentrations higher than 10 nM inhibited fMLP-activated neutrophil chemotaxis. The ETA receptor antagonist BQ123, the ET receptor agonist sarafotoxin S6c, and the ETB receptor antagonist IRL 1038 inhibited ET-3- and fMLP-activated migration. All of these compounds reversed the inhibitory effect of high concentrations of ET-3 on fMLP-activated chemotaxis. The results suggest that the ETA and the ETB receptor are both involved in the activating and inhibitory effects of ET-3.