FENSPIRIDE AND MEMBRANE TRANSDUCTION SIGNALS IN RAT ALVEOLAR MACROPHAGES

Fenspiride inhibits the calcium signal evoked by the inflammatory pept ide formyl-Met-Leu-Phe (fMLP) in peritoneal macrophages, but at concen trations (approximate to 1 mM) far above the therapeutic range (approx imate to 1 mu M) Here, in rat alveolar macrophages, high fenspiride co ncentrations (1 mM) were required to inhibit the calcium signals evoke d by the calcium agonist Bay K8644 or by ionomycin. Moreover, fenspiri de (1 mM) was a poor inhibitor of the cell membrane depolarization ind uced by gramicidine D. By contrast, fenspiride blocked Na+-H+ antiport activation by (i) fMLP with an IC50 = 3.1 +/- 1.9 nM and (ii) PMA (ph orbol 12-myristate 13-acetate) with an IC50 = 9.2 +/- 3.1 nM. Finally, protein kinase C (PKC) activity of macrophage homogenate was not sign ificantly modified by 10 or 100 mu M fenspiride (at 100 mu M: 2.57 +/- 1.60 vs. 2.80 +/- 1.71 pmol/10(6) cells/min). In conclusion, fenspiri de inhibits fMLP- and PMA-induced pH signals in rat alveolar macrophag es, probably by acting distally on the PKC transduction signal. This p H antagonistic action may be relevant for the antiinflammatory mechani sm of fenspiride and requires further investigation. (C) 1997 Elsevier Science Inc.