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Fenspiride and membrane transduction signals in rat alveolar macrophages
J C Féray1, K Mohammadi, K Taouil
1INSERM U400, Faculté de Médecine, Créteil, France.
Abstract:
Fenspiride inhibits the calcium signal evoked by the inflammatory peptide formyl-Met-Leu-Phe (fMLP) in peritoneal macrophages, but at concentrations (approximately 1 mM) far above the therapeutic range (approximately 1 microM). Here, in rat alveolar macrophages, high fenspiride concentrations (1 mM) were required to inhibit the calcium signals evoked by the calcium agonist Bay K8644 or by ionomycin. Moreover, fenspiride (1 mM) was a poor inhibitor of the cell membrane depolarization induced 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 (phorbol 12-myristate 13-acetate) with an IC50 = 9.2 +/- 3.1 nM. Finally, protein kinase C (PKC) activity of macrophage homogenate was not significantly modified by 10 or 100 microM fenspiride (at 100 microM: 2.57 +/- 1.60 vs. 2.80 +/- 1.71 pmol/10(6) cells/min). In conclusion, fenspiride inhibits fMLP- and PMA-induced pH signals in rat alveolar macrophages, probably by acting distally on the PKC transduction signal. This pH antagonistic action may be relevant for the antiinflammatory mechanism of fenspiride and requires further investigation.
Insights
Fenspiride effectively inhibits pH signals in rat alveolar macrophages, likely through protein kinase C (PKC) pathways. This pH antagonism may contribute to fenspiride's anti-inflammatory effects, warranting further research.
Area of Science:
- Immunology and Pharmacology
- Cellular Signaling
Background:
- Fenspiride's anti-inflammatory effects are recognized, but its precise cellular mechanisms remain incompletely understood.
- Previous studies indicated fenspiride inhibits calcium signaling in peritoneal macrophages at high concentrations, exceeding therapeutic levels.
Purpose of the Study:
- To investigate the effect of fenspiride on intracellular pH regulation in rat alveolar macrophages.
- To elucidate the potential role of protein kinase C (PKC) in fenspiride's action on macrophage signaling.
Main Methods:
- Assessment of fenspiride's impact on calcium signals induced by agonists like Bay K8644 and ionomycin.
- Evaluation of fenspiride's inhibition of Na+-H+ antiport activation stimulated by formyl-Met-Leu-Phe (fMLP) and phorbol 12-myristate 13-acetate (PMA).
- Measurement of protein kinase C (PKC) activity in macrophage homogenates following fenspiride treatment.
Main Results:
- Fenspiride required high concentrations (1 mM) to inhibit calcium signals evoked by Bay K8644 or ionomycin in rat alveolar macrophages.
- Fenspiride potently inhibited Na+-H+ antiport activation by fMLP (IC50 = 3.1 nM) and PMA (IC50 = 9.2 nM).
- PKC activity was not significantly altered by fenspiride concentrations up to 100 microM.
Conclusions:
- Fenspiride demonstrates potent inhibition of fMLP- and PMA-induced pH signals in rat alveolar macrophages.
- The mechanism likely involves distal actions on the PKC transduction pathway, rather than direct PKC inhibition.
- This pH antagonistic action represents a potential contributor to fenspiride's anti-inflammatory properties.