Effect of calcium on phenothiazine inhibition of neutrophil degranulation

Abstract

The phenothiazines are known to be potent inhibitors of calmodulin and have been used as probes for examining calmodulin-dependent cellular functions. We report here that the characteristics of phenothiazine inhibition of exocytosis in neutrophils more closely resemble their interaction with the annexins in vitro. Ca(2+)-dependent aggregation of liposomes mediated by either annexin I or annexin II was inhibited by the phenothiazines. Inhibition of liposome aggregation was not caused by interference with the binding of annexins to phospholipids. Rather, the phenothiazines increased the concentration of Ca2+ required for aggregation. Likewise, in neutrophils permeabilized with streptolysin O, inhibition of degranulation by phenothiazines could be overcome by increasing [Ca2+]. These results suggest that inhibition by phenothiazines of neutrophil degranulation is secondary to the ability of these compounds to inhibit membrane-membrane contact promoted by the annexins.

The proteolytic environment of chronic wounds

“…Functional modulation of neutrophils is another potential treatment avenue. Anti‐inflammatory agents that block or inhibit one or more neutrophil functions such as chemotaxis, adherence, infiltration, or degranulation may be worth exploring 72‐79 . Glucocorticoid steroids exert powerful, negative effects on inflammation and at first glance would appear to be excellent candidates for use in the modulation of neutrophil function.…”

In vivoadministration of acepromazine or promethazine to horse decreases the reactive oxygen species production response of subsequently isolated neutrophils to stimulation with phorbol myristate acetate

“…PHEs inhibit the superoxide anion (O 2 ˙ − ) production of phorbol myristate acetate (PMA)‐stimulated human neutrophils (Szuster‐Ciesielska et al. , 2004), modulate degranulation (Elferink, 1979; Richter, 1990; Blackwood & Hessler, 1995) and result in the formation of immature neutrophils when used over longer periods in the treatment of schizophrenic patients (Delieu et al. , 2001).…”

Modulating effects of acepromazine on the reactive oxygen species production by stimulated equine neutrophils

“…Among these molecules phenothiazines are of special interest because they can inhibit the production of O ˙− 2 by PMA‐stimulated human neutrophils (Szuster‐Ciesielska et al. 2004) and modulate their degranulation (Elferink 1979; Richter 1990; Blackwood & Hessler 1995).…”

“…Some phenothiazines like e.g. thioridazine, trifluoperazine and chlorpromazine have been described to exhibit immunomodulating activities, depending on the drug, the dose and the leucocyte model used (Elferink 1979; Richter 1990; Blackwood & Hessler 1996). Phenothiazines inhibit the production of reactive oxygen species (ROS) by phorbol myristate acetate (PMA)‐stimulated human neutrophils (Szuster‐Ciesielska et al.…”