Antiallergic Effect of Epinastine (WAL 801 CL) on Immediate Hypersensitivity Reactions: (I) Elucidation of the Mechanism for Histamine Release Inhibition

Abstract

Epinastine caused an inhibition of histamine release from rat peritoneal mast cells induced by both antigen-antibody reaction and compound 48/80. Epinastine was similarly effective in inhibiting compound 48/80-induced histamine release not only from isolated rat peritoneal mast cells but also from rat mesenterial pieces. Also, histamine release from lung pieces obtained from actively sensitized guinea pigs after exposure to antigen challenge was markedly inhibited by epinastine. The drug was effective in inhibiting not only Ca2+ uptake into lung mast cells in actively sensitized guinea pigs but also Ca2+ release from the intracellular Ca store of rat peritoneal mast cells exposed to both compound 48/80 and substance P. No significant changes were observed in phosphodiesterase activity in rat peritoneal mast cells treated with epinastine, while adenylate cyclase activity was augmented by epinastine. Epinastine has no inhibitory effect on histamine release induced by Ca2+ or IP3 from permeabilized mast cells. However, the drug significantly and dose-dependently suppressed calmodulin activity suggesting that histamine release inhibition due to epinastine may be partly attributable to Ca(2+)-calmodulin dependent process(es). The drug caused no visible changes in thermodynamic behavior of lipids, either in order parameter or in differential scanning calorimetry, indicating that the drug has no influence on membrane fluidity.

In vitro investigations with the histamine H 1 receptor antagonist, epinastine (WAL 801 CL), on isolated human allergic effector cells

“…Generally, high concentrations (> 0.1mmol/l) of the compound were needed to observe inhibitory effects. This is in concordance with previous observations obtained from animal models [8,12]. As observed in experiments with other HRA [15,[18][19][20], IgEmediated production of LTC 4 from basophils was more sensitive to epinastine compared with histamine release due to immunologic (anti-IgE, con A, priming factors) or non immunologic stimuli (Table 1) from basophils or ECP release from eosinophils.…”

“…Epinastine is a potent H1 receptor antagonist (HRA) with high receptor binding affinity [4] which is orally active in these diseases [4,5]. The drug appears to have additional anti-inflammatory activity in different cellular models [6][7][8][9] as well as in animal models [8,[10][11][12].…”

“…Previous studies have demonstrated that epinastine also exerts inhibitory activity on antigen-as well as compound 48/80-induced histamine release from isolated rat peritoneal mast cells and from the rat mesentery [12].…”

Inhibitory Effect of Epinastine on Superoxide Generation by Rat Neutrophils

“…The NADPHoxidase system may be partially inhibited due to the membrane stabilizing action of these drugs. However, epinastine had no influence on the membrane fluidity (2). Epinastine augmented the adenylate cyclase activity, and inhibited Ca 2+ release from the intracellular Ca store of rat peritoneal mast cells and calmodulin activity (2).…”

“…However, epinastine had no influence on the membrane fluidity (2). Epinastine augmented the adenylate cyclase activity, and inhibited Ca 2+ release from the intracellular Ca store of rat peritoneal mast cells and calmodulin activity (2). The increase in cyclic AMP content prevents 02-generation from neutrophils (unpublished data, N. Fukuishi and M. Akagi), and the initiation of 02-generation may be attributable to the Ca 2+-calmodulin dependent process(es) (14).…”