Effects of azelastine on membrane currents in tracheal smooth muscle cells isolated from the guinea-pig.

Azelastine [4-(p-chlorobenzyl)-2-(hexahydro-1-methyl -1H-azepin-4-yl)-1-(2H)-phthalazinone hydrochloride], an anti-allergic agent, inhibited the high K(+)-induced contraction in tracheal smooth muscle cells isolated from the guinea-pig. In order to investigate the ionic mechanisms, we examined the effects of azelastine on membrane currents, using the tight-seal whole cell voltage clamp technique. Azelastine (1-100 microM) caused an inhibition of the Ba2+ inward current (IBa) through the voltage-dependent L-type Ca2+ channel in a concentration-dependent manner. The inhibitory effect of azelastine on IBa was fully reversible. The IC50 value for azelastine-induced inhibition of IBa was approximately 8 microM, and 100 microM azelastine completely suppressed IBa. Azelastine exerted mainly a tonic block of IBa but did not show use dependence. Azelastine (10 microM) shifted the quasi-steady-state inactivation curve of IBa to more negative membrane potentials by approximately -20 mV, suggesting that the inhibitory effect of azelastine on IBa was voltage-dependent. In addition, azelastine produced inhibitory actions on other membrane currents (i.e. the voltage-dependent transient outward K+ current and the Ca(2+)-activated oscillatory K+ current) at doses higher than 10 microM. These results suggest that azelastine inhibits the voltage-dependent L-type Ca2+ current in single tracheal smooth muscle cells, which may contribute to the anti-allergic actions of azelastine in airways.