Facilitatory effect of verapamil on adrenergic transmitter release and its relation to calmodulin

The mechanisms of verapamil (Ver) cnhanced transmitter release from rat tail artery prelabelled with [3H]NE were studied. It was found that Ver (10-100 umol/L) increased both the spontaneous and high-K+ (65 mmol/L) induced [3H]NE release. After pretreating with Mn2+ or a Ca2+-free, EGTA-containing solution, the facilitatory effects of Ver on [3H]NE release were either diminished or abolished. 2,4-Dinitrophenol. an ATP production inhibitor, had no effect on [3H]NE spontaneous release when administered alone, but it did inhibit Ver-evoked [3H]NE release. Calcimycin (A-23187), a calcium ionophore, was unable to antagonize the [3H]NE release caused by Ver. These results indicate that the facilitatory effect of Ver on the [3H]NE release requires an energy supply and Ca2+ influx, which is not caused by blocking Ca2+ channels. The facilitatory effect of Ver on [3H]NE release was reduced by 42% by tetrodotoxin. a sodium channel blocker. This implies that depolarizotion may be involved. Ver inhibited calmodulin activity in a dose-dependent manner. with 100 umol/L Ver significantly inhibiting calmodulin activity at a rate of 60%. It is possible that the effect of Ver on [3H]NE release is a result of the inhibition of calmodulin activity, similar to the effect of trifluoperazine on transmitter release. The data provides further evidence to support the hypothesis that calmodulin plays a dual role in regulating transmitter release.