Chlordiazepoxide block of two types of calcium channels in neuroblastoma cells.

Chlordiazepoxide is a benzodiazepine that is widely used as a minor tranquilizer. It is also effective in the treatment of acute alcohol withdrawal. In this setting, chlordiazepoxide acts as a sedative and prevents the development of epileptiform activity. Although benzodiazepines are known to augment gamma-aminobutyric acid-activated chloride channels, an action which at least partially accounts for their anticonvulsant properties, there is some evidence to suggest that voltage-activated calcium channels may also be the target of these agents. We therefore studied the effect of chlordiazepoxide in blocking two distinct types of voltage-activated calcium channels in N1E-115 neuroblastoma cells. Chlordiazepoxide reversibly blocked calcium channels in both closed and open configurations. It was slightly more potent in blocking the transient (T-type or type I) than the long-lasting (L-type or type II) type of calcium channels with apparent Ki values of 311 and 398 microM, respectively. In the presence of chlordiazepoxide, the currents of both types of calcium channel currents decayed more quickly than control, an observation that suggests open channel block. Chlordiazepoxide-induced block of T-type calcium channels was use dependent, increasing with an increase in stimulus frequency. This was due primarily to the acceleration of current decay and slowing of recovery from inactivation by chlordiazepoxide. These calcium channel blocking actions could contribute some to the sedative and anticonvulsant properties of chlordiazepoxide in patients suffering from acute alcohol withdrawal and in electric shock-induced seizures in animal models.