Diphenylhydantoin blocks cardiac calcium channels and binds to the dihydropyridine receptor

Diphenylhydantoin was studied for its effects on Ca currents in single isolated guinea pig ventricular cells. The whole-cell patch-clamp technique was used, and Ca currents were studied after suppressing Na and K currents. At low frequencies (0.1 Hz) and negative holding potentials (-50 mV), diphenylhydantoin produced a concentration-dependent decrease in Ca currents without any significant change in the current-voltage relations. Half blocking effect occurred at 2 X 10(-4) M. The effects of diphenylhydantoin on Ca currents were dependent upon the holding potential. Inactivation curves for Ca currents were shifted to more negative potentials by the drug. The recovery of Ca currents from inactivation was prolonged by diphenylhydantoin, and the repriming of the current displayed an additional component, attributed to slow release of the drug from the channels. The voltage-dependent block was attributed to preferred binding by the inactivated channel state. Diphenylhydantoin also blocked specific [3H]-nitrendipine binding to guinea pig ventricular membrane preparations. The inhibition of [3H]-nitrendipine binding by diphenylhydantoin was competitive. Diphenylhydantoin also blocks cardiac Na channels in a voltage-dependent manner. We suggest that diphenylhydantoin binding sites exist on both Ca and Na channels.