Interval- and voltage-dependent effects of the calcium channel-blocking agents D600 and AQA 39 on mammalian ventricular muscle.

Myocardial depressant actions of D600 and AQA 39, a D600-like compound, have been studied in rabbit and cat ventricular muscle using simultaneous action potential and tension measurements and the single hybrid sucrose gap technique to measure the slow inward current (Isi). D600-induced depression of Isi is shown to be greater after a depolarization (action potential or clamp pulse) than before. When a muscle is stimulated with depolarizing clamp steps, the degree of Isi depression increases with the number and voltage of the activating pulses. The degree of si-channel block also depends on the length of the diastolic interval and on the membrane potential during diastole. At diastolic potentials between -50 and -90 mV, there is a restoration of channels to the conducting pool. The rate of this dissociation of drug from si-channels is faster at more negative potentials (T1/2 of 15 sec at -90 mV, 350 sec at -50 mV). AQA 39 has a chemical structure similar to that of D600 but is much less hydrophobic. It also blocks si-channels in a frequency- and voltage-dependent manner. The major difference between the two compounds is in the voltage-dependent rate of recovery from si-channel block. In comparison to the rate of unblock of D600-bound channels, unblock with AQA 39 is about twice as fast at -50 mV and nearly 100 times as fast at -80 mV.