On the mechanism of slow calcium channel block in heart.

1. D600 (methoxyverapamil, 2 x 10(-6) M) has little activity when it is applied during a rest interval. Its ability to depress Isi and contraction is much reduced when the muscle is rested. 2. Upon each activation the blockade of the slow channel increases until the use-dependent increase of blockade equals the diastolic removal, thus resulting in a frequency-dependent steady-state blockade. 3. Removal of block during a variable rest interval at various holding potentials is the faster the more negative the holding potential and gets slower in the more positive and gets slower in the more positive potential range. This process can be described by two voltage-dependent time constants (tau 1, tau 2). Similarities in the action of D600 on the si-channel to the action of local anaesthetics on the Na+-channel in nerve and heart are pointed out.