Calcium channel block and recovery from block in mammalian ventricular muscle treated with organic channel inhibitors

Abstract

The effects of a bradycardic agent, AQA 39, on the action potential, tension and membrane current of cat ventricular muscle have been compared with the effects of

• 1. AQA 39 and D600 both lengthened the action potential duration; neither drug affected the resting potential (−83 to −85 mV). Both drugs depressed the action potential plateau amplitude and tension when the stimulation rate was 120 min⁻¹; ED₅₀'s for the negative inotropic effect were 7×10⁻⁸ M for D600 and 3×10⁻⁵ M for AQA 39. At 20 min⁻¹, D600 was only slightly less depressant (ED₅₀ for negative inotropy 4×10⁻⁷ M) but 5×10⁻⁵ M AQA 39 had no effect, neither on tension nor on the action potential plateau amplitude.

• 2. In voltage clamp experiments (holding potential −50 mV), 2×10⁻⁵ M AQA 39 and 2×10⁻⁶ M D600 were equipotent. With depolarizing pulses (250 ms steps to −10 mV at 20 min⁻¹), they depressed slow inward calcium current (I_si) by 70% and peak tension by 80% in 30 min.

• 3. At a membrane potential of −50 mV, I_si in muscle exposed to either drug for 30 min without stimulation was not depressed during the first post-rest clamp but the block of calcium channels was rapid upon resumption of stimulation (i.e. a “use-dependent” block).

• 4. Following steady-state block, I_si could be restored to control amplitude with hyperpolarizing pre-pulses, whereas depolarizing pre-pulses enhanced the block of I_si.

• 5. It seems that both drugs block calcium channels only after the channels have been activated (opened) and that the degree of activation and the degree of block are linked. The drugs dissociate from a blocking site at a rate dependent upon the diastolic membrane potential; the more negative the membrane potential inbetween subsequent depolarizations, the quicker the dissociation. While the dissociation of AQA 39 at −50 mV is only about twice as fast as that of D600, it is nearly 100 times faster at −80 mV and more than 150 times faster at potentials more negative than −90 mV. These differences might be related to the different lipophilic properties of the two drugs.