| Research Abstract |
1. The inhibitory effect of Class-I antiarrhythmic drugs on the maximum upstroke velocity (Vmax) of action potential was investigated in isolated guinea pig ventricular muscles based on the "modulated receptor hypothesis".
2. A conditioning clamp pulse was applied from the resting potential to 0 mV level using the single sucrose-gap voltage clamp technique, and Vmax of test action potential elicited 100 msec after termination of the clamp pulse was measured as an index of sodium channel availability. Such clamp pulses caused various Vmax decreases in the presence of the drugs. The decrease in Vmax by 10 msec clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 msec was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 (0.36-0.51) for disopyramide and quinidine, and much greater than 1.0 (2.61-11.23) for mexiletine, lidocaine, tocainide and aprindine. These findings suggest that the former group of drugs may block the sodium channel mainly during the upstroke phase of action potential, while the latter do so mainly during the plateau phase of action potential.
3. An interaction between aprindine and lidocaine was also investigated. The use-dependent block of Vmax by aprindine was significantly attenuated after additional application of lidocaine. In the presence of both aprindine and lidocaine, Vmax after a clamp pulse of 1.0 sec recovered in dual exponential function, where the short and the long time constant corresponded to the values for single treatment with each drug. These findings suggest that the two drugs may block the sodium channel by binding to a common receptor site with different kinetics, leading to a competitive displacement with each other.
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