In guinea pig cardiac myocytes, quinidine caused use-dependent block of the sodium current with time- and voltage-dependent recovery, supporting the modulated receptor hypothesis.
Quinidine causes use-dependent block of sodium channels with altered kinetics, supporting the modulated receptor hypothesis.
In guinea pig cardiac myocytes quinidine (20 microM) caused less than 10% tonic block reduction of the sodium current at -120 mV, but a fast pulse train reduced it more than 90%. Recovery from use-dependent block was time and voltage dependent, and was always slow (tau = 34 +/- 10 seconds at -160 mV; tau = 90 +/- 35 seconds at -120 mV; n = 15, mean +/- SD, p less than 0.001, paired t test). However, in association with repeated activation a fast component of recovery from block was observed: use-dependent unblocking. Availability of sodium channels for use-dependent unblocking was enhanced by hyperpolarization until a plateau was reached near -160 mV. Compared with the availability of drug-free sodium channels (h-curve), the voltage dependence of availability for use-dependent unblocking (h'-curve) was shifted by about 30 mV to more negative potentials, and its slope was reduced 2.5-fold. At -160 mV, the kinetics of development of availability of sodium channels for use-dependent unblocking were rapid (tau less than 10 msec). Depolarization to -120 mV reduced the availability of sodium channels for fast unblocking with a time constant of 191 +/- 46 msec (n = 14). Finally, block established by frequent brief depolarizations (activations) declined during prolonged inactivation. From these results we concluded that the time and voltage dependence of the availability of sodium channels for unblocking are considerably different from the availability for activation of drug-free channels, that rested drug-associated channels do exist, and that drug-associated channels do not conduct (or at least have a greatly reduced conductance) upon activation unless they first unblock. Furthermore, activated and inactivated channels have a different affinity for quinidine, and since quinidine can occupy the channel receptor even when "guarded," our results are incompatible with the guarded receptor hypothesis but can be explained within the framework of the modulated receptor hypothesis.
Snyders et al. (1990) studied this question. Quinidine vs. Drug-free sodium channels was evaluated on Sodium current block and recovery kinetics. In guinea pig cardiac myocytes, quinidine caused use-dependent block of the sodium current with time- and voltage-dependent recovery, supporting the modulated receptor hypothesis.