Use-dependent block of sodium currents by tocainide, proline derivatives, and related benzylated analogs
Potency of drug in producing a use-dependent block of sodium currents. For each drug used, the concentration for determining the 50% block of the current (IC50) is shown, evaluated from the residual current in the presence of drug after 30-s trains of 10-ms test pulses to −20 mV from a holding potential of −100 mV at the frequency of either 2 or 10 Hz. The block at the first pulse was caused by the block of the resting channel before the start of the high-frequency stimulation, and it has been considered tonic block produced at −100 mV of holding potential. The IC50 values were obtained during non-linear least squares fits of the concentration-response data to the logistic equation described under Materials and Methods. The gain of potency over the tonic block is shown for each compound as the ratio between the IC50 values for tonic block and use-dependent block (TB/UDB) at either 2 or 10 Hz. The higher the ratio, the stronger the gain of potency obtained during the high frequency of stimulation.
| Compound | Tonic Block (HP −100 mV) IC50 | Use-Dependent Block | |||
|---|---|---|---|---|---|
| 2 Hz | 10 Hz | ||||
| IC50 | TB/UDB | IC50 | TB/UDB | ||
| μM | μM | μM | |||
| Toc | 523 ± 32 | 350 ± 11 | 1.5 | 248 ± 14 | 2.1 |
| Benzyl-Toc | 5.4 ± 0.6a,b | 5.5 ± 0.6a,b | 0.98 | 2.9 ± 0.4a,b | 1.9 |
| To5 | 168 ± 12c | 47 ± 4.8c | 3.6 | 23.2 ± 1.4c | 7.2 |
| Benzyl-To5 | 29.7 ± 4.9a,b | 29.8 ± 6a,b | 0.99 | 15.8 ± 3a,b | 1.9 |
| To9 | 94 ± 19c | 42.1 ± 9.6c | 2.2 | 38.2 ± 9c | 2.5 |
| Benzyl-To9 | 3.9 ± 0.8a | 1.2 ± 0.2a | 3.3 | 0.50 ± 0.06a | 7.8 |
↵ a Significant difference of benzyl-analogs with respect to related nonbenzylated parent compounds (P < 0.05 for Benzyl-To5; P < 0.001 for Benzyl-Toc and Benzyl-To9).
↵ b Significant difference of benzyl-analogs with respect to Benzyl-To9 (P < 0.001).
↵ c Significant difference of proline-like analogs with respect to tocainide (P < 0.001).