Table 2.
Simulation parameters of INa blockade by flecainide and mexiletine according to the modulated receptor hypothesis
| Drug | KR (μM) | KI (μM) | Channel | V1/2 (mV) | S (mV) | h | KAPP (μM) | IC50 (μM) |
|---|---|---|---|---|---|---|---|---|
| Mexiletine | 800 | 6 | Wild-type | –79.1 ± 2.5 | 7.9 ± 0.2 | 0.987 ± 0.004 | 294.1 | 236 ± 14.8 |
| G1306E | –66.5 ± 1.8 | 8.4 ± 0.5 | 0.997 ± 0.007 | 572.7 | 642 ± 49.4 | |||
| R1448C | –89.9 ± 3.1 | 12.9 ± 0.7 | 0.880 ± 0.014 | 47.4 | 48 ± 1.9 | |||
| Flecainide | 480 | 18 | Wild-type | –79.1 ± 2.5 | 7.9 ± 0.2 | 0.987 ± 0.004 | 359.9 | 407 ± 39.1 |
| G1306E | –66.5 ± 1.8 | 8.4 ± 0.5 | 0.997 ± 0.007 | 445.7 | 435 ± 42.4 | |||
| R1448C | –89.9 ± 3.1 | 12.9 ± 0.7 | 0.880 ± 0.014 | 117.6 | 117 ± 2.8 |
The values of dissociation constants for closed channels (KR) and inactivated channels (KI) were calculated experimentally in the present study for flecainide and a previous study for mexiletine (Desaphy et al. 2001). Each drug showed the same state-specific affinities to all the three channels. The half-maximum inactivation potential (V1/2) and the slope factor (S) were determined from the fit of steady-state availability curves specific to each channel and are given along with the s.e. of the fit. The proportion of closed channels (h) at a holding potential (HP) of –120 mV is given as mean ± s.e.m. from 17–33 cells. The theoretical apparent affinities KAPP were calculated from eqn (6) (see Results) and were compared to the IC50 values (indicated along with the s.e.of the fit) calculated from dose–response curves obtained experimentally at the HP of –120 mV (see Fig. 6).