PH-Dependent effects of quinidine on the kinetics of dV/dtmax in guinea pig ventricular myocardium.

Steady state studies have shown that quinidine is more depressant at low pH. To determine whether changes in pH affect the kinetics of quinidine interaction with the sodium channel, we measured transmembrane potential and dV/dtmax in guinea pig papillary muscles mounted in a single sucrose gap. pH was changed from 7.4 to 6.9 by changing either the bicarbonate concentration [HC(V] (25–7.5 mm) or the CO2 content (5–20%). dV/dtn,., kinetics were studied by stimulating the preparation with 20-second trains having 500- or 1000-msec interstimulus intervals and 20 seconds between the trains. Time constants (TO) for the onset of block were 6.2 pulses and 2.7 pulses at interstimulus intervals of 500 and 1000 msec, respectively (P < 0.05) in fibers treated with 4 mg/liter quinidine. Time constant for the onset of block did not show any pH dependence. Recovery from block was not frequency dependent (4.7 ± 0.8 seconds at an interstimulus interval of 500 and 4.0 ± 1.0 second at an interstimulus interval of 1000 msec, P > 0.1). At an interstimulus interval of 500 msec, the recovery time constant increased from 4.7 ± 0.8 to 7.8 ± 2 seconds (P < 0.05) as the pH was lowered to 6.9 by decreasing [HCO3-]o. This effect was fully reversed when the pH was restored to 7.4 (7.8 ± 2 back to 4 ± 0.4 seconds). Lowering the pH by elevating the CO2 content gave similar results. The results at an interstimulus interval of 1000 msec parallel those of 500 msec. Elevating the drug concentration from 4 to 16 mg/liter increased the rate of onset of block (TO 5.8 ± 2 pulses to 4.2 ± 1.6 pulses, P < 0.05) but not the rate of recovery from block. These results are consistent with the hypothesis that slowing of the recovery process at low pH is the result of increased protonation of receptor-bound drug and are similar to data previously reported for lidocaine. The data support the view that quinidine and lidocaine interact with the sodium channel in a similar manner, despite suggestions that they have fundamentally different mechanisms of action.