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

Abstract

Steady state studies showed that quinidine is more depressant at low pH. To determine whether changes in pH affect the kinetics of quinidine interaction with the Na channel, transmembrane potential and dV/dtmax were measured 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 [HCO2-] (25-7.5 mm) or the CO2 content (5-20%). The dV/dtmax kinetics were studied by stimulating the preparation with 20-s trains having 500 or 1000 ms interstimulus intervals and 20 s between the trains. Time constants (.tau.o) for the onset of block were 6.2 pulses and 2.7 pulses at interstimulus intervals of 500 and 1000 ms, respectively (P < 0.05) in fibers treated with 4 mg/l quinidine. Time constant for the onset of block did not show pH dependence. Recovery from block was not frequency dependent (4.7 .+-. 0.8 s at an interstimulus interval of 500 and 4.0 .+-. 1.0 s at an interstimulus interval of 1000 ms, P > 0.1). At an interstimulus interval of 500 ms, the recovery time constant increased from 4.7 .+-. 0.8 to 7.8 .+-. 2 s (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 s). Lowering the pH by elevating the CO2 content gave similar results. The results at an interstimulus interval of 1000 ms parallel those of 500 ms. Elevating the drug concentration from 4 to 16 mg/l increased the rate of onset of block (.tau.o 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. Quinidine and lidocaine interact with the Na channel in a similar manner, despite suggestions that they have fundamentally different mechanisms of action.