Quinidine blocks cardiac sodium current after removal of the fast inactivation process with chloramine-T.

To determine if the fast sodium current inactivation process is necessary for sodium current (INa) blockade by quinidine, we studied the effects of quinidine on INa in guinea-pig ventricular myocytes treated with chloramine-T, which removes the fast inactivation process of INa. Following exposure to chloramine-T (2 mM), INa amplitude was reduced at all voltages and INa decay was irreversibly prevented. Quinidine (10 microM) produced resting block of INa of 36 +/- 2% (n = 5) at the peak potential of -30 mV in chloramine-T treated myocytes. Quinidine decreased INa in a dose-dependent manner. The half-blocking concentration (KD) was 1.9 +/- 0.2 x 10(-5) M (n = 4). The steady-state inactivation curve (hx) was shifted in the negative potential direction (-5.2 +/- 0.4 mV, n = 4). Even after removal of the fast inactivation process of INa, use-dependent block was observed in the presence of quinidine when various depolarizing pulse durations (5 ms approximately 200 ms) were applied repetitively at intervals of 300 ms approximately 2 s. Longer depolarizing pulses and higher frequency pulse trains produced greater use-dependent block. Use-dependent block was also enhanced at more positive holding potentials. These results suggest that quinidine produces both resting block and use-dependent block of sodium channels in the absence of the fast INa inactivation process.

[1]  D. Eaton,et al.  Removal of sodium channel inactivation in squid axon by the oxidant chloramine-T , 1985, The Journal of general physiology.

[2]  G. Strichartz,et al.  Inhibition of sodium currents by local anesthetics in chloramine-T- treated squid axons. The role of channel activation , 1987, The Journal of general physiology.

[3]  H. Irisawa,et al.  Modulation by intracellular ATP and cyclic AMP of the slow inward current in isolated single ventricular cells of the guinea‐pig. , 1983, The Journal of physiology.

[4]  G. Wang.  Irreversible modification of sodium channel inactivation in toad myelinated nerve fibres by the oxidant chloramine‐T. , 1984, The Journal of physiology.

[5]  M. Cahalan.  Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons. , 1978, Biophysical journal.

[6]  J. Yeh.  Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons. , 1978, Biophysical journal.

[7]  T. C. West,et al.  Single fiber recording of the effects of quinidine at atrial and pacemaker sites in the isolated right atrium of the rabbit. , 1960, The Journal of pharmacology and experimental therapeutics.

[8]  K. Courtney.  Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. , 1975, The Journal of pharmacology and experimental therapeutics.

[9]  B. Katzung,et al.  Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. , 1977, Biochimica et biophysica acta.

[10]  D. Marquardt.  An Algorithm for Least-Squares Estimation of Nonlinear Parameters , 1963 .

[11]  A. Brown,et al.  Sodium current depression by lidocaine and quinidine in isolated ventricular cells , 1981, Nature.

[12]  M. Kohlhardt,et al.  On the Mechanism of Drug‐Induced Blockade of Na+ Currents: Interaction of Antiarrhythmic Compounds With DPI‐Modified Single Cardiac Na+ Channels , 1989, Circulation research.

[13]  J. Salata,et al.  Effects of Quinidine on Action Potentials and Ionic Currents in Isolated Canine Ventricular Myocytes , 1988, Circulation research.

[14]  A. Noma,et al.  Transient Depolarization and Spontaneous Voltage Fluctuations in Isolated Single Cells from Guinea Pig Ventricles: Calcium‐Mediated Membrane Potential Fluctuations , 1982, Circulation research.

[15]  T. Colatsky.  Mechanisms of Action of Lidocaine and Quinidine on Action Potential Duration in Rabbit Cardiac Purkinje Fibers: An Effect on Steady State Sodium Currents? , 1982, Circulation research.

[16]  B. Hille,et al.  Local anesthetics: hydrophilic and hydrophobic pathways for the drug- receptor reaction , 1977, The Journal of general physiology.

[17]  B. Katzung,et al.  Effect of Lidocaine and Quinidine on Steady‐State: Characteristics and Recovery Kinetics of (dV/dt)max in Guinea Pig Ventricular Myocardium , 1975, Circulation research.

[18]  B. Hille,et al.  Local anesthetics. Effect of pH on use-dependent block of sodium channels in frog muscle. , 1977, Biophysical journal.

[19]  L. Hondeghem,et al.  Quinidine blocks cardiac sodium channels during opening and slow inactivation in guinea‐pig papillary muscle , 1988, British journal of pharmacology.

[20]  P. Poole‐Wilson,et al.  The Effects of Verapamil, Quiescence, and Cardioplegia on Calcium Exchange and Mechanical Function in Ischemic Rabbit Myocardium , 1982, Circulation research.

[21]  G. Strichartz,et al.  The Inhibition of Sodium Currents in Myelinated Nerve by Quaternary Derivatives of Lidocaine , 1973, The Journal of general physiology.

[22]  C F Starmer,et al.  Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. , 1984, Biophysical journal.

[23]  J. Yeh,et al.  Removal of sodium inactivation and block of sodium channels by chloramine-T in crayfish and squid giant axons. , 1987, Biophysical journal.

[24]  J. Bigger,et al.  Mechanisms of Quinidine‐Induced Depression of Maximum Upstroke Velocity in Ovine Cardiac Purkinje Fibers , 1982, Circulation research.

[25]  K. Brown,et al.  pH‐Dependent Effects of Quinidine on the Kinetics of dV/dtmax in Guinea Pig Ventricular Myocardium , 1982, Circulation research.