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.
Koumi
S
S
First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
Sato
R
R
Hayakawa
H
H
Okumura
H
H
D000818:Animals; D002700:Chloramines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D009206:Myocardium / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014105:Tosyl Compounds
D002700:Chloramines; D015222:Sodium Channels; D014105:Tosyl Compounds; C016300:chloramine-T; D011802:Quinidine