Original-experimentalRole of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine
Introduction
Quinidine is a class IA antiarrhythmic drug with the effect of reducing multiple ion currents, including both Na+ and K+ channel currents (e.g., INa, IKr, IKs, IK1, IK-ATP, Ito).1, 2, 3 Quinidine is used to treat both atrial and ventricular tachyarrhythmias. By virtue of its electrophysiologic actions of inhibiting IK and increasing the ventricular effective refractory period, quinidine can also reduce arrhythmic activity in patients with short QT syndrome caused by gain of function of potassium channels3, 4 and in patients with Brugada syndrome caused by loss-of-function sodium channelopathies.3, 4, 5, 6 However, it has been recognized for decades that clinical use of quinidine is associated with recurrent syncope (i.e., quinidine syncope) and sudden death due to QT prolongation and polymorphic ventricular tachycardia (torsade de pointes [TdP]).1, 2 The incidence of TdP caused by quinidine is 1.5% to 8.8% or higher per patient-year of treatment.1, 7 Because the incidence of TdP is dose independent and the sensitivity of patients to the proarrhythmic effects of quinidine is highly variable,1 an understanding of the causes of proarrhythmic effects of quinidine in patients has been difficult to achieve.
In cardiac tissue, quinidine produces an open-state block of the sodium channel, decreases the upstroke velocity of the action potential, and causes a use-dependent increase in the QRS interval. It also blocks IKr and prolongs action potential duration (APD), an effect that is greater at slower than at faster heart rates.8 Both Na+ and K+ channel block caused by a multi–ion-channel blocker are concentration dependent and can be potential mechanisms of either antiarrhythmic or proarrhythmic activity.9 Therefore, it has been difficult to clarify the mechanisms that are responsible for the proarrhythmic activity of quinidine. We hypothesized that if block of IKr by quinidine reduced repolarization reserve more than block of INa increased it, the drug would be proarrhythmic. This situation is likely to exist when repolarization reserve is decreased due to an enhancement of late INa. Because repolarization reserve is reduced in the female rabbit heart treated with a low concentration of sea anemone toxin II (ATX-II) and exposure to ATX-II mimics the congenital or acquired conditions that increase late INa, we investigated the proarrhythmic and antiarrhythmic effects of quinidine using this rabbit heart model. In addition, by taking advantage of the unusual biphasic quinidine-induced changes in electrophysiologic parameters and in the occurrence of TdP, it was possible in this study to analyze the probability of TdP as a function of increases in the values of a number of these individual parameters.
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Methods
Animal use conformed to the “Guide for the Care and Use of Laboratory Animals” published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was approved by the Institutional Animal Care and Use Committee of CV Therapeutics (Palo Alto, CA, USA). New Zealand white female rabbits (weight 2.5–3.5 kg) were sedated and then anesthetized using IM and IV xylazine and ketamine, respectively.
Proarrhythmic and antiarrhythmic effects of quinidine in absence and presence of ATX-II
Quinidine at concentrations of 0.3 and 1 μM caused ectopic ventricular beats and spontaneous episodes of TdP in only 1 (7%) and 2 (14%) of 14 female rabbit hearts studied, respectively (Figure 1, Figure 2B). No ectopic ventricular beats or TdP were observed during exposures to quinidine at concentrations ≤0.1 μmol/L or 10–30 μmol/L. The proarrhythmic effects of quinidine were greatly enhanced by ATX-II. In the presence of 1 nmol/L ATX-II, quinidine at concentrations of 0.3, 1, and 3 μmol/L
Discussion
Quinidine is used in clinical practice to control atrial and ventricular arrhythmias. Because the drug prolongs VERP and APD and inhibits Ito, it is increasingly used to treat patients with short QT syndrome or Brugada syndrome.4, 14 However, quinidine itself is a cause of TdP and arrhythmic sudden death. The mechanism of quinidine-induced TdP has been attributed to QT prolongation due to inhibition of IKr.15, 16 The present study examines the critical role of late INa in modulating the
Conclusion
The presence of late INa modulates the arrhythmogenicity of quinidine. The proarrhythmic effects of quinidine were significantly greater in the presence than in the absence of ATX-II, suggesting that an increased level of late INa, which is associated with a wide variety of pathophysiologic conditions, may lead to an increased incidence of TdP in patients exposed to low or subtherapeutic concentrations of quinidine. Increases of BVR, index of Tpeak-Tend/QT interval, and Tpeak-Tend have higher
Acknowledgment
We thank Dr. Whedy Wang for assistance with statistical analysis of experimental data.
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Cited by (0)
Dr. Wu, Hong Li, Dr. Shryock, and Dr. Belardinelli are full-time employees of CV Therapeutics. Dr. Guo, Dr. Yan, and Dr. Jiao receive grant support from CV Therapeutics. Dr. Hackett and Dr. Antzelevitch are consultants for CV Therapeutics.