Quinidine Interactions With Human Atrial Potassium Channels

Apr 24, 2018 • By Neviana I. Nenov, William J. Crumb, Jr, John D. Pigott, Lynn H. Harrison, Jr, Craig W. Clarkson


Clinical studies have suggested that quinidine is less effective when used for the treatment of atrial arrhythmias
in pediatric patients compared with its clinical effectiveness in the adult patient population. Age-related changes in the cardiac actions of quinidine on action potential duration and interaction with potassium channels in several mammalian species also have been reported. We investigated the effects of postnatal development on quinidine’s interaction with major repolarizing currents (Ito, IKur, Ins, and IK1) in human atrial myocytes, using the whole-cell configuration of the voltage-clamp technique. Our results indicate that there are age-related changes in both the IC50 for quinidine blockade of Ito, as well as the mechanism of quinidine unblocking. In contrast, quinidine was found to inhibit both adult and pediatric IK1 and IKur in an age-independent manner, whereas the nonselective cation current (Ins), which contributes to the sustained outward current (Isus), was insensitive to quinidine. The results from this study help to clarify the electrophysiological mechanism by which quinidine elicits its antiarrhythmic effect in the pediatric and adult human population.

Quinidine is one of the most commonly used drugs for treatment of both atrial and ventricular rhythm disturbances. Quinidine’s efficacy as an antiarrhythmic agent is believed to result from its effects on conduction velocity and repolarization of the cardiac action potential.1,2 Quinidine’s ability to prolong the duration of the cardiac action potential has been attributed to its ability to inhibit several different types of potassium ion channels expressed in mammalian cardiac tissue, including the transient outward K current (Ito), the inwardly rectifying K current (IK1), the rapidly activating delayed rectifier (IKr), and the ultrarapid delayed rectifier (IKur).3 However, the mechanisms by which quinidine exerts its inhibitory effects on these potassium currents are not understood fully. Previous studies in dog, rabbit, and rat cardiac tissue have documented that the ability of quinidine and other antiarrhythmic agents to alter conduction and repolarization change significantly during postnatal development.4–8 Quinidine has been shown to prolong both the QT interval9 and repolarization of the Purkinje fiber action potential to a significantly greater extent in young canines compared with adult animals. Recent evidence suggests that developmental changes in the effects of antiarrhythmic agents on cardiac tissue may be attributed to age-related changes in drug-channel interactions. 6–8 For example, quinidine block of rabbit ventricular Ito and IK1 has been shown to be significantly different in neonatal versus adult myocytes, with cells from neonates being more sensitive to the action of quinidine than adults. It seems likely that age-related differences in quinidine
interaction with cardiac ion channels may also exist in man. Recent clinical studies have documented that quinidine and flecainide exhibit a markedly reduced clinical efficacy against atrial tachyarrhythmias in pediatric patients10 compared with their relatively high clinical efficacy in adults. Because changes in drug-channel interaction have been indicated as a potential mechanism underlying postnatal changes in the actions of antiarrhythmic agents, we initiated a study to compare the effects of quinidine on major repolarization currents (Ito, IK1, IKur, and the nonselective cation current, Ins) expressed in pediatric and adult human atrial myocytes.

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