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Quinidine interactions with human atrial potassium channels: developmental aspects
N I Nenov1, W J Crumb, J D Pigott
1Departments of Pharmacology, Pediatrics and Surgery, Tulane University School of Medicine, Louisiana State University School of Medicine New Orleans, Louisiana, USA.
Insights
Quinidine is less effective in pediatric patients due to age-related changes in its interaction with cardiac potassium channels, specifically Ito. This study clarifies age-dependent effects on antiarrhythmic drug action.
Area of Science:
- Cardiology
- Pharmacology
- Electrophysiology
Background:
- Clinical studies indicate reduced quinidine effectiveness for pediatric atrial arrhythmias compared to adults.
- Age-related alterations in quinidine's cardiac effects and potassium channel interactions are documented in mammals.
Purpose of the Study:
- To investigate postnatal developmental effects on quinidine's interaction with major repolarizing currents (Ito, IKur, Ins, IK1) in human atrial myocytes.
- To elucidate the electrophysiological basis for age-dependent quinidine efficacy in treating arrhythmias.
Main Methods:
- Utilized the whole-cell voltage-clamp technique on human atrial myocytes.
- Examined quinidine's blockade and unblocking mechanisms on Ito, IKur, Ins, and IK1 currents.
Main Results:
- Identified age-related changes in quinidine's IC50 for Ito blockade and its unblocking kinetics.
- Demonstrated age-independent inhibition of IK1 and IKur by quinidine.
- Found that the nonselective cation current (Ins) is insensitive to quinidine.
Conclusions:
- Age-dependent modulation of Ito is a key factor in quinidine's variable efficacy between pediatric and adult patients.
- Quinidine's effects on IK1 and IKur are consistent across age groups.
- These findings clarify the electrophysiological mechanisms underlying quinidine's antiarrhythmic action in different populations.
Abstract:
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.