Quinidine Interactions With Human Atrial Potassium Channels

Abstract

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 (I to , I Kur , I ns , and I K1 ) 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 IC 50 for quinidine blockade of I to , as well as the mechanism of quinidine unblocking. In contrast, quinidine was found to inhibit both adult and pediatric I K1 and I Kur in an age-independent manner, whereas the nonselective cation current (I ns ), which contributes to the sustained outward current (I sus ), 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. (Circ Res. 1998;83:1224-1231.)uinidine is one of the most commonly used drugs for treatment of both atrial and ventricular rhythm disturbances. 1 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 (I to ), the inwardly rectifying K current (I K1 ), the rapidly activating delayed rectifier (I Kr ), and the ultrarapid delayed rectifier (I Kur ). 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 interval 9 and repolarization 4 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 I to and I K1 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. 8 It seems likely that age-related differences in quinidine interaction with cardiac ion channels may also exist in man. Recent clinical studies have d...

Properties and Molecular Determinants of the Natural Flavone Acacetin for Blocking hKv4.3 Channels

“…It has been documented that an increase of I to amplitude by gain-of-function mutations in the KCND3 -encoded Kv4.3 channels is the molecular pathogenesis for the lethal arrhythmia in patients with Brugada syndrome [30]. Suppression of ventricular arrhythmia in Brugada patients with quinidine [32], [33] is believed to be related to its I to blocking effect [34]–[36].…”

2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures

“…Quinidine is a Vaughan Williams class IA antiarrhythmic agent that inhibits sodium conduction [89] as well as conductance of a variety of potassium currents, including I Kr , I KI and I to [90]. The use of oral quinidine for management of AF has largely been discontinued, due to evidence that quinidine may increase mortality [2], [3], [91].…”

Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito

“…Moreover, regional and transmural differences in the balance between I to and Na ϩ current (I Na ) may underlie ventricular fibrillation and sudden death in patients with inherited arrhythmias such as Brugada syndrome (9,40). Finally, inhibition of I to by several antiarrhythmic agents such as flecainide, quinidine, and propafenone contributes to both their therapeutic and proarrhythmic effects (24,33,42). Therefore, defining the molecular identity and electrophysiological properties of ventricular I to is essential for a comprehensive understanding of arrhythmia mechanisms in a wide variety of pathologies and may aid in the proper choice and design of antiarrhythmic drug therapy.…”