Pharmacological response of quinidine induced early afterdepolarisations in canine cardiac Purkinje fibres: insights into underlying ionic mechanisms

Abstract

The purpose of these experiments was to study the pharmacological response of quinidine induced early afterdepolarisations to gain insights into underlying ionic mechanisms. Quinidine (8.5 microM) induced stable early afterdepolarisations at low activation frequencies in 80% of canine cardiac Purkinje fibres superfused with a modified Tyrode's solution. Early afterdepolarisations arose from a secondary plateau in the voltage range of -30 to -60 mV. Calcium channel blockers (verapamil, 1 microM, in 3/6 preparations; verapamil, 10 microM in 6/6 preparations; nifedipine, 0.1 microM in 5/5 preparations) completely eliminated early afterdepolarisations, despite continued quinidine superfusion, without altering the underlying action potential. Isoprenaline (0.2-1 microM) restored them in 75% of these preparations during continued calcium blocker superfusion. Tetrodotoxin (5/5 preparations) eliminated early afterdepolarisations by abbreviating action potentials and reducing or eliminating the quinidine induced secondary plateau. While low concentrations of isoprenaline favoured the occurrence of early afterdepolarisations, larger concentrations eliminated them by enhancing spontaneous automaticity. These experiments suggest that voltage dependent and/or receptor regulated slow inward current plays an important role in quinidine induced early afterdepolarisations. Beta receptor stimulation can enhance or suppress early afterdepolarisations, depending on whether effects on slow inward current (tending to favour them) or on automaticity (suppressing them) predominate.

Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide.

“…Furthermore, changes in repolarization of ventricular muscle may not parallel those in the His-Purkinje system, which appears to be the primary target for drug-induced arrhythmogenic early afterdepolarizations. 41 Although we adjusted vagal stimulation frequency to compensate for antivagal actions of ambasilide, we cannot be sure of the quantitative precision of the correction because changes in sinus rate were used to adjust vagal tone, and vagal effects on the atrium may not exactly parallel those on the sinus node. Furthermore, some of the effects of sotalol and ambasilide on vagotonic AF could be due to inhibition of IKACh, an action that might be relatively much less important in nonvagal AF.…”

Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers

“…Key Words: heart failure Ⅲ remodeling Ⅲ ventricular dyssynchrony Ⅲ connexins Ⅲ specialized conducting system C ardiac Purkinje fibers (PFs) play an important role in ensuring rapid and appropriately timed conduction of electric impulses to the ventricles 1 and are an important arrhythmogenic source for a variety of cardiac arrhythmias. [2][3][4][5] Congestive heart failure (CHF) changes ion channel distribution and function, with important electrophysiological consequences, 6 and sudden arrhythmic death contributes importantly to CHF-related mortality. 7 We previously demonstrated discrete CHF-induced remodeling of repolarizing ion current function in canine cardiac PFs.…”

“…[2][3][4][5] Congestive heart failure (CHF) changes ion channel distribution and function, with important electrophysiological consequences, 6 and sudden arrhythmic death contributes importantly to CHF-related mortality. 7 We previously demonstrated discrete CHF-induced remodeling of repolarizing ion current function in canine cardiac PFs.…”

Anestesia e síndrome do QT longo

“…Alguns antidisrítmicos, como o verapamil e a amiodarona, podem eventualmente causar TdP, embora seja interessante notar que a amiodarona prolonga o intervalo QT por mais de 500 ms e ainda assim seja rara a ocorrência de TdP. Por outro lado, fármacos, como o antihistamínico terfenadina, não causam prolongamento do intervalo, mas podem causar TdP [14][15][16][17] . Muitos casos de morte súbita são relacionados com fármacos que não prolongam o iQT 18 .…”

“…Some antiarrhythmic drugs, such as verapamil and amiodarone, could cause TdP, but it is interesting that even though amiodarone prolongs the QT interval by more than 500 msec, the development of TdP associated with its use is rare. On the other hand, drugs such as the antihistamine terfenadine, do not prolong the QT interval, but can cause TdP [14][15][16][17] . Several cases of sudden death are related to drugs that do not prolong the QTi 18 .…”