Ibuprofen is a widely used non-steroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 µM; n=6) and rabbit (100 µM; n=7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1 Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated, and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 µM) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n=7). In dog myocytes, ibuprofen (250 µM) did not significantly influence IK1, but decreased the amplitude of Ito and IKr potassium currents by 28.2% (60 mV) and 15.2% (20 mV) respectively. Ibuprofen also depressed INaL and ICa currents by 19.9% and 16.4%. We conclude that ibuprofen seems to be free from effects on AP parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients.

Racemic mexiletine is a widely used antiarrhythmic agent which blocks sodium channels. The effects of R-(-) and S-(+) mexiletine stereoisomers on maximum rate of depolarization (Vmax), conduction time and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(-) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 µM of therapeutically and experimentally relevant concentration, significantly depressed the Vmax at fast heart rates (BCLs 300 -700 ms). R-(-) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine significantly inhibited the Vmax of early extrasystoles measured at 70 ms diastolic interval induced by S1-S2 stimuli. R-(-) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(-) and S-(+) mexiletine increased significantly the ERP/APD 90 ratio. The time constant (τ) of recovery of Vmax was found to be τ = 376.0 ± 77.8 ms for R-(-) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine which indicates a slower offset kinetics for R-(-) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(-) mexiletine might be more potent antiarrhythmic agent than S-(+) mexiletine.

Introduction: Activation of the parasympathetic nervous system has been reported to have an antiarrhythmic role during ischemia-reperfusion injury by decreasing the arrhythmia triggers. Furthermore, it was reported that the parasympathetic neurotransmitter acetylcholine is able to modulate the ATP-dependent K-current (IK-ATP), a crucial current activated during hypoxia. However, the possible significance of this current modulation in the antiarrhythmic mechanism is not fully clarified. Methods: Action potentials were measured using the conventional microelectrode technique from canine left ventricular papillary muscle and free-running Purkinje fibers, under normal and hypoxic conditions. Ionic currents were measured using the whole-cell configuration of the patch clamp method. Results: 5 μM acetylcholine did not influence the action potential duration (APD) either in Purkinje fibers or in papillary muscle preparations. In contrast, it significantly lengthened the APD and suppressed the Purkinje–ventricle APD dispersion when it was administered after 5 μM pinacidil application. 3 μM carbachol reduced the pinacidil-activated IK-ATP under voltage-clamp condition. Acetylcholine lengthened the ventricular action potential under simulated ischemia condition. Conclusion: In this study we found that acetylcholine inhibits the IK-ATP and thus suppresses the ventricle-Purkinje APD dispersion. We conclude that parasympathetic tone may reduce the arrhythmogenic substrate exerting a complex antiarrhythmic mechanism during hypoxic conditions.