Mexiletine-like cellular electrophysiological effects of GS967 in canine ventricular myocardium

Abstract

Enhancement of the late Na+ current (INaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of INaL. In the present study, effects of GS967 on INaL and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, INaL was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of INaL measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of INaL towards negative potentials. GS967 and mexiletine dissected inward INaL profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of −0.37 ± 0.07 and −0.28 ± 0.03 A/F, and current integrals of −56.7 ± 9.1 and −46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na+ current (INaP) were assessed by recording the maximum velocity of AP upstroke (V+max) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V+max block. However, since GS967 depressed V+max and INaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block INaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.

Reply to: "Concerns about cognitive performance at chance level"

“…Despite the poor performance of participants in this study, it is important to publish unconventional findings to mitigate publication bias when experimental methodology is deemed sound, which was the case here. Moreover, Jost 1 agrees himself that the converging evidence of gaze behaviours, pupillometric and reaction time data presented by Toth and Campbell 2 suggest that it is plausible that cognitive resources were over taxed, evidencing the difficulty participants had with the test which may have led them to guess at the end of trials, resulting in the overall observed poor performance. However, determining with certainty the presence of guessing and potential for malingering can be very difficult, with previous research showing that the performance of those specifically instructed to guess in forced choice tests can overlap those who display genuine low performance 9 .…”

“…The following is a response to Jost 1 , who contests findings from a recently published mental rotation study 2 . In the original study, participants scored 2.765 ± 0.182 out of 20, when scored such that a point was awarded when both ‘same’ images on the V&K MRT 3 (Vandenberg and Kuse Mental Rotations Test) were correctly identified in a given trial.…”

“…These scores indeed are close to chance, with Hegarty 4 defining chance performance to be 3.33 out of 20 when using the same scoring method. In his critique, Jost 1 poses two questions regarding the findings presented by Toth and Campbell 2 . Firstly, he asks how it is possible that participants performed this poorly and secondly, whether one can meaningfully analyze performance at chance level.…”

“…In his hypothesis to his first question, Jost 1 cites that performance at chance level may suggest a possible misunderstanding of the task by participants, causing them to perform a different cognitive task than that of mental rotation. However, in the original study by Toth and Campbell 2 , it is outlined that participants were presented clear instructions on how to perform the task and were also presented with three practice sample trials.…”

“…Jost 1 also poses that, while possible that participants were simply poor at mental rotation tasks, this is highly improbable as according to Jost 1 “in no mental rotation study have adult participants ever performed even close to this poorly”. However, several previous studies have demonstrated poor to very poor performance on the V&K MRT in multiple samples 5 – 8 with Kruger and colleagues even reporting low performance among security screeners despite the removal of ‘more difficult questions’.…”