Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology

Canto, Irene del; Santamaría, Laura; Genovés, Patricia; Such-Miquel, Luis; Arias-Mutis, O J; Zarzoso, Manuel; Soler, Carlos; Parra, Germán; Tormos, Álvaro; Alberola, Arcadio García; Such, Luis; Chorro, Francisco J.

doi:10.1007/s10557-018-6822-x

Cited by 5 publications

(11 citation statements)

References 53 publications

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“…Accordingly, the regulation of increases in sarcoplasmic Ca 2+ could prevent Ca 2+ -induced alterations, such as shortening of refractoriness and focal ectopic activity, involved in the mechanisms underlying AF (Song et al, 2008;Nattel and Dobrev, 2012;Shryock et al, 2013). In previous investigations in isolated hearts, comparable effects on stretchinduced activation patterns remodeling have been described (Chorro et al, 2015;Del Canto et al, 2018). These previous observations, together with the results obtained in our study, seem to confirm the role of late sodium current in the mechanisms of stretch.…”

Section: Modification Of the Stretch-induced Effects By Ranolazinesupporting

confidence: 90%

“…In fact, a reduction in tip meandering allows faster circumscription of the core of the rotor. These stretch effects are frequently associated to shorter refractoriness (Chorro et al, 2015;Del Canto et al, 2018), which is consistent with previous experimental studies in isolated rabbit hearts that showed a stretch-induced decrease in refractory periods and action potential duration (Ravelli and Allessie, 1997;Quinn and Kohl, 2016;Del Canto et al, 2018). Shortening of action potential duration has been related to stretch-induced increased intracellular Na + accumulation through several mechanisms:…”

Section: Modification Of the Stretch-induced Effects By Ranolazinesupporting

confidence: 88%

“…This effect could be associated to the increase in refractoriness produced by the drug, due to repolarizing I Kr block effect and a prolongation of the recovery of Na + channels (postrepolarization refractoriness) (Quinn and Kohl, 2016;Caves et al, 2017;Karagueuzian et al, 2017). In previous studies, DF has shown an inverse correlation to the electrophysiological parameters related to ventricular refractoriness (Chorro et al, 2015;Del Canto et al, 2018). Moreover, the lower activation frequency observed is related to a reduction of CV as a consequence of the inhibition of peak I Na (Berenfeld et al, 2000;Caves et al, 2017).…”

Section: Effects Of Ranolazine On Baseline Fibrillation Characteristicsmentioning

confidence: 91%

“…In order to evaluate the effects of mechanical stretch on activation pattern characteristics, the cultured myocyte monolayers were stretched in a ST-CH-04 strain unit (Bridge), giving rise to 10% longitudinal increment along the horizontal axe (resting length: 2 cm, stretch length: 2.2 cm) for 10 min, and after this period, stretch was suppressed. The stretch percentage applied was according to previous studies where activation pattern changes were observed for a degree of mechanical stretch in the range of 10–15% ( Tsai et al, 2011 ; Seo et al, 2014 ; Del Canto et al, 2018 ). The stretching was applied for 10 min in order to analyze the time evolution of stretch-induced effects, based on previous studies ( Chorro et al, 2015 ; Del Canto et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…The stretch percentage applied was according to previous studies where activation pattern changes were observed for a degree of mechanical stretch in the range of 10–15% ( Tsai et al, 2011 ; Seo et al, 2014 ; Del Canto et al, 2018 ). The stretching was applied for 10 min in order to analyze the time evolution of stretch-induced effects, based on previous studies ( Chorro et al, 2015 ; Del Canto et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

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Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

et al. 2020

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Background: Mechanical stretch increases Na + inflow into myocytes, related to mechanisms including stretch-activated channels or Na + /H + exchanger activation, involving Ca 2+ increase that leads to changes in electrophysiological properties favoring arrhythmia induction. Ranolazine is an antianginal drug with confirmed beneficial effects against cardiac arrhythmias associated with the augmentation of I NaL current and Ca 2+ overload. Objective: This study investigates the effects of mechanical stretch on activation patterns in atrial cell monolayers and its pharmacological response to ranolazine. Methods: Confluent HL-1 cells were cultured in silicone membrane plates and were stretched to 110% of original length. The characteristics of in vitro fibrillation (dominant frequency, regularity index, density of phase singularities, rotor meandering, and rotor curvature) were analyzed using optical mapping in order to study the mechanoelectric response to stretch under control conditions and ranolazine action. Results: HL-1 cell stretch increased fibrillatory dominant frequency (3.65 ± 0.69 vs. 4.35 ± 0.74 Hz, p < 0.01) and activation complexity (1.97 ± 0.45 vs. 2.66 ± 0.58 PS/cm 2 , p < 0.01) under control conditions. These effects were related to stretchinduced changes affecting the reentrant patterns, comprising a decrease in rotor meandering (0.72 ± 0.12 vs. 0.62 ± 0.12 cm/s, p < 0.001) and an increase in wavefront curvature (4.90 ± 0.42 vs. 5.68 ± 0.40 rad/cm, p < 0.001). Ranolazine reduced stretchinduced effects, attenuating the activation rate increment (12.8% vs. 19.7%, p < 0.01) and maintaining activation complexity-both parameters being lower during stretch than under control conditions. Moreover, under baseline conditions, ranolazine slowed and regularized the activation patterns (3.04 ± 0.61 vs. 3.65 ± 0.69 Hz, p < 0.01). Conclusion: Ranolazine attenuates the modifications of activation patterns induced by mechanical stretch in atrial myocyte monolayers.

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Section: Modification Of the Stretch-induced Effects By Ranolazinesupporting

confidence: 90%

Section: Modification Of the Stretch-induced Effects By Ranolazinesupporting

confidence: 88%

Section: Effects Of Ranolazine On Baseline Fibrillation Characteristicsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

et al. 2020

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

Hézsô

Naveed

Dienes

et al. 2021

Sci Rep

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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.

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Is Selective Late Na+ Current Inhibition Different From Class I/B Antiarrhythmic Action? Comparison of The Effects of GS967 to Mexiletine in Canine Ventricular Myocardium

Hézsô

Khan

Dienes

et al. 2021

Preprint

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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, on L-type calcium current (ICa), and on action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. These effects of GS967 were compared to tetrodotoxin (TTX) and to the class I/B antiarrhythmic compound mexiletine. 1 µM GS967, 40 µM mexiletine, and 10 µM TTX dissected largely similarly shaped inward currents under action potential voltage clamp conditions. In case of GS967 and mexiletine, the amplitude and integral of this current was significantly smaller when measured in the presence of 1 µM nisoldipine, while no difference was observed in case of TTX. Under conventional voltage clamp conditions, INaL was significantly decreased by 1 µM GS967 and 40 µM mexiletine (79.0±3.0% and 63.3±2.7% reduction of current integrals, respectively). The integral of ICa was moderately but significantly diminished by both drugs (reduction of 9.3±3.3% and 14.1±1.5%, respectively). These changes were associated with acceleration of inactivation of ICa. Drug effects on peak Na+ current (INaP) were also assessed by recording AP upstroke in multicellular preparations. Both GS967 and mexiletine showed fast onset and offset kinetics: 110 ms and 289 ms offset time constants, respectively, as determined from V+max measurements in right ventricular papillary muscles, while the onset kinetics was characterized by 5.3 AP and 2.6 AP, respectively, at 2.5 Hz. Effects on beat-to-beat variability of AP duration (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 questiond and it is suggested that GS967 should be classified as a class I/B (or I/B + IV) antiarrhythmic agent.

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Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology

Abstract: GS967 attenuates stretch-induced changes in cardiac electrophysiology.

Cited by 5 publications

References 53 publications

Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

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

Is Selective Late Na+ Current Inhibition Different From Class I/B Antiarrhythmic Action? Comparison of The Effects of GS967 to Mexiletine in Canine Ventricular Myocardium

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