Effect of flecainide on RyR2 mediated diastolic Ca2+ release in sparks and waves, including source of cells and brief description of experimental conditions and most significant results
| Sparks, waves . | Preparation . | Main effect of flecainide . |
|---|---|---|
| Watanabe et al. (2009) | ISO-stimulated intact CSQ2−/− myocytes | 6 µM reduced the rate of spontaneous Ca2+ release events in the presence and absence of extracellular Na+ and Ca2+ |
| Hilliard et al. (2010) | (1) Field stimulated intact ventricular CSQ2−/− myocytes. Ca2+ waves triggered by 100 nM ISO (2) Permeabilized rat ventricular myocytes without ISO | 6 µM reduced Ca2+ wave rates, spark amplitude and width. Spark mass reduced by 40% Increase in spark frequency No effect on spark-mediated SR Ca2+ leak or SR Ca2+ content |
| Hwang et al. (2011) | (1) Field stimulated intact ventricular CSQ2−/− myocytes. Ca2+ waves with 100 nM ISO | Flecainide and R-propafenone decreased rate of Ca2+ waves IC50 of 2.2 and 1.1 µM respectively. S-propafenone much less effective. SR Ca2+ content not altered by any of the three drugs |
| Liu et al. (2011) | (1) Permeabilized mouse RyR2-R4496C+/− ventricular myocytes (2) Intact ventricular myocytes with ISO | Tetracaine, but not flecainide, (1) reduces spontaneous Ca2+ waves and sparks and (2) spontaneous Ca2+ release events and triggered beats, but no effect on DADs |
| Savio-Galimberti and Knollman (2015) | Permeabilized CSQ2−/− ventricular myocytes | Of all class I antiarrhythmic drugs, flecainide and R-propafenone inhibit Ca2+ waves with the highest potency and efficacy. Suggest reduced spark mass, not frequency, causes wave suppression. |
| Sikkel et al. (2013) | Intact rat ventricular myocytes with patch clamp Stimulation frequency adjusted to induce Ca2+ waves | 5 µM did not alter Ca2+ transients or SR Ca2+ load. Ca2+ wave and spark frequency and wave velocity declined INa block (pharmacological or voltage-dependent inactivation) similarly reduced Ca2+ waves, spark frequency, and wave velocity. NCX implicated with INa change |
| Savio-Galimberti and Knollman (2015) | Saponin-permeabilized ventricular myocytes from CSQ2−/−, RyR2-R4496C+/−, C57BL/6 WT mice and WT rabbits | RyR2 activity determines the potency of open-state blockers flecainide and R-propafenone, but not tetracaine, for suppressing arrhythmogenic Ca2+ waves |
| Bannister et al. (2016) | Intact rat ventricular myocytes, drugs infused into cells through patch electrodes | Spark frequency declined with flecainide and QX-FL, but not with NU-FL No change in spark amplitude or mass with any of the compounds |
| Hwang et al. (2019) | CSQ2−/− and RyR2-R4496C+/− intact ventricular myocytes | Spontaneous Ca2+ release blocked, IC50 ∼2 µM. Similar efficacy in both models despite different phenotype severity |
| Kryshtal et al. (2021) | CSQ2−/− ventricular myocytes | Flecainide, but not QX-FL and NU-FL, reduced Ca2+ wave frequency in both permeabilized myocytes (lacking surface membrane and Na+ channels) and in voltage clamped TTX-treated myocytes |
| Sparks, waves . | Preparation . | Main effect of flecainide . |
|---|---|---|
| Watanabe et al. (2009) | ISO-stimulated intact CSQ2−/− myocytes | 6 µM reduced the rate of spontaneous Ca2+ release events in the presence and absence of extracellular Na+ and Ca2+ |
| Hilliard et al. (2010) | (1) Field stimulated intact ventricular CSQ2−/− myocytes. Ca2+ waves triggered by 100 nM ISO (2) Permeabilized rat ventricular myocytes without ISO | 6 µM reduced Ca2+ wave rates, spark amplitude and width. Spark mass reduced by 40% Increase in spark frequency No effect on spark-mediated SR Ca2+ leak or SR Ca2+ content |
| Hwang et al. (2011) | (1) Field stimulated intact ventricular CSQ2−/− myocytes. Ca2+ waves with 100 nM ISO | Flecainide and R-propafenone decreased rate of Ca2+ waves IC50 of 2.2 and 1.1 µM respectively. S-propafenone much less effective. SR Ca2+ content not altered by any of the three drugs |
| Liu et al. (2011) | (1) Permeabilized mouse RyR2-R4496C+/− ventricular myocytes (2) Intact ventricular myocytes with ISO | Tetracaine, but not flecainide, (1) reduces spontaneous Ca2+ waves and sparks and (2) spontaneous Ca2+ release events and triggered beats, but no effect on DADs |
| Savio-Galimberti and Knollman (2015) | Permeabilized CSQ2−/− ventricular myocytes | Of all class I antiarrhythmic drugs, flecainide and R-propafenone inhibit Ca2+ waves with the highest potency and efficacy. Suggest reduced spark mass, not frequency, causes wave suppression. |
| Sikkel et al. (2013) | Intact rat ventricular myocytes with patch clamp Stimulation frequency adjusted to induce Ca2+ waves | 5 µM did not alter Ca2+ transients or SR Ca2+ load. Ca2+ wave and spark frequency and wave velocity declined INa block (pharmacological or voltage-dependent inactivation) similarly reduced Ca2+ waves, spark frequency, and wave velocity. NCX implicated with INa change |
| Savio-Galimberti and Knollman (2015) | Saponin-permeabilized ventricular myocytes from CSQ2−/−, RyR2-R4496C+/−, C57BL/6 WT mice and WT rabbits | RyR2 activity determines the potency of open-state blockers flecainide and R-propafenone, but not tetracaine, for suppressing arrhythmogenic Ca2+ waves |
| Bannister et al. (2016) | Intact rat ventricular myocytes, drugs infused into cells through patch electrodes | Spark frequency declined with flecainide and QX-FL, but not with NU-FL No change in spark amplitude or mass with any of the compounds |
| Hwang et al. (2019) | CSQ2−/− and RyR2-R4496C+/− intact ventricular myocytes | Spontaneous Ca2+ release blocked, IC50 ∼2 µM. Similar efficacy in both models despite different phenotype severity |
| Kryshtal et al. (2021) | CSQ2−/− ventricular myocytes | Flecainide, but not QX-FL and NU-FL, reduced Ca2+ wave frequency in both permeabilized myocytes (lacking surface membrane and Na+ channels) and in voltage clamped TTX-treated myocytes |
Publications are listed in chronological order. ISO, isoproterenol.