https://ogma.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14428 Wed 11 Apr 2018 13:17:59 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39630 N-methyl flecainide) and showed that N-methylation reduces flecainide’s inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N-methylation did not alter flecainide’s inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2−/−) CPVT mouse model. In membrane-permeabilized Casq2−/− cardiomyocytes—lacking intact sarcolemma and devoid of sodium channel contribution—flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2−/− cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and N-methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2−/− mice, whereas N-methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block. Conclusions: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.]]> Thu 16 Jun 2022 11:46:05 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:9879 Sat 24 Mar 2018 08:12:48 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19544 Sat 24 Mar 2018 07:58:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17743 -/- myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca²⁺ waves at clinically relevant concentrations, whereas Na⁺ channel inhibitors without RyR2 blocking properties did not. In Casq2^-/- mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na⁺ channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy. RyR2 cardiac Ca²⁺ release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2^-/- mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.]]> Sat 24 Mar 2018 07:57:39 AEDT ]]>