https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:9879 Sat 24 Mar 2018 08:12:48 AEDT ]]> https://nova.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 ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:33272 2+ release channels in the sarcoplasmic reticulum in striated muscle which play an important role in excitation-contraction coupling and cardiac pacemaking. Single channel recordings have revealed a wealth of information about ligand regulation of RyRs from mammalian skeletal and cardiac muscle (RyR1 and RyR2, respectively). RyR subunit has a Ca²⁺ activation site located in the luminal and cytoplasmic domains of the RyR. These sites synergistically feed into a common gating mechanism for channel activation by luminal and cytoplasmic Ca²⁺. RyRs also possess two inhibitory sites in their cytoplasmic domains with Ca²⁺ affinities of the order of 1 µM and 1 mM. Magnesium competes with Ca²⁺ at these sites to inhibit RyRs and this plays an important role in modulating their Ca²⁺-dependent activity in muscle. This review focuses on how these sites lead to RyR modulation by Ca²⁺ and Mg²⁺ and how these mechanisms control Ca²⁺ release in excitation-contraction coupling and cardiac pacemaking.]]> Mon 24 Sep 2018 13:26:20 AEST ]]>