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- Title
Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes.
- Authors
Valli, Haseeb; Ahmad, Shiraz; Sriharan, Sujan; Dean, Lydia D.; Grace, Andrew A.; Jeevaratnam, Kamalan; Matthews, Hugh R.; Huang, Christopher L‐H
- Abstract
Summary: Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro‐arrhythmic effects. Loose patch‐clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage‐dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of −20.23 ± 1.48 (17) and −29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8‐CPT (1 μmol/L) reduced these currents to −11.21 ± 0.91 (12) (<italic>P</italic> < .004) and −19.3 ± 1.6 (11) pA/μm2 (<italic>P</italic> < .04) respectively. Currents following further addition of the RyR2 inhibitor dantrolene (10 μmol/L) (−19.91 ± 2.84 (13) and −26.6 ± 1.7 (17)), and dantrolene whether alone (−19.53 ± 1.97 (8) and −27.6 ± 1.9 (14)) or combined with 8‐CPT (−19.93 ± 2.59 (12) and −29.9 ± 2.5(11)), were indistinguishable from pretreatment values (all <italic>P </italic>>> .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half‐maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double‐pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff‐perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (d<italic>V</italic>/d<italic>t</italic>)max. We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro‐arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically‐modified <italic>RyR2‐</italic>P2328S hearts.
- Subjects
RYANODINE receptors; HEART cells; CYCLIC adenylic acid; SODIUM in the body; DANTROLENE; LABORATORY mice; HOMEOSTASIS
- Publication
Clinical & Experimental Pharmacology & Physiology, 2018, Vol 45, Issue 3, p278
- ISSN
0305-1870
- Publication type
Article
- DOI
10.1111/1440-1681.12870