Arrhythmic effects of Epac‐mediated ryanodine receptor activation in Langendorff‐perfused murine hearts are associated with reduced conduction velocity

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Abstract
Summary: Recent papers have attributed arrhythmic substrate in murineRyR2‐P2328Shearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated bycAMP(Epac)‐mediated ryanodine receptor‐2 (RyR2) activation on arrhythmic substrate andCV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff‐perfused wild‐type mouse ventricles before pharmacological intervention. The Epac activator 8‐CPT(8‐(4‐chlorophenylthio)‐2′‐O‐methyladenosine‐3′,5′‐cyclic monophosphate) (VTin 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8‐CPT(0 of 9) did not then increaseVTincidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced noVTin untreated hearts (n=20 and n=9 respectively). 8‐CPTchallenge then increasedVTincidences (5 of 7 and 4 of 8 hearts respectively;P<.05). However, dantrolene, whether alone (0 of 10 and 1 of 13) or combined with 8‐CPT(0 of 10 and 0 of 13) did not increaseVTincidence relative to those observed in untreated hearts (P>.05). 8‐CPTbut not dantrolene, whether alone or combined with 8‐CPT, correspondingly increasedAPlatencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast,APdurations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly inducesVTin specific association with reducedCV.
Funding Information
  • Wellcome Trust (105727/Z/14/Z)
  • Medical Research Council (MR/M001288/1)
  • British Heart Foundation (PG/08/116)

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