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Arrhythmic effects of Epac‐mediated ryanodine receptor activation in Langendorff‐perfused murine hearts are associated with reduced conduction velocity
Author(s) -
Li Mengye,
Hothi Sandeep S,
Salvage Samantha C,
Jeevaratnam Kamalan,
Grace Andrew A,
Huang Christopher LH
Publication year - 2017
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12751
Subject(s) - ryanodine receptor , dantrolene , medicine , ventricular tachycardia , endocrinology , dantrolene sodium , nerve conduction velocity , ryanodine receptor 2 , chemistry , cardiology , receptor , calcium
Summary Recent papers have attributed arrhythmic substrate in murine RyR2‐P2328S hearts 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 by cAMP (Epac)‐mediated ryanodine receptor‐2 (RyR2) activation on arrhythmic substrate and CV . 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) ( VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8‐ CPT (0 of 9) did not then increase VT incidence ( P >.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8‐ CPT challenge then increased VT incidences (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 increase VT incidence relative to those observed in untreated hearts ( P >.05). 8‐ CPT but not dantrolene, whether alone or combined with 8‐ CPT , correspondingly increased AP latencies (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, AP durations, 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 induces VT in specific association with reduced CV .