Data_Sheet_1_Action Potential Prolongation, β-Adrenergic Stimulation, and Angiotensin II as Co-factors in Sarcoplasmic Reticulum Instability.PDF
Introduction: Increases in action potential duration (APD), genetic or acquired, and arrhythmias are often associated; nonetheless, the relationship between the two phenomena is inconstant, suggesting coexisting factors. β-adrenergic activation increases sarcoplasmic reticulum (SR) Ca2+-content; angiotensin II (ATII) may increase cytosolic Ca2+ and ROS production, all actions stimulating RyRs opening. Here we test how APD interacts with β-adrenergic and AT-receptor stimulation in facilitating spontaneous Ca2+ release events (SCR).
Methods: Under “action potential (AP) clamp”, guinea-pig cardiomyocytes (CMs) were driven with long (200 ms), normal (150 ms), and short (100 ms) AP waveforms at a CL of 500 ms; in a subset of CMs, all the 3 waveforms could be tested within the same cell. SCR were detected as inward current transients (ITI) following repolarization; ITI incidence and repetition within the same cycle were measured under increasing isoprenaline concentration ([ISO]) alone, or plus 100 nM ATII (30 min incubation+superfusion).
Results: ITI incidence and repetition increased with [ISO]; at longer APs the [ISO]-response curve was shifted upward and ITI coupling interval was reduced. ATII increased ITI incidence more at low [ISO] and under normal (as compared to long) APs. Efficacy of AP shortening in suppressing ITI decreased in ATII-treated myocytes and at higher [ISO].
Conclusions: AP prolongation sensitized the SR to the destabilizing actions of ISO and ATII. Summation of ISO, ATII and AP duration effects had a “saturating” effect on SCR incidence, thus suggesting convergence on a common factor (RyRs stability) “reset” by the occurrence of spontaneous Ca2+ release events.
History
References
- https://doi.org//10.1113/JP276319
- https://doi.org//10.1111/j.1540-8167.2000.tb00342.x
- https://doi.org//10.1152/ajpheart.01155.2007
- https://doi.org//10.1016/s0008-6363(00)00147-4
- https://doi.org//10.1016/j.bbamcr.2016.11.017
- https://doi.org//10.1016/j.amjcard.2005.10.028
- https://doi.org//10.1016/j.phrs.2017.05.008
- https://doi.org//10.1016/j.yjmcc.2008.05.014
- https://doi.org//10.1161/01.RES.0000172556.05576.4c
- https://doi.org//10.1016/s0960-9822(00)00624-2
- https://doi.org//10.1253/circj.66.87
- https://doi.org//10.1016/j.gde.2015.06.009
- https://doi.org//10.1152/physrev.00014.2006
- https://doi.org//10.1016/s0143-4160(03)00026-5
- https://doi.org//10.1016/j.yjmcc.2012.11.011
- https://doi.org//10.1016/s0008-6363(02)00846-5
- https://doi.org//10.1093/europace/eux236
- https://doi.org//10.1161/01.Cir.92.12.3381
- https://doi.org//10.1161/01.cir.103.1.89
- https://doi.org//10.1161/CIRCULATIONAHA.113.002764
- https://doi.org//10.1016/j.bpj.2015.03.011
- https://doi.org//10.1007/s11906-018-0823-9
- https://doi.org//10.1006/jmcc.2002.2075
- https://doi.org//10.1093/cvr/cvm009
- https://doi.org//10.1093/europace/euv307
- https://doi.org//10.1172/JCI27374
- https://doi.org//10.1093/cvr/cvx020
- https://doi.org//10.1097/00005344-200111000-00010