Wang, L., Myles, R. C. , Lee, I.-J., Bers, D. M. and Ripplinger, C. M. (2021) Role of reduced sarco-endoplasmic reticulum Ca2+-ATPase function on sarcoplasmic reticulum Ca2+ alternans in the intact rabbit heart. Frontiers in Physiology, 12, 656516. (doi: 10.3389/fphys.2021.656516) (PMID:34045974) (PMCID:PMC8144333)
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Abstract
Sarcoplasmic reticulum (SR) Ca2+ cycling is tightly regulated by ryanodine receptor (RyR) Ca2+ release and sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ uptake during each excitation–contraction coupling cycle. We previously showed that RyR refractoriness plays a key role in the onset of SR Ca2+ alternans in the intact rabbit heart, which contributes to arrhythmogenic action potential duration (APD) alternans. Recent studies have also implicated impaired SERCA function, a key feature of heart failure, in cardiac alternans and arrhythmias. However, the relationship between reduced SERCA function and SR Ca2+ alternans is not well understood. Simultaneous optical mapping of transmembrane potential (Vm) and SR Ca2+ was performed in isolated rabbit hearts (n = 10) using the voltage-sensitive dye RH237 and the low-affinity Ca2+ indicator Fluo-5N-AM. Alternans was induced by rapid ventricular pacing. SERCA was inhibited with cyclopiazonic acid (CPA; 1–10 μM). SERCA inhibition (1, 5, and 10 μM of CPA) resulted in dose-dependent slowing of SR Ca2+ reuptake, with the time constant (tau) increasing from 70.8 ± 3.5 ms at baseline to 85.5 ± 6.6, 129.9 ± 20.7, and 271.3 ± 37.6 ms, respectively (p < 0.05 vs. baseline for all doses). At fast pacing frequencies, CPA significantly increased the magnitude of SR Ca2+ and APD alternans, most strongly at 10 μM (pacing cycle length = 220 ms: SR Ca2+ alternans magnitude: 57.1 ± 4.7 vs. 13.4 ± 8.9 AU; APD alternans magnitude 3.8 ± 1.9 vs. 0.2 ± 0.19 AU; p < 0.05 10 μM of CPA vs. baseline for both). SERCA inhibition also promoted the emergence of spatially discordant alternans. Notably, at all CPA doses, alternation of SR Ca2+ release occurred prior to alternation of diastolic SR Ca2+ load as pacing frequency increased. Simultaneous optical mapping of SR Ca2+ and Vm in the intact rabbit heart revealed that SERCA inhibition exacerbates pacing-induced SR Ca2+ and APD alternans magnitude, particularly at fast pacing frequencies. Importantly, SR Ca2+ release alternans always occurred before the onset of SR Ca2+ load alternans. These findings suggest that even in settings of diminished SERCA function, relative refractoriness of RyR Ca2+ release governs the onset of intracellular Ca2+ alternans.
| Item Type: | Articles |
|---|---|
| Additional Information: | This study was supported by the National Institutes of Health R01 HL111600 (CR) and P01 HL141084 (CR and DB) and by the Wellcome Trust 105907/Z/14/Z (RM). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Myles, Dr Rachel |
| Authors: | Wang, L., Myles, R. C., Lee, I.-J., Bers, D. M., and Ripplinger, C. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Frontiers in Physiology |
| Publisher: | Frontiers Media |
| ISSN: | 1664-042X |
| ISSN (Online): | 1664-042X |
| Copyright Holders: | Copyright © 2021 Wang, Myles, Lee, Bers and Ripplinger |
| First Published: | First published in Frontiers in Physiology 12:656516 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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