Improved Ca 2+ release synchrony following selective modification of I tof and phase 1 repolarization in normal and failing ventricular myocytes.

Autor: Fowler ED; School of Physiology, Pharmacology & Neuroscience, Faculty of Biomedical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK., Wang N; School of Physiology, Pharmacology & Neuroscience, Faculty of Biomedical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK., Hezzell MJ; University of Bristol Veterinary School, Langford, Bristol BS40 5DU, UK., Chanoit G; University of Bristol Veterinary School, Langford, Bristol BS40 5DU, UK., Hancox JC; School of Physiology, Pharmacology & Neuroscience, Faculty of Biomedical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK., Cannell MB; School of Physiology, Pharmacology & Neuroscience, Faculty of Biomedical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK. Electronic address: mark.cannell@bristol.ac.uk.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2022 Nov; Vol. 172, pp. 52-62. Date of Electronic Publication: 2022 Jul 29.
DOI: 10.1016/j.yjmcc.2022.07.009
Abstrakt: Loss of ventricular action potential (AP) early phase 1 repolarization may contribute to the impaired Ca 2+ release and increased risk of sudden cardiac death in heart failure. Therefore, restoring AP phase 1 by augmenting the fast transient outward K + current (I tof ) might be beneficial, but direct experimental evidence to support this proposition in failing cardiomyocytes is limited. Dynamic clamp was used to selectively modulate the contribution of I tof to the AP and Ca 2+ transient in both normal (guinea pig and rabbit) and in failing rabbit cardiac myocytes. Opposing native I tof in non-failing rabbit myocytes increased Ca 2+ release heterogeneity, late Ca 2+ sparks (LCS) frequency and AP duration. (APD). In contrast, increasing I tof in failing myocytes and guinea pig myocytes (the latter normally lacking I tof ) increased Ca 2+ transient amplitude, Ca 2+ release synchrony, and shortened APD. Computer simulations also showed faster Ca 2+ transient decay (mainly due to fewer LCS), decreased inward Na + /Ca 2+ exchange current and APD. When the I tof conductance was increased to ~0.2 nS/pF in failing cells (a value slightly greater than seen in typical human epicardial myocytes), Ca 2+ release synchrony improved and AP duration decreased slightly. Further increases in I tof can cause Ca 2+ release to decrease as the peak of the bell-shaped I Ca -voltage relationship is passed and premature AP repolarization develops. These results suggest that there is an optimal range for I tof enhancement that may support Ca 2+ release synchrony and improve electrical stability in heart failure with the caveat that uncontrolled I tof enhancement should be avoided.
(Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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