Al-Owais Moza M, Steele Derek S, Holden Arun V, Benson Alan P
School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
Front Pharmacol. 2021 Apr 28;12:651050. doi: 10.3389/fphar.2021.651050. eCollection 2021.
Chronic exposure to low levels of Carbon Monoxide is associated with an increased risk of cardiac arrhythmia. Microelectrode recordings from rat and guinea pig single isolated ventricular myocytes exposed to CO releasing molecule CORM-2 and excited at 0.2/s show repolarisation changes that develop over hundreds of seconds: action potential prolongation by delayed repolarisation, EADs, multiple EADs and oscillations around the plateau, leading to irreversible repolarisation failure. The measured direct effects of CO on currents in these cells, and ion channels expressed in mammalian systems showed an increase in prolonged late Na, and a decrease in the maximal T- and L-type Ca. peak and late Na, ultra-rapid delayed, delayed rectifier, and the inward rectifier K currents. Incorporation of these CO induced changes in maximal currents in ventricular cell models; (Gattoni et al., J. Physiol., 2016, 594, 4193-4224) (rat) and (Luo and Rudy, Circ. Res., 1994, 74, 1071-1096) (guinea-pig) and human endo-, mid-myo- and epi-cardial (O'Hara et al., PLoS Comput. Biol., 2011, 7, e1002061) models, by changes in maximal ionic conductance reproduces these repolarisation abnormalities. Simulations of cell populations with Gaussian distributions of maximal conductance parameters predict a CO induced increase in APD and its variability. Incorporation of these predicted CO induced conductance changes in human ventricular cell electrophysiology into ventricular tissue and wall models give changes in indices for the probability of the initiation of re-entrant arrhythmia.
长期暴露于低水平一氧化碳会增加心律失常的风险。对暴露于一氧化碳释放分子CORM - 2并以0.2次/秒频率刺激的大鼠和豚鼠单个分离心室肌细胞进行微电极记录，结果显示复极化变化会在数百秒内逐渐发展：动作电位因延迟复极化、早后去极化、多个早后去极化以及平台期振荡而延长，最终导致不可逆的复极化失败。一氧化碳对这些细胞电流以及在哺乳动物系统中表达的离子通道的直接测量效应表明，晚期钠电流延长增加，而最大T型和L型钙电流峰值以及晚期钠电流、超快速延迟整流电流、延迟整流电流和内向整流钾电流减小。将这些一氧化碳诱导的心室细胞模型最大电流变化纳入其中；（加托尼等人，《生理学杂志》，2016年，594卷，4193 - 4224页）（大鼠）以及（罗和鲁迪，《循环研究》，1994年，74卷，1071 - 1096页）（豚鼠）和人类心内膜、中层心肌和心外膜（奥哈拉等人，《公共科学图书馆·计算生物学》，2011年，7卷，e1002061）模型中，通过最大离子电导率的变化可重现这些复极化异常。对具有最大电导率参数高斯分布的细胞群体进行模拟预测，一氧化碳会导致动作电位时程增加及其变异性增大。将这些预测的一氧化碳诱导的电导率变化纳入人类心室细胞电生理学，再应用于心室组织和壁模型，会使折返性心律失常起始概率指数发生变化。
