Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
Transl Res. 2021 Apr;230:82-97. doi: 10.1016/j.trsl.2020.10.010. Epub 2020 Nov 1.
Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity is associated with left ventricular (LV) dysfunction in cases of cardiac ischemia/reperfusion (I/R) injury. Electrical stimulation to increase vagal activity has been shown to reduce infarct size and decrease fatal arrhythmias in cardiac I/R injury. However, the benefits of a parasympathomimetic drug on the heart during I/R are unclear. We hypothesized that administration of donepezil provides cardioprotection in cardiac I/R injury via reducing cellular apoptosis, oxidative stress, mitochondrial dysfunction, mitochondrial dynamic imbalance, increasing autophagy, and mitophagy. Fifty-four male Wistar rats were randomly assigned into sham and I/R groups. Acute cardiac I/R injury was induced by 30-minutes left anterior descending (LAD) coronary artery occlusion followed by 120-minutes reperfusion. These rats with induced I/R injury were randomly assigned to be treated with either: (1) Saline (vehicle group) or donepezil 3 mg/kg via intravenous injection given (2) before ischemia, (3) during ischemia, or (4) at the onset of reperfusion. Rats with cardiac I/R injury showed an increase in infarct size and arrhythmia score, LV dysfunction, impaired mitochondrial dynamic balance, autophagy and mitophagy, mitochondrial dysfunction, and increased apoptosis. All the donepezil-treated rats, regardless of the time of administration, showed a similar reduction in these impairments, and rebalancing in cardiac mitochondrial dynamics, leading to reduced myocardial infarct size and arrhythmia, and improved LV function. These findings suggested that donepezil effectively protected the heart against I/R injury through cardiac mitochondrial protection regardless of the time of administration.
心脏自主神经失衡，包括交感神经活性亢进和副交感神经活性减弱，与心肌缺血/再灌注（I/R）损伤中的左心室（LV）功能障碍有关。增加迷走神经活动的电刺激已被证明可减少心肌 I/R 损伤中的梗塞面积和致命性心律失常。然而，拟副交感神经药物对心脏在 I/R 期间的益处尚不清楚。我们假设，多奈哌齐通过减少细胞凋亡、氧化应激、线粒体功能障碍、线粒体动力学失衡、增加自噬和线粒体自噬来提供心脏保护作用。54 只雄性 Wistar 大鼠被随机分为假手术和 I/R 组。通过 30 分钟的左前降支（LAD）冠状动脉闭塞后 120 分钟再灌注来诱导急性心肌 I/R 损伤。这些诱导 I/R 损伤的大鼠被随机分为以下几组：（1）生理盐水（载体组）或多奈哌齐 3mg/kg 通过静脉注射（2）在缺血前，（3）在缺血期间，或（4）在再灌注开始时给予治疗。心肌 I/R 损伤的大鼠表现出梗塞面积和心律失常评分增加、LV 功能障碍、线粒体动力学平衡受损、自噬和线粒体自噬、线粒体功能障碍和凋亡增加。所有接受多奈哌齐治疗的大鼠，无论给药时间如何，都表现出这些损伤的类似减少，以及心脏线粒体动力学的重新平衡，导致心肌梗塞面积和心律失常减少，LV 功能改善。这些发现表明，多奈哌齐通过心脏线粒体保护有效地保护心脏免受 I/R 损伤，而与给药时间无关。
