Sun Junqing, Pan Shiyue, Karey Emma, Chen Yi-Je, Pinkerton Kent E, Wilson Christopher G, Chen Chao-Yin
Department of Pharmacology, University of California, Davis, Davis, CA, United States.
Department of Pediatrics and Center for Health and the Environment, University of California, Davis, Davis, CA, United States.
Front Physiol. 2021 Sep 24;12:727000. doi: 10.3389/fphys.2021.727000. eCollection 2021.
Secondhand smoke (SHS), a major indoor pollutant, is a significant risk factor for cardiovascular morbidity and mortality including arrhythmias and sudden cardiac death. Exposure to SHS can produce autonomic imbalance, as evidenced by reduced heart rate variability (HRV)-a clinical metric of cardiac vagal regulation. Currently, the mechanisms through which SHS changes the vagal preganglionic neuronal inputs to the heart to produce this remains unknown. To characterize the effect of SHS on both the excitability and action potential (AP) characteristics of anatomically identified cardiac vagal neurons (CVNs) in the nucleus ambiguus and examine whether SHS alters small conductance calcium-activated potassium (SK) channel activity of these CVNs. Adult male mice were exposed to four weeks of filtered air or SHS (3 mg/m) 6 h/day, 5 day/week. Using patch-clamp recordings on identified CVNs in brainstem slices, we determined neuronal excitability and AP characteristics with depolarizing step- and ramp-current injections. Four weeks of SHS exposure reduced spiking responses to depolarizing current injections and increased AP voltage threshold in CVNs. Perfusion with apamin (20 nM) magnified these SHS-induced effects, suggesting reduced SK channel activity may serve to minimize the SHS-induced decreases in CVNs excitability. Medium afterhyperpolarization (a measurement of SK channel activity) was smaller in the SHS group, further supporting a lower SK channel activity. AP amplitude, rise rate, fast afterhyperpolarization amplitude (a measurement of voltage-gated channel activity), and decay rate were higher in the SHS group at membrane voltages more positive to 0 mV, suggesting altered inactivation properties of voltage-dependent channels underlying APs. SHS exposure reduced neuronal excitability of CVNs with compensatory attenuation of SK channel activity and altered AP characteristics. Neuroplasticity of CVNs could blunt regulatory cardiac vagal signaling and contribute to the cardiovascular consequences associated with SHS exposure, including reduced HRV.
二手烟（SHS）是一种主要的室内污染物，是心血管疾病发病率和死亡率（包括心律失常和心源性猝死）的重要危险因素。接触二手烟会导致自主神经失衡，心率变异性（HRV）降低就是证据之一，HRV是心脏迷走神经调节的一项临床指标。目前，二手烟改变迷走神经节前神经元对心脏的输入从而产生这种情况的机制尚不清楚。为了阐明二手烟对疑核中解剖学上已确定的心脏迷走神经神经元（CVNs）的兴奋性和动作电位（AP）特性的影响，并研究二手烟是否会改变这些CVNs的小电导钙激活钾（SK）通道活性。成年雄性小鼠连续四周每天6小时、每周5天暴露于过滤空气或二手烟（3毫克/立方米）环境中。通过对脑干切片中已确定的CVNs进行膜片钳记录，我们利用去极化阶跃电流和斜坡电流注入来测定神经元兴奋性和AP特性。四周的二手烟暴露降低了CVNs对去极化电流注入的放电反应，并提高了AP电压阈值。用蜂毒明肽（20纳摩尔）灌注可放大这些二手烟诱导的效应，表明SK通道活性降低可能有助于最小化二手烟诱导的CVNs兴奋性降低。二手烟组的中等后超极化（SK通道活性的一种测量指标）较小，进一步支持了较低的SK通道活性。在膜电压更正于0毫伏时，二手烟组的AP幅度、上升速率、快速后超极化幅度（电压门控通道活性的一种测量指标）和衰减速率更高，这表明APs基础的电压依赖性通道的失活特性发生了改变。二手烟暴露降低了CVNs的神经元兴奋性，同时SK通道活性出现代偿性衰减，并改变了AP特性。CVNs的神经可塑性可能会削弱心脏迷走神经调节信号，并导致与二手烟暴露相关的心血管后果，包括HRV降低。
