Table_2_Drivers of Sinoatrial Node Automaticity in Zebrafish: Comparison With Mechanisms of Mammalian Pacemaker Function.pdf

Cardiac excitation originates in the sinoatrial node (SAN), due to the automaticity of this distinct region of the heart. SAN automaticity is the result of a gradual depolarisation of the membrane potential in diastole, driven by a coupled system of transarcolemmal ion currents and intracellular Ca2+ cycling. The frequency of SAN excitation determines heart rate and is under the control of extra- and intracardiac (extrinsic and intrinsic) factors, including neural inputs and responses to tissue stretch. While the structure, function, and control of the SAN have been extensively studied in mammals, and some critical aspects have been shown to be similar in zebrafish, the specific drivers of zebrafish SAN automaticity and the response of its excitation to vagal nerve stimulation and mechanical preload remain incompletely understood. As the zebrafish represents an important alternative experimental model for the study of cardiac (patho-) physiology, we sought to determine its drivers of SAN automaticity and the response to nerve stimulation and baseline stretch. Using a pharmacological approach mirroring classic mammalian experiments, along with electrical stimulation of intact cardiac vagal nerves and the application of mechanical preload to the SAN, we demonstrate that the principal components of the coupled membrane- Ca2+ pacemaker system that drives automaticity in mammals are also active in the zebrafish, and that the effects of extra- and intracardiac control of heart rate seen in mammals are also present. Overall, these results, combined with previously published work, support the utility of the zebrafish as a novel experimental model for studies of SAN (patho-) physiological function.

心脏兴奋起源于窦房结（sinoatrial node, SAN），这源于心脏这一特殊区域的自律性。窦房结自律性的本质是舒张期膜电位的缓慢去极化，该过程由跨细胞膜离子流（transarcolemmal ion currents）与细胞内钙循环（intracellular Ca2+ cycling）的耦合系统所驱动。窦房结兴奋的频率决定心率，其受心外与心内（即外源性和内源性）因素调控，包括神经输入及对组织牵拉的响应。尽管哺乳动物窦房结的结构、功能与调控机制已被广泛研究，且斑马鱼的部分关键特征与哺乳动物相似，但斑马鱼窦房结自律性的具体驱动因素，以及其兴奋对迷走神经（vagal nerve）刺激与机械前负荷（mechanical preload）的响应机制仍未完全阐明。鉴于斑马鱼是研究心脏（病理）生理学的重要替代实验模型，本研究旨在明确其窦房结自律性的驱动因素，以及其对神经刺激与基础牵拉的响应。研究采用复刻经典哺乳动物实验的药理学方法，结合完整心脏迷走神经的电刺激，并对窦房结施加机械前负荷，结果证实：驱动哺乳动物自律性的膜-钙耦合起搏系统的主要组分，在斑马鱼中同样具有活性；且哺乳动物中心外与心内调控心率的效应在斑马鱼中也存在。综上，这些结果结合已发表的研究成果，支持斑马鱼可作为研究窦房结（病理）生理功能的新型实验模型。