Dexmedetomidine Exerts a Negative Chronotropic Action on Sinoatrial Node Cells Through the Activation of Imidazoline Receptors
Dexmedetomidine Exerts a Negative Chronotropic Action on Sinoatrial Node Cells Through the Activation of Imidazoline Receptors
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DOI：
10.1097/fjc.0000000000001133
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发表时间：
2021-12-01
影响因子：
3
通讯作者：
Matsuura，Hiroshi
中科院分区：
文献类型：
--
作者：
Ishihara，Mariko;Kojima，Akiko;Matsuura，Hiroshi
右美托咪定（DEX）是一种α 2-肾上腺素受体（α 2-AR）和咪唑啉受体激动剂，最常用于重症监护病房患者的镇静。它的使用与心动过缓的发生率增加有关；然而，dex诱导的心动过缓的确切机制尚未完全阐明。本研究旨在检测DEX是否通过α 2-AR和咪唑啉受体改变起搏器活性和潜在的离子通道功能。采用全细胞膜片钳技术记录豚鼠窦房结细胞的动作电位和相关离子电流。DEX（≥10 nM）降低窦房结自动性和舒张期去极化率。即使在生理起搏器电位范围内，DEX也能降低超极化激活阳离子电流（I / I h）的幅度。DEX减缓了I - f电流激活动力学，并导致通道激活对电压的依赖性向负电位的显著转变。此外，α 2-AR和咪唑啉I - 1受体拮抗剂依法罗珊可以减弱DEX对窦房结自动性和I -电流活性的抑制作用，而α 2-AR选择性拮抗剂育亨宾则没有。DEX不影响其他通道的电流活性，包括快速和缓慢激活延迟整流K+电流（I Kr和I Ks）、L型ca2 +电流（I Ca， L）、Na+/ ca2 +交换电流（I NCX）和毒碱K+电流（I K, ACh）。我们的研究结果表明，在临床相关浓度下，DEX通过咪唑啉I - 1受体（而非α 2-AR）下调I - f电流，对窦房结功能产生负变时作用。
Dexmedetomidine (DEX), an α 2-adrenoreceptor (α 2-AR) and imidazoline receptor agonist, is most often used for the sedation of patients in the intensive care unit. Its administration is associated with an increased incidence of bradycardia; however, the precise mechanism of DEX-induced bradycardia has yet to be fully elucidated. This study was undertaken to examine whether DEX modifies pacemaker activity and the underlying ionic channel function through α 2-AR and imidazoline receptors. The whole-cell patch-clamp techniques were used to record action potentials and related ionic currents of sinoatrial node cells in guinea pigs. DEX (≥ 10 nM) reduced sinoatrial node automaticity and the diastolic depolarization rate. DEX reduced the amplitude of hyperpolarization-activated cation current (I f or I h) the pacemaker current, even within the physiological pacemaker potential range. DEX slowed the I f current activation kinetics and caused a significant shift in the voltage dependence of channel activation to negative potentials. In addition, efaroxan, an α 2-AR and imidazoline I 1 receptor antagonist, attenuated the inhibitory effects of DEX on sinoatrial node automaticity and I f current activity, whereas yohimbine, an α 2-AR–selective antagonist, did not. DEX did not affect the current activities of other channels, including rapidly and slowly activating delayed rectifier K+ currents (I Kr and I Ks), L-type Ca 2+ current (I Ca, L), Na+/Ca 2+ exchange current (I NCX), and muscarinic K+ current (I K, ACh). Our results indicate that DEX, at clinically relevant concentrations, induced a negative chronotropic effect on the sinoatrial node function through the downregulation of I f current through an imidazoline I 1 receptor other than the α 2-AR in the clinical setting.