Wengrowski Anastasia M, Wang Xin, Tapa Srinivas, Posnack Nikki Gillum, Mendelowitz David, Kay Matthew W
Department of Biomedical Engineering, The George Washington University, Phillips Hall, Room 607, 801 22nd Street NW, Washington, DC 20052, USA.
Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA.
Cardiovasc Res. 2015 Feb 1;105(2):143-50. doi: 10.1093/cvr/cvu258. Epub 2014 Dec 16.
Release of norepinephrine (NE) from sympathetic neurons enhances heart rate (HR) and developed force through activation of β-adrenergic receptors, and this sympathoexcitation is a key risk for the generation of cardiac arrhythmias. Studies of β-adrenergic modulation of cardiac function typically involve the administration of exogenous β-adrenergic receptor agonists to directly elicit global β-adrenergic receptor activation by bypassing the involvement of sympathetic nerve terminals. In this work, we use a novel method to activate sympathetic fibres within the myocardium of Langendorff-perfused hearts while measuring changes in electrical and mechanical function.
The light-activated optogenetic protein channelrhodopsin-2 (ChR2) was expressed in murine catecholaminergic sympathetic neurons. Sympathetic fibres were then photoactivated to examine changes in contractile force, HR, and cardiac electrical activity. Incidence of arrhythmia was measured with and without exposure to photoactivation of sympathetic fibres, and hearts were optically mapped to detect changes in action potential durations and conduction velocities. Results demonstrate facilitation of both developed force and HR after photostimulated release of NE, with increases in contractile force and HR of 34.5 ± 5.5 and 25.0 ± 9.3%, respectively. Photostimulation of sympathetic fibres also made hearts more susceptible to arrhythmia, with greater incidence and severity. In addition, optically mapped action potentials displayed a small but significant shortening of the plateau phase (-5.5 ± 1.0 ms) after photostimulation.
This study characterizes a powerful and clinically relevant new model for studies of cardiac arrhythmias generated by increasing the activity of sympathetic nerve terminals and the resulting activation of myocyte β-adrenergic receptors.
交感神经元释放去甲肾上腺素（NE）可通过激活β-肾上腺素能受体提高心率（HR）和增强心肌收缩力，而这种交感神经兴奋是引发心律失常的关键风险因素。对心脏功能的β-肾上腺素能调节的研究通常涉及给予外源性β-肾上腺素能受体激动剂，以绕过交感神经末梢的参与直接引发整体β-肾上腺素能受体激活。在本研究中，我们使用一种新方法激活Langendorff灌流心脏心肌内的交感纤维，同时测量电和机械功能的变化。
光激活的光遗传学蛋白通道视紫红质-2（ChR2）在小鼠儿茶酚胺能交感神经元中表达。然后对交感纤维进行光激活，以检查收缩力、心率和心脏电活动的变化。在有或无交感纤维光激活暴露的情况下测量心律失常的发生率，并对心脏进行光学标测以检测动作电位持续时间和传导速度的变化。结果表明，光刺激释放NE后，收缩力和心率均增加，收缩力和心率分别增加34.5±5.5%和25.0±9.3%。交感纤维的光刺激也使心脏更容易发生心律失常，发生率和严重程度更高。此外，光学标测的动作电位在光刺激后显示平台期有小幅但显著的缩短（-5.5±1.0毫秒）。
本研究描述了一种强大且与临床相关的新模型，用于研究因交感神经末梢活动增加及由此导致的心肌细胞β-肾上腺素能受体激活而产生的心律失常。
