Cardiorespiratory Anomalies in Mice Lacking CB1 Cannabinoid Receptors

Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage), or breathing (whole-body plethysmograph). Increases in arterial pressure and heart rate on passing from the light (rest) to the dark (activity) period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (β1) or vascular (α1) adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD.

1型大麻素（Cannabinoid type 1, CB1）受体在神经系统与心血管系统中均有表达。在小鼠模型中，CB1受体缺失可抵御高脂饮食（high-fat diet, HFD）引发的代谢紊乱，增强棕色脂肪的交感神经活性，并会诱发睡眠异常。本研究旨在探究CB1受体缺失小鼠的睡眠-觉醒状态与饮食依赖型心肺调节功能是否发生改变。实验中将CB1受体敲除（knock-out, KO）小鼠与野生型（wild-type, WT）正常小鼠分为两组，分别饲喂标准饲料与高脂饲料，持续3个月；随后为所有小鼠植入遥测式动脉压传感器与用于睡眠评分的电极。研究分别在居家饲养笼中同步评估小鼠的睡眠状态、动脉压与心率，或通过全身体积描记仪检测其呼吸状态。与野生型小鼠相比，CB1敲除小鼠从光照（休息）期过渡至黑暗（活动）期时，其动脉压与心率的升高幅度显著增强，且该升高效应不受心脏β1受体或血管α1受体肾上腺素能阻断的影响。CB1敲除小鼠睡眠期间的呼吸节律也较野生型小鼠更为紊乱。高脂饮食会使小鼠心率升高、心脏迷走神经调节功能受损，并削弱睡眠期间的中枢自主心脏调控能力；同时高脂饮食还会降低CB1敲除小鼠的心脏压力反射敏感性，但对野生型小鼠无此影响。综上，本研究首次在自发性睡眠-觉醒行为过程中，对CB1受体缺失小鼠的心血管功能开展系统性研究，结果证实CB1受体敲除会改变心肺调节功能，尤其在高脂饮食条件下该效应更为显著。由此可见，CB1受体信号通路可能参与生理性心肺调节，并可抵御高脂饮食引发的部分不良心血管后果。