Abstract
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.
Highlights
Endogenous cannabinoids, such as arachidonoylethanolamide and 2-arachidonoylglycerol (2-AG), play contrasting roles in cardiovascular regulation [1]
Endocannabinoids decrease cardiac contractility and lower arterial pressure in a model of genetic hypertension [2], and contribute to vasodilation during hemorrhagic shock [3]. These effects are mediated by cannabinoid type 1 (CB1) receptors, which are expressed in the heart and blood vessels, sympathetic ganglia, and throughout the brain [4,5]
Increases in mean arterial pressure (MAP) and heart rate (HR) across the LDT were significantly greater for the KO compared with the WT (Figure 1C–D)
Summary
Endogenous cannabinoids, such as arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG), play contrasting roles in cardiovascular regulation [1]. Endocannabinoids decrease cardiac contractility and lower arterial pressure in a model of genetic hypertension [2], and contribute to vasodilation during hemorrhagic shock [3] These effects are mediated by cannabinoid type 1 (CB1) receptors, which are expressed in the heart and blood vessels, sympathetic ganglia, and throughout the brain [4,5]. We have shown that lack of CB1 receptors protects from adverse metabolic consequences of a high-fat diet (HFD), e.g. visceral obesity and high plasma glucose, cholesterol, and triglycerides [5] These protective effects are associated with increased sympathetic activation of brown adipose tissue, which burns fat to produce heat [5]. Absence of CB1 receptors is associated with multiple sleep-related anomalies and greater arousal during the active period of the day [11], and systemic cannabinoid administration seems to stabilize breathing rhythm during sleep [12]
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