Abstract
Heart rate (HR) and blood pressure as well as adverse cardiovascular events show clear circadian patterns, which are linked to interdependent daily variations in physical activity and cardiac autonomic nerve system (ANS) activity. We set out to assess the relative contributions of the ANS (alone) and physical activity to circadian HR fluctuations. To do so, we measured HR (beats per minute, bpm) in mice that were either immobilized using isoflurane anesthesia or free-moving. Nonlinear fits of HR data to sine functions revealed that anesthetized mice display brisk circadian HR fluctuations with amplitudes of 47.1±7.4bpm with the highest HRs in middle of the dark (active) period (ZT 18: 589±46bpm) and lowest HRs in the middle of the light (rest) period (ZT 6: 497±54bpm). The circadian HR fluctuations were reduced by ~70% following blockade of cardiac parasympathetic nervous activity (PNA) with atropine while declining by <15% following cardiac sympathetic nerve activity (SNA) blockade with propranolol. Small HR fluctuation amplitudes (11.6±5.9bpm) remained after complete cardiac ANS blockade. Remarkably, circadian HR fluctuation amplitudes in freely moving, telemetrized mice were only ~32% larger than in anesthetized mice. However, after gaining access to running wheels for 1week, circadian HR fluctuations increase to 102.9±12.1bpm and this is linked directly to increased O2 consumption during running. We conclude that, independent of physical activity, the ANS is a major determinant of circadian HR variations with PNA playing a dominant role compared to SNA. The effects of physical activity to the daily HR variations are remarkably small unless mice get access to running wheels.
Highlights
Almost every physiological system in the body possesses a circadian rhythm which is modulated by the superchiasmatic nucleus (SCN), the master clock of the mammalian brain (Foster, 1998)
We began by assessing the relative contribution of the autonomic nervous system (ANS) alone to circadian heart rate (HR) fluctuations in anesthetized mice to eliminate the contribution of physical activity to our measures
Given that the amplitudes of the HR fluctuations after complete autonomic nerve system (ANS) blockade are similar to those seen following parasympathetic nervous activity (PNA) blockade alone, and given that sympathetic nerve activity (SNA) blockade reduced daily HR variations, our results demonstrate a non-additivity of the PNA versus SNA in circadian HR regulation
Summary
Almost every physiological system in the body possesses a circadian rhythm which is modulated by the superchiasmatic nucleus (SCN), the master clock of the mammalian brain (Foster, 1998). Many studies have previously established that the ANS plays a role in circadian HR fluctuation in humans (Burgess et al, 1997; Massin et al, 2000; Boudreau et al, 2012) and other species (Warren et al, 1994; Kriegsfeld et al, 2004) including mice (Tong et al, 2013), recent studies have suggested that diurnal variation in the intrinsic beating rates of the sinoatrial (SA) node is the dominant factor in controlling diurnal HR fluctuation in mice (D'Souza et al, 2020), with the ANS playing a minor role (Yamashita et al, 2003; Durgan et al, 2005) This conclusion seems at odds with the expectation that physical activity causes HR changes (Xiang and Hester, 2016) by recruiting the ANS in order to help match cardiac output with tissue demands during exercise (Gordan et al, 2015; Xiang and Hester, 2016)
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