Treating hypertension by targeting orexin receptors: potential effects on the sleep‐related blood pressure dipping profile

We read with interest the recent paper by Li et al. (2013) concerning the cardiovascular effects of the dual orexin receptor antagonist Almorexant on the spontaneously hypertensive rat (SHR) model of essential hypertension. The finding that Almorexant caused a significant reduction in blood pressure (BP) in SHR, but not in normotensive control rats of the Wistar–Kyoto (WKY) strain (Li et al. 2013) is of clear pathophysiological interest and is supported by a recent independent report (Lee et al. 2013). Our comment concerns the claim by Li et al. (2013) that the effect of Almorexant on BP did not differ significantly between wakefulness and non-rapid eye movement sleep (NREMS) in SHR in either the light (rest) or dark (activity) period of the day. This led Li et al. (2013) to suggest that modulation of BP by orexin in SHR is not dependent on the state of arousal or diurnal cycle. We would like to draw attention to a few issues which need to be addressed before this suggestion can be accepted. First, the recording protocol employed by Li et al. (2013) may not have been sufficiently sensitive to detect changes in BP related to sleep states and the day–light cycle. The mean value of BP robustly decreases on passing from wakefulness to NREMS in human subjects and animal models (Silvani, 2008), including SHR and WKY rats (Kuo & Yang, 2005; Berteotti et al. 2007). At least during wakefulness, BP is also higher during the dark than during the light period in normotensive rats (Sei et al. 1997) and mice (Bastianini et al. 2011). However, Li et al. (2013) reported that, before Almorexant treatment, BP in SHR was lower during NREMS than during wakefulness in the light period, but not in the dark period, and did not differ between the light and dark periods. Second, Li et al. (2013) did not report the effects of Almorexant on sleep structure in SHR and WKY rats. This is of relevance because changes in sleep structure may exert a significant impact on BP (Silvani, 2008; Silvani et al. 2009). Li et al. (2013) appropriately discussed this issue with reference to a previous study of theirs on normotensive Sprague-Dawley rats (Li & Nattie, 2010). However, SHR show distinct derangements in sleep phenotype, and their poor sleep quality may be linked to sympathetic overdrive via α1 adrenergic receptors (Kuo et al. 2012). Thus, the effects of Almorexant on sleep in SHR may have differed from those in normotensive WKY or Sprague-Dawley rats, potentially confounding the observed results on BP. Third, even with the caveats just mentioned, the paper by Li et al. (2013) did not indicate whether Almorexant modified the difference in BP between wakefulness and NREMS in SHR and WKY rats. Sleep-related differences in BP are preserved in rats with a partial postnatal loss of orexin neurons (Schwimmer et al. 2010). Conversely, the BP reduction on passing from wakefulness to NREMS is significantly attenuated in either knock-out mice with congenital orexin deficiency (Bastianini et al. 2011) or transgenic mice with complete postnatal loss of orexin neurons (Bastianini et al. 2011; Lo Martire et al. 2012; Silvani et al. 2013) compared with wild-type controls. The changes in BP on falling asleep and those on awakening from sleep are also attenuated in patients with narcolepsy with cataplexy (NC), which is a debilitating sleep disorder associated with virtually complete loss of orexin neurons (Grimaldi et al. 2012). Moreover, patients with NC are at high risk of having a non-dipper BP profile (Dauvilliers et al. 2012; Grimaldi et al. 2012). Fourth, Li et al. (2013) did not report the effects of Almorexant on BP during rapid-eye-movement sleep (REMS) in SHR and WKY rats. REMS represents a minor fraction of total sleep time but in different species including humans, it entails an increase in BP towards waking levels compared with NREMS (Silvani, 2008). The increase in BP during REMS compared with NREMS may be detected also in SHR and WKY rats (Berteotti et al. 2007). Importantly, such an increase in BP during REMS was found to be significantly enhanced in knock-out and transgenic mice with congenital orexin deficiency (Bastianini et al. 2011; Lo Martire et al. 2012; Silvani et al. 2013) and in human NC patients (Grimaldi et al. 2012) compared with the respective controls. In conclusion, we have raised a few issues concerning the interpretation of data recently reported by Li et al. (2013) in this journal. In general, these issues are expansions of points recognized by the authors, but with a focus on the role of orexins in sleep-related cardiovascular control. This focus may be of clinical as well as physiological relevance, because growing evidence links cardiovascular risk to high BP values during sleep and to a reduced difference in BP between night-time sleep and daytime wakefulness (i.e. a non-dipping BP profile) (Ben-Dov et al. 2007; Hermida et al. 2011, 2013). However, orexin neurons fire almost solely during wakefulness (Mileykovskiy et al. 2005), yet extracellular orexin concentration remains substantial during sleep (Kiyashchenko et al. 2002), thus potentially continuing to exert physiological effects. The very finding by Li et al. (2013) that Almorexant is effective in SHR also during sleep is at least consistent with this view.