Respiratory and cardiovascular actions of orexin-A in mice

Department of Molecular & Integrative Physiology, Chiba University Graduate School of Medicine, Inohana 1-8-1 Chuo-ku, Chiba-city, Chiba 260-8670, Japan.
Neuroscience Letters (Impact Factor: 2.03). 10/2005; 385(2):131-6. DOI: 10.1016/j.neulet.2005.05.032
Source: PubMed


Ample evidence has been reported to show a probable contribution of orexin in the central cardiovascular regulation. Although cardiovascular and respiratory centers in the brain are located close to each other and are interconnected, the possible participation of orexin in respiratory regulation has not been fully documented. Here we examined the effects of intracerebroventricular administration of orexin-A on respiratory and cardiovascular parameters in urethane-anesthetized mice. Respiratory frequency and tidal volume were recorded simultaneously with blood pressure and heart rate. Orexin-A (0.003-3 nmol in 2 microL) or vehicle was administered into the lateral ventricle or cisterna magna. Lateral ventricular administration induced a rise in respiratory frequency (by 11% at the highest dose), tidal volume (76%), blood pressure (13%) and heart rate (6%) in a dose-dependent manner. With intracisternal administration, however, respiratory frequency did not change while a similar increase in tidal volume (75%) was observed. A relatively larger cardiovascular response was elicited with intracisternal administration (blood pressure 26%, heart rate 9%). On the other hand, with either administration route, orexin-A did not affect reflex increases in respiratory frequency and tidal volume in response to hypoxia and hypercapnia. These results show possible participation of orexin-A not only in the cardiovascular regulation but also in the respiratory control system. Moreover, orexin can affect the cardiorespiratory control system at multiple sites in different ways. Orexin-A seems not to be involved in respiratory reflex regulation in mice at least under anesthetized condition.

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    • "February 2014 | Volume 8 | Article 22 | 1 neurons are most active during wakefulness (Hassani et al., 2009), and activation of orexin receptors promotes wakefulness (De Lecea, 2010, 2012; Sakurai et al., 2010), feeding, and energy metabolism (Tsujino and Sakurai, 2009; Teske et al., 2010; Girault et al., 2012; Nixon et al., 2012), excites breathing, and stimulates sympathetic nerve activity (SNA) leading to an increase in blood pressure (Matsumura et al., 2001; Shirasaka et al., 2002; Zhang et al., 2005; Huang et al., 2010; Shahid et al., 2011, 2012; Nattie and Li, 2012). In contrast, MCH neurons are most active during sleep (Hassani et al., 2009), and MCH promotes sleep or physical inactivity (Nahon, 2006; Peyron et al., 2009; Konadhode et al., 2013; Monti et al., 2013), and regulates the autonomic nervous system. "
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    ABSTRACT: In this review we focus on the role of orexin in cardio-respiratory functions and its potential link to hypertension. (1) Orexin, cardiovascular function, and hypertension. In normal rats, central administration of orexin can induce significant increases in arterial blood pressure (ABP) and sympathetic nerve activity (SNA), which can be blocked by orexin receptor antagonists. In spontaneously hypertensive rats (SHRs), antagonizing orexin receptors can significantly lower blood pressure under anesthetized or conscious conditions. (2) Orexin, respiratory function, and central chemoreception. The prepro-orexin knockout mouse has a significantly attenuated ventilatory CO2 chemoreflex, and in normal rats, central application of orexin stimulates breathing while blocking orexin receptors decreases the ventilatory CO2 chemoreflex. Interestingly, SHRs have a significantly increased ventilatory CO2 chemoreflex relative to normotensive WKY rats and blocking both orexin receptors can normalize this exaggerated response. (3) Orexin, central chemoreception, and hypertension. SHRs have higher ABP and SNA along with an enhanced ventilatory CO2 chemoreflex. Treating SHRs by blocking both orexin receptors with oral administration of an antagonist, almorexant (Almxt), can normalize the CO2 chemoreflex and significantly lower ABP and SNA. We interpret these results to suggest that the orexin system participates in the pathogenesis and maintenance of high blood pressure in SHRs, and the central chemoreflex may be a causal link to the increased SNA and ABP in SHRs. Modulation of the orexin system could be a potential target in treating some forms of hypertension.
    Frontiers in Neuroscience 02/2014; 8(8):22. DOI:10.3389/fnins.2014.00022 · 3.66 Impact Factor
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    • "Figure taken from Kuwaki et al. (2010) by permission. Lin et al., 2002; Machado et al., 2002; Matsumura et al., 2001, 2003; Samson et al., 1999; Shahid et al., 2011; Shirasaka et al., 1999, 2003; Smith et al., 2002, 2007; Zhang et al., 2005) as well as body temperature regulation (Mochizuki et al., 2006; Plazzi et al., 2011; Rusyniak et al., 2011; Tupone et al., 2011). "
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    ABSTRACT: Orexin, a small neuropeptide released from neurons in the hypothalamus with widespread projections throughout the central nervous system, has broad biological roles including the modulation of breathing and autonomic function. That orexin activity is fundamentally dependent on sleep-wake state, and circadian cycle requires consideration of orexin function in physiological control systems in respect to these two state-related activity patterns. Both transgenic mouse studies and focal orexin receptor antagonism support a role for orexins in respiratory chemosensitivity to CO₂ predominantly in wakefulness, with further observations limiting this role to the dark period. In addition, orexin neurons participate in the regulation of sympathetic activity, including effects on blood pressure and thermoregulation. Orexin is also essential in physiological responses to stress. Orexin-mediated processes may operate at two levels: (1) in sleep-wake and circadian states and (2) in stress, for example, the defense or "fight-or-flight" response and panic-anxiety syndrome.
    Progress in brain research 07/2012; 198:25-46. DOI:10.1016/B978-0-444-59489-1.00004-5 · 2.83 Impact Factor
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    • "Although the total number of orexin neurons is fairly small, axonal projections from these cells extend from the LH to many regions of the rat brain and spinal cord (Chen et al. 1999; Nixon and Smale 2007; Cutler et al. 1999; Date et al. 1999; Peyron et al. 1998; Nambu et al. 1999), and the distribution of these neurons and axonal projections is very similar across rodent strains and species (Nixon and Smale 2007). The overall distribution of orexin fibers in the brain and spinal cord allows this small population of neurons to play roles in integrating multiple autonomic and behavioral functions, primarily feeding, sleep/wake behavior, and arousal (Niimi et al. 2001a; Kotz et al. 2002; Rodgers et al. 2000; Kunii et al. 1999; Haynes et al. 2000; Mondal et al. 1999; Yamanaka et al. 2000; Tsujino and Sakurai 2009; Nunez et al. 2009; Siegel 1999; Lin et al. 1999; Piper et al. 2000; Hungs and Mignot 2001), as well as nociception, respiratory, motor, neuroendocrine, and cardiovascular systems (Nixon and Smale 2007; Cutler et al. 1999; Date et al. 1999; Peyron et al. 1998; Nambu et al. 1999; Volgin et al. 2002; Zhang and Luo 2002; Samson et al. 1999; Shirasaka et al. 2002; Zhang et al. 2005a; Berthoud et al. 2005). Disruptions or deficiencies in orexin signaling have been linked to a number of sleep/wake and endocrine disorders in humans and in animal models (Lin et al. 1999; Petersén et al. 2005; Nevsimalova et al. 2005; Thannickal et al. 2000; Nishino et al. 2000). "
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    ABSTRACT: In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.
    Handbook of experimental pharmacology 01/2012; 209(209):77-109. DOI:10.1007/978-3-642-24716-3_4
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