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Orexin, cardio-respiratory function, and hypertension.

Li A, Nattie E - Front Neurosci (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Focal application of an OX1R antagonist in the RTN and the medullary raphe magnus decreases the CO2 chemoreflex. Inhibition of OX1R in the region of RTN (unilateral, A) or raphe magnus (B) by an OX1R antagonist (SB334867) significantly decreased the CO2 chemoreflex by 30 or 16% respectively in wakefulness. (Figure adapted with permission from Dias et al., 2009 and Dias et al., 2010).
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Figure 10: Focal application of an OX1R antagonist in the RTN and the medullary raphe magnus decreases the CO2 chemoreflex. Inhibition of OX1R in the region of RTN (unilateral, A) or raphe magnus (B) by an OX1R antagonist (SB334867) significantly decreased the CO2 chemoreflex by 30 or 16% respectively in wakefulness. (Figure adapted with permission from Dias et al., 2009 and Dias et al., 2010).

Mentions: In addition to their intrinsic CO2/pH sensitivity, orexin neurons also modulate the activity of brainstem chemosensitive neurons such as those in medullary raphe nuclei and RTN (Dias et al., 2010; Lazarenko et al., 2011; Tupone et al., 2011; Nattie and Li, 2012). Electrophysiological studies in slices from neonatal (P6-P10) Phox2b-eGFP transgenic mice showed that orexin A excites the acid sensitive eGFP/Phox2b-expressing RTN neurons in a dose dependent manner (ED50 ~250 nM, Figure 9), and these neurons increased activity upon bath acidification, decreased firing with alkalization, and exhibited an ~5 Hz dynamic range of response between pH 7.0 and 7.5 (Figures 9A,B) (Lazarenko et al., 2011). Functional studies have shown that the orexin system participates in the regulation of respiration and the CO2 central chemoreflex (Dutschmann et al., 2007; Nakamura et al., 2007; Williams et al., 2007; Dias et al., 2009, 2010; Li and Nattie, 2010; Lazarenko et al., 2011). Microinjection of orexin into the RVLM at the level of the pre-Bötzinger complex causes a significant increase in amplitude of integrated phrenic nerve activity (an index of tidal volume) in anesthetized and vagotomized rats (Young et al., 2005; Shahid et al., 2012). Injection of OX-B into the Kölliker–Fuse nucleus significantly increases breathing frequency in P21–42 day rats using the intra-arterially perfused working heart-brainstem preparation (Dutschmann et al., 2007). In the decerebrate cat, OX-A application into the hypoglossal motor nucleus increases genioglossus muscle activity (Peever et al., 2003). The pp-OX knockout mouse with a complete lack of orexin has normal resting breathing but a significantly attenuated respiratory chemoreflex in wakefulness compare to the wide type control mice and supplementation of orexins can partially restore the reflex (Deng et al., 2007; Nakamura et al., 2007). Unilateral administration of an OX1R antagonist (SB334867) in the RTN significantly reduced the respiratory response to hypercapnia (7%CO2) with a substantial effect in wakefulness (−30%; Figure 10A) and a much smaller effect in sleep (−9%) (Dias et al., 2009). In the medullary raphe, inhibition of the OX1R produced a significant reduction of the CO2 chemoreflex in wakefulness (−16%; Figure 10B) but not in sleep (Dias et al., 2010). Antagonism both OX1R and OX2R by orally administrating a dual OXR antagonist, Almxt, significantly decreased the hypercapnic chemoreflex only in wakefulness during the dark period of diurnal cycle (−31%); the CO2 chemoreflex was not significantly changed in sleep in the dark period and wakefulness and sleep in the light period of the diurnal cycles (Figure 11) (Li and Nattie, 2010). Antagonism of orexin receptors had no effect on resting breathing (Dias et al., 2009, 2010; Li and Nattie, 2010). These in vitro and in vivo experiments demonstrate that the orexin system is significantly involved in the control of breathing, particularly in the central CO2 chemoreflex.


Orexin, cardio-respiratory function, and hypertension.

Li A, Nattie E - Front Neurosci (2014)

Focal application of an OX1R antagonist in the RTN and the medullary raphe magnus decreases the CO2 chemoreflex. Inhibition of OX1R in the region of RTN (unilateral, A) or raphe magnus (B) by an OX1R antagonist (SB334867) significantly decreased the CO2 chemoreflex by 30 or 16% respectively in wakefulness. (Figure adapted with permission from Dias et al., 2009 and Dias et al., 2010).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921571&req=5

Figure 10: Focal application of an OX1R antagonist in the RTN and the medullary raphe magnus decreases the CO2 chemoreflex. Inhibition of OX1R in the region of RTN (unilateral, A) or raphe magnus (B) by an OX1R antagonist (SB334867) significantly decreased the CO2 chemoreflex by 30 or 16% respectively in wakefulness. (Figure adapted with permission from Dias et al., 2009 and Dias et al., 2010).
Mentions: In addition to their intrinsic CO2/pH sensitivity, orexin neurons also modulate the activity of brainstem chemosensitive neurons such as those in medullary raphe nuclei and RTN (Dias et al., 2010; Lazarenko et al., 2011; Tupone et al., 2011; Nattie and Li, 2012). Electrophysiological studies in slices from neonatal (P6-P10) Phox2b-eGFP transgenic mice showed that orexin A excites the acid sensitive eGFP/Phox2b-expressing RTN neurons in a dose dependent manner (ED50 ~250 nM, Figure 9), and these neurons increased activity upon bath acidification, decreased firing with alkalization, and exhibited an ~5 Hz dynamic range of response between pH 7.0 and 7.5 (Figures 9A,B) (Lazarenko et al., 2011). Functional studies have shown that the orexin system participates in the regulation of respiration and the CO2 central chemoreflex (Dutschmann et al., 2007; Nakamura et al., 2007; Williams et al., 2007; Dias et al., 2009, 2010; Li and Nattie, 2010; Lazarenko et al., 2011). Microinjection of orexin into the RVLM at the level of the pre-Bötzinger complex causes a significant increase in amplitude of integrated phrenic nerve activity (an index of tidal volume) in anesthetized and vagotomized rats (Young et al., 2005; Shahid et al., 2012). Injection of OX-B into the Kölliker–Fuse nucleus significantly increases breathing frequency in P21–42 day rats using the intra-arterially perfused working heart-brainstem preparation (Dutschmann et al., 2007). In the decerebrate cat, OX-A application into the hypoglossal motor nucleus increases genioglossus muscle activity (Peever et al., 2003). The pp-OX knockout mouse with a complete lack of orexin has normal resting breathing but a significantly attenuated respiratory chemoreflex in wakefulness compare to the wide type control mice and supplementation of orexins can partially restore the reflex (Deng et al., 2007; Nakamura et al., 2007). Unilateral administration of an OX1R antagonist (SB334867) in the RTN significantly reduced the respiratory response to hypercapnia (7%CO2) with a substantial effect in wakefulness (−30%; Figure 10A) and a much smaller effect in sleep (−9%) (Dias et al., 2009). In the medullary raphe, inhibition of the OX1R produced a significant reduction of the CO2 chemoreflex in wakefulness (−16%; Figure 10B) but not in sleep (Dias et al., 2010). Antagonism both OX1R and OX2R by orally administrating a dual OXR antagonist, Almxt, significantly decreased the hypercapnic chemoreflex only in wakefulness during the dark period of diurnal cycle (−31%); the CO2 chemoreflex was not significantly changed in sleep in the dark period and wakefulness and sleep in the light period of the diurnal cycles (Figure 11) (Li and Nattie, 2010). Antagonism of orexin receptors had no effect on resting breathing (Dias et al., 2009, 2010; Li and Nattie, 2010). These in vitro and in vivo experiments demonstrate that the orexin system is significantly involved in the control of breathing, particularly in the central CO2 chemoreflex.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA.

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.

No MeSH data available.


Related in: MedlinePlus