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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

In conscious rats, hypercapnia increases arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA). Hypercapnia increased mean ABP [from 105 to 117 mm Hg; (A)], RSNA [from 100 to 115%, (A,B)], and the respiratory rate [from 63 to 151 breaths/min; (A)], but decreased HR [from 374 to 302 beats/min; (A,B)]. Hypercapnia significantly increased mean ABP and RSNA in intact (A), carotid body destroyed (CBD), aortic nerve denervated (AD), carotid body destroyed and aortic denervated (CBAD), and sinoaortic denervated (SAD) rats (C). There were also no significant differences in the magnitudes of increase in ABP and RSNA during hypercapnia between the intact and the three chemo-denervated groups. (Figure adapted with permission from Oikawa et al., 2005).
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Figure 12: In conscious rats, hypercapnia increases arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA). Hypercapnia increased mean ABP [from 105 to 117 mm Hg; (A)], RSNA [from 100 to 115%, (A,B)], and the respiratory rate [from 63 to 151 breaths/min; (A)], but decreased HR [from 374 to 302 beats/min; (A,B)]. Hypercapnia significantly increased mean ABP and RSNA in intact (A), carotid body destroyed (CBD), aortic nerve denervated (AD), carotid body destroyed and aortic denervated (CBAD), and sinoaortic denervated (SAD) rats (C). There were also no significant differences in the magnitudes of increase in ABP and RSNA during hypercapnia between the intact and the three chemo-denervated groups. (Figure adapted with permission from Oikawa et al., 2005).

Mentions: Activation of central chemoreceptors by CO2/H+ increases ABP and SNA in both humans and experimental animals (Hanna et al., 1981; Lioy and Trzebski, 1984; Somers et al., 1989; Nattie et al., 1992, 1993; Oikawa et al., 2005; Guyenet et al., 2010). In humans, hyperoxic hypercapnia (7%CO2/93%O2) induced greater increases in ventilation (E), blood pressure and SNA than did hypoxia (10%O2/93%N2) (Somers et al., 1989). In conscious rats (Figure 12), Oikawa et al. (2005) showed that hypercapnia induced significant increases in mean ABP, RSNA, and the respiratory rate (Figure 12B) in intact animals and in animals with varied peripheral chemoreceptor input, e.g., carotid body destroyed (CBD), aortic nerve denervated (AD), carotid body destroyed plus aortic denervated (CBAD), and sinoaortic denervated (SAD) (Figure 12C). There were also no significant differences in the magnitudes of increase in ABP and RSNA during hypercapnia between the intact and the chemo-denervated groups (Figure 12). The fact that the increased ABP and rSNA response to hypercapnia was not affected by bilateral carotid chemo-denervation, aortic denervation, or sinoaortic-denervation suggests that the peripheral chemoreceptors do not play a major role in the cardiovascular response to hypercapnia in normal conscious rats (Oikawa et al., 2005). Blockade of glutamate receptors in the RTN or lesion of the rostral part of the RVLM decreased respiratory (phrenic nerve activity, PNA) and SNA responses to hypercapnic stimulation in decerebrate, paralyzed, vagotomized, and servo-ventilated cats (Nattie et al., 1992, 1993).


Orexin, cardio-respiratory function, and hypertension.

Li A, Nattie E - Front Neurosci (2014)

In conscious rats, hypercapnia increases arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA). Hypercapnia increased mean ABP [from 105 to 117 mm Hg; (A)], RSNA [from 100 to 115%, (A,B)], and the respiratory rate [from 63 to 151 breaths/min; (A)], but decreased HR [from 374 to 302 beats/min; (A,B)]. Hypercapnia significantly increased mean ABP and RSNA in intact (A), carotid body destroyed (CBD), aortic nerve denervated (AD), carotid body destroyed and aortic denervated (CBAD), and sinoaortic denervated (SAD) rats (C). There were also no significant differences in the magnitudes of increase in ABP and RSNA during hypercapnia between the intact and the three chemo-denervated groups. (Figure adapted with permission from Oikawa et al., 2005).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 12: In conscious rats, hypercapnia increases arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA). Hypercapnia increased mean ABP [from 105 to 117 mm Hg; (A)], RSNA [from 100 to 115%, (A,B)], and the respiratory rate [from 63 to 151 breaths/min; (A)], but decreased HR [from 374 to 302 beats/min; (A,B)]. Hypercapnia significantly increased mean ABP and RSNA in intact (A), carotid body destroyed (CBD), aortic nerve denervated (AD), carotid body destroyed and aortic denervated (CBAD), and sinoaortic denervated (SAD) rats (C). There were also no significant differences in the magnitudes of increase in ABP and RSNA during hypercapnia between the intact and the three chemo-denervated groups. (Figure adapted with permission from Oikawa et al., 2005).
Mentions: Activation of central chemoreceptors by CO2/H+ increases ABP and SNA in both humans and experimental animals (Hanna et al., 1981; Lioy and Trzebski, 1984; Somers et al., 1989; Nattie et al., 1992, 1993; Oikawa et al., 2005; Guyenet et al., 2010). In humans, hyperoxic hypercapnia (7%CO2/93%O2) induced greater increases in ventilation (E), blood pressure and SNA than did hypoxia (10%O2/93%N2) (Somers et al., 1989). In conscious rats (Figure 12), Oikawa et al. (2005) showed that hypercapnia induced significant increases in mean ABP, RSNA, and the respiratory rate (Figure 12B) in intact animals and in animals with varied peripheral chemoreceptor input, e.g., carotid body destroyed (CBD), aortic nerve denervated (AD), carotid body destroyed plus aortic denervated (CBAD), and sinoaortic denervated (SAD) (Figure 12C). There were also no significant differences in the magnitudes of increase in ABP and RSNA during hypercapnia between the intact and the chemo-denervated groups (Figure 12). The fact that the increased ABP and rSNA response to hypercapnia was not affected by bilateral carotid chemo-denervation, aortic denervation, or sinoaortic-denervation suggests that the peripheral chemoreceptors do not play a major role in the cardiovascular response to hypercapnia in normal conscious rats (Oikawa et al., 2005). Blockade of glutamate receptors in the RTN or lesion of the rostral part of the RVLM decreased respiratory (phrenic nerve activity, PNA) and SNA responses to hypercapnic stimulation in decerebrate, paralyzed, vagotomized, and servo-ventilated cats (Nattie et al., 1992, 1993).

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