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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

Prepro-orexin knockout mice have lower blood pressures throughout the circadian cycle. The knockout mice have lower blood pressure in both the light and dark periods of the diurnal cycle relative to the wild type control mice. Filled circles: KO mice; crosses: WT mice. (Figure used with permission from Kayaba et al., 2003).
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Figure 3: Prepro-orexin knockout mice have lower blood pressures throughout the circadian cycle. The knockout mice have lower blood pressure in both the light and dark periods of the diurnal cycle relative to the wild type control mice. Filled circles: KO mice; crosses: WT mice. (Figure used with permission from Kayaba et al., 2003).

Mentions: Functional studies in vivo have demonstrated that orexin participates in blood pressure regulation. Transgenic orexin deficient animals, both prepro-orexin knockout (pp-OX KO) mice (Figure 3) and rats with orexin neurons-genetically ablated (orexin/ataxin-3), have lower resting blood pressure (Kayaba et al., 2003; Schwimmer et al., 2010) relative to their wild type controls. In both anesthetized and unanesthetized normotensive animals, central administration of OX-A or OX-B activates sympathetic activity and increases both arterial blood pressure (ABP) and HR (Samson et al., 1999; Shirasaka et al., 1999, 2002; Chen et al., 2000; Antunes et al., 2001; Matsumura et al., 2001; Machado et al., 2002; Shahid et al., 2011, 2012). In conscious rats and rabbits (Shirasaka et al., 1999; Matsumura et al., 2001; Samson et al., 2007) central administration (icv) of orexin increases ABP (Samson et al., 1999; Shirasaka et al., 1999; Matsumura et al., 2001), and SNA (Shirasaka et al., 1999; Matsumura et al., 2001) in a dose dependent manner, and the increased ABP, HR and SNA induced by orexin is accompanied by an increase in plasma catecholamines (Figure 4) (Shirasaka et al., 1999; Matsumura et al., 2001). Intravenous injection of a ganglionic-blocking agent, pentolinium, can abolish OX-A induced increases in ABP and plasma epinephrine concentrations, which suggests that the pressor response induced by the icv injection of orexin-A can be attributed primarily to enhanced sympathetic outflow (Matsumura et al., 2001). Focal injection of OX-A into the RVLM can also induce a significant increase in ABP and HR in both anesthetized (Chen et al., 2000; Shahid et al., 2012) and conscious (Machado et al., 2002) rats. In anesthetized rats, the increased ABP is accompanied by increased splanchnic SNA(sSNA) and ventilation (phrenic nerve activity) that can be attenuated by blocking OX1R (Shahid et al., 2012). The peak effects following OX-A injection into the RVLM were observed at a dose of 50 pmol with ~42 mmHg increase in ABP and 45% increase in SNA (Shahid et al., 2012).


Orexin, cardio-respiratory function, and hypertension.

Li A, Nattie E - Front Neurosci (2014)

Prepro-orexin knockout mice have lower blood pressures throughout the circadian cycle. The knockout mice have lower blood pressure in both the light and dark periods of the diurnal cycle relative to the wild type control mice. Filled circles: KO mice; crosses: WT mice. (Figure used with permission from Kayaba et al., 2003).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Prepro-orexin knockout mice have lower blood pressures throughout the circadian cycle. The knockout mice have lower blood pressure in both the light and dark periods of the diurnal cycle relative to the wild type control mice. Filled circles: KO mice; crosses: WT mice. (Figure used with permission from Kayaba et al., 2003).
Mentions: Functional studies in vivo have demonstrated that orexin participates in blood pressure regulation. Transgenic orexin deficient animals, both prepro-orexin knockout (pp-OX KO) mice (Figure 3) and rats with orexin neurons-genetically ablated (orexin/ataxin-3), have lower resting blood pressure (Kayaba et al., 2003; Schwimmer et al., 2010) relative to their wild type controls. In both anesthetized and unanesthetized normotensive animals, central administration of OX-A or OX-B activates sympathetic activity and increases both arterial blood pressure (ABP) and HR (Samson et al., 1999; Shirasaka et al., 1999, 2002; Chen et al., 2000; Antunes et al., 2001; Matsumura et al., 2001; Machado et al., 2002; Shahid et al., 2011, 2012). In conscious rats and rabbits (Shirasaka et al., 1999; Matsumura et al., 2001; Samson et al., 2007) central administration (icv) of orexin increases ABP (Samson et al., 1999; Shirasaka et al., 1999; Matsumura et al., 2001), and SNA (Shirasaka et al., 1999; Matsumura et al., 2001) in a dose dependent manner, and the increased ABP, HR and SNA induced by orexin is accompanied by an increase in plasma catecholamines (Figure 4) (Shirasaka et al., 1999; Matsumura et al., 2001). Intravenous injection of a ganglionic-blocking agent, pentolinium, can abolish OX-A induced increases in ABP and plasma epinephrine concentrations, which suggests that the pressor response induced by the icv injection of orexin-A can be attributed primarily to enhanced sympathetic outflow (Matsumura et al., 2001). Focal injection of OX-A into the RVLM can also induce a significant increase in ABP and HR in both anesthetized (Chen et al., 2000; Shahid et al., 2012) and conscious (Machado et al., 2002) rats. In anesthetized rats, the increased ABP is accompanied by increased splanchnic SNA(sSNA) and ventilation (phrenic nerve activity) that can be attenuated by blocking OX1R (Shahid et al., 2012). The peak effects following OX-A injection into the RVLM were observed at a dose of 50 pmol with ~42 mmHg increase in ABP and 45% increase in SNA (Shahid et al., 2012).

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