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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 SHR, carotid body denervation decreases blood pressure, respiratory frequency and sympathetic nerve activity. Bilateral denervation of carotid sinus nerves (CSD) significantly decrease resting blood pressure, respiratory frequency (RR; transiently) and a SNA index (SBP LF) in SHRs. Systolic pressure decreased over 5–10 days to reach a plateau of −17 ± 3 mmHg (n = 10, P < 0.05). Mean arterial and diastolic pressures fell by −15 ± 2 (P < 0.05) and −17 ± 2 (P < 0.05) mmHg, respectively. Lowered arterial pressure was maintained with no sign of recovery for at least 3 weeks. SBP LF: Systolic blood pressure, low frequency band. (Figure used with permission from Abdala et al., 2012). #Significant difference (P < 0.05).
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Figure 13: In SHR, carotid body denervation decreases blood pressure, respiratory frequency and sympathetic nerve activity. Bilateral denervation of carotid sinus nerves (CSD) significantly decrease resting blood pressure, respiratory frequency (RR; transiently) and a SNA index (SBP LF) in SHRs. Systolic pressure decreased over 5–10 days to reach a plateau of −17 ± 3 mmHg (n = 10, P < 0.05). Mean arterial and diastolic pressures fell by −15 ± 2 (P < 0.05) and −17 ± 2 (P < 0.05) mmHg, respectively. Lowered arterial pressure was maintained with no sign of recovery for at least 3 weeks. SBP LF: Systolic blood pressure, low frequency band. (Figure used with permission from Abdala et al., 2012). #Significant difference (P < 0.05).

Mentions: A link between neurogenic hypertension and an enhanced carotid body chemoreflex has been more extensively studied in patients and in animal models of sleep apnea (Fletcher et al., 1992; Lesske et al., 1997; Fletcher, 2001; Prabhakar et al., 2001, 2005, 2012; Schultz et al., 2007; Simms et al., 2010; Zoccal and Machado, 2011; Costa-Silva et al., 2012; Moraes et al., 2012a,b; Paton et al., 2013). The peripheral chemoreceptor reflex response has been shown to be significantly enhanced in patients with primary hypertension (Trzebski et al., 1982; Tafil-Klawe et al., 1985a,b; Somers et al., 1988a,b; Sinski et al., 2012) and in animal models of systemic hypertension, e.g., SHRs (Fukuda et al., 1987; Simms et al., 2009; Tan et al., 2010). Rats exposed to chronic intermittent hypoxia (CIH) develop hypertension and persistent sympathetic activation, and elimination of the carotid bodies prevents such CIH-induced hypertension (Fletcher et al., 1992; Lesske et al., 1997). Enhanced carotid body activity has been suggested to result in alterations in respiratory–sympathetic coupling (Simms et al., 2009; Zoccal et al., 2009b) and increased muscle vasoconstrictor activity, which may contribute to the development of hypertension (Trzebski et al., 1982; Somers et al., 1988a). The hyperactive carotid chemoreceptors are accompanied by overexpression of ASIC/TASK (acid-sensing ion channel/2-pore domain acid-sensing K+ channel) channels in young pre-hypertensive SHRs (Tan et al., 2010). Abdala et al., further showed that bilateral denervation of the carotid sinus nerves (CSD) in SHRs can significantly lower the resting blood pressure (~25 mmHg), respiratory frequency (transiently) and the low frequency component of the frequency analysis of systolic blood pressure, an index of sympathetic vasomotor tone (Figure 13), and they suggested that the inputs of carotid sinus nerve from the carotid body are partially responsible for increased SNA and blood pressure in SHR (Abdala et al., 2012).


Orexin, cardio-respiratory function, and hypertension.

Li A, Nattie E - Front Neurosci (2014)

In SHR, carotid body denervation decreases blood pressure, respiratory frequency and sympathetic nerve activity. Bilateral denervation of carotid sinus nerves (CSD) significantly decrease resting blood pressure, respiratory frequency (RR; transiently) and a SNA index (SBP LF) in SHRs. Systolic pressure decreased over 5–10 days to reach a plateau of −17 ± 3 mmHg (n = 10, P < 0.05). Mean arterial and diastolic pressures fell by −15 ± 2 (P < 0.05) and −17 ± 2 (P < 0.05) mmHg, respectively. Lowered arterial pressure was maintained with no sign of recovery for at least 3 weeks. SBP LF: Systolic blood pressure, low frequency band. (Figure used with permission from Abdala et al., 2012). #Significant difference (P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 13: In SHR, carotid body denervation decreases blood pressure, respiratory frequency and sympathetic nerve activity. Bilateral denervation of carotid sinus nerves (CSD) significantly decrease resting blood pressure, respiratory frequency (RR; transiently) and a SNA index (SBP LF) in SHRs. Systolic pressure decreased over 5–10 days to reach a plateau of −17 ± 3 mmHg (n = 10, P < 0.05). Mean arterial and diastolic pressures fell by −15 ± 2 (P < 0.05) and −17 ± 2 (P < 0.05) mmHg, respectively. Lowered arterial pressure was maintained with no sign of recovery for at least 3 weeks. SBP LF: Systolic blood pressure, low frequency band. (Figure used with permission from Abdala et al., 2012). #Significant difference (P < 0.05).
Mentions: A link between neurogenic hypertension and an enhanced carotid body chemoreflex has been more extensively studied in patients and in animal models of sleep apnea (Fletcher et al., 1992; Lesske et al., 1997; Fletcher, 2001; Prabhakar et al., 2001, 2005, 2012; Schultz et al., 2007; Simms et al., 2010; Zoccal and Machado, 2011; Costa-Silva et al., 2012; Moraes et al., 2012a,b; Paton et al., 2013). The peripheral chemoreceptor reflex response has been shown to be significantly enhanced in patients with primary hypertension (Trzebski et al., 1982; Tafil-Klawe et al., 1985a,b; Somers et al., 1988a,b; Sinski et al., 2012) and in animal models of systemic hypertension, e.g., SHRs (Fukuda et al., 1987; Simms et al., 2009; Tan et al., 2010). Rats exposed to chronic intermittent hypoxia (CIH) develop hypertension and persistent sympathetic activation, and elimination of the carotid bodies prevents such CIH-induced hypertension (Fletcher et al., 1992; Lesske et al., 1997). Enhanced carotid body activity has been suggested to result in alterations in respiratory–sympathetic coupling (Simms et al., 2009; Zoccal et al., 2009b) and increased muscle vasoconstrictor activity, which may contribute to the development of hypertension (Trzebski et al., 1982; Somers et al., 1988a). The hyperactive carotid chemoreceptors are accompanied by overexpression of ASIC/TASK (acid-sensing ion channel/2-pore domain acid-sensing K+ channel) channels in young pre-hypertensive SHRs (Tan et al., 2010). Abdala et al., further showed that bilateral denervation of the carotid sinus nerves (CSD) in SHRs can significantly lower the resting blood pressure (~25 mmHg), respiratory frequency (transiently) and the low frequency component of the frequency analysis of systolic blood pressure, an index of sympathetic vasomotor tone (Figure 13), and they suggested that the inputs of carotid sinus nerve from the carotid body are partially responsible for increased SNA and blood pressure in SHR (Abdala 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