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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.


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In SHR, antagonism of OXRs with a systemic OXR antagonist, Almxt, decreases arterial pressure. One does of orally administered amlxt significantly decreased arterial pressure in SHR for ~8 h (A), and Almxt had no effect on arterial pressure in normotensive WKY rats (B). The largest decrease of BP after Almxt is in wakefulness during the dark period (−37 mmHg) and smallest change is in NREM sleep during the light period (−25 mmHg) relative to the pretreatment baseline (C). *P < 0.02 (Figure adapted with permission from Li et al., 2013a).
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Figure 6: In SHR, antagonism of OXRs with a systemic OXR antagonist, Almxt, decreases arterial pressure. One does of orally administered amlxt significantly decreased arterial pressure in SHR for ~8 h (A), and Almxt had no effect on arterial pressure in normotensive WKY rats (B). The largest decrease of BP after Almxt is in wakefulness during the dark period (−37 mmHg) and smallest change is in NREM sleep during the light period (−25 mmHg) relative to the pretreatment baseline (C). *P < 0.02 (Figure adapted with permission from Li et al., 2013a).

Mentions: The observations that: (a) orexin participates in the regulation of cardiovascular homeostasis, (b) exogenous orexins can increase SNA and blood pressure in normal animals, and (c) transgenic orexin deficient animals have lower resting blood pressure, have led two independent groups to test the hypothesis that orexin may participate in the development of neurogenic hypertension in spontaneously hypertensive rats (SHRs) (Lee et al., 2013; Li et al., 2013a). The SHR is one of the most studied animal models of neurogenic hypertension. As in human essential hypertension, the blood pressure of the SHR rises with age, starting at about 6 weeks, accompanied by an overactive sympathetic nervous system (Smith and Hutchins, 1979; Zicha and Kunes, 1999; Simms et al., 2009). We found (Li et al., 2013a,b) in unanesthetized freely moving adult SHRs that: (1) there is a strong trend toward a significant increase in orexin-A mRNA expression in the RVLM (Figure 5A), a projection site for orexinergic LHA neurons; (2) blocking both orexin receptors by oral administration of an antagonist, Almxt: (a) significantly lowers blood pressure in wakefulness and sleep during both the dark and light periods of the diurnal cycle, (b) the largest average decrease of ABP after blocking orexin receptors was in wakefulness during the dark period (−37 mmHg) and the smallest average change in NREM sleep during the light period (−25 mmHg) relative to the pretreatment baseline, (c) one dose of Almxt produced a remarkable and long-lasting (~8 h) reduction of ABP in SHRs (Figure 6); (3) the anti-hypertensive effect was accompanied by: (a) a significantly decreased SNA assessed by power spectral analysis of systolic ABP, and (b) decreased noradrenaline levels in cerebrospinal fluid and plasma (Figures 5B,C); (4) antagonizing orexin receptors had no effect on resting blood pressure in normotensive WKY rats (Figure 6B). Our findings are supported by a recent publication (Lee et al., 2013), which showed that blocking OX2R centrally by microinjection of an OX2R antagonist, TCS-OX2-29, into either the cerebral ventricle (icv) or the RVLM in anesthetized SHRs significantly decreased blood pressure (Figure 7) (Lee et al., 2013). The significant decrease in ABP following TCS-OX2-29 was observed at 3, 10, and 30 nmol doses, and the maximum reduction of ABP was ~21 or ~30 mmHg at 30 nmol with icv or RVLM injection respectively. It is important to note that in both studies antagonism of orexin receptor(s) with either Almxt or TCS-OX2-29 had no significant effect on ABP in conscious or anesthetized normotensive Wistar- Kyoto (WKY) control rats.


Orexin, cardio-respiratory function, and hypertension.

Li A, Nattie E - Front Neurosci (2014)

In SHR, antagonism of OXRs with a systemic OXR antagonist, Almxt, decreases arterial pressure. One does of orally administered amlxt significantly decreased arterial pressure in SHR for ~8 h (A), and Almxt had no effect on arterial pressure in normotensive WKY rats (B). The largest decrease of BP after Almxt is in wakefulness during the dark period (−37 mmHg) and smallest change is in NREM sleep during the light period (−25 mmHg) relative to the pretreatment baseline (C). *P < 0.02 (Figure adapted with permission from Li et al., 2013a).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 6: In SHR, antagonism of OXRs with a systemic OXR antagonist, Almxt, decreases arterial pressure. One does of orally administered amlxt significantly decreased arterial pressure in SHR for ~8 h (A), and Almxt had no effect on arterial pressure in normotensive WKY rats (B). The largest decrease of BP after Almxt is in wakefulness during the dark period (−37 mmHg) and smallest change is in NREM sleep during the light period (−25 mmHg) relative to the pretreatment baseline (C). *P < 0.02 (Figure adapted with permission from Li et al., 2013a).
Mentions: The observations that: (a) orexin participates in the regulation of cardiovascular homeostasis, (b) exogenous orexins can increase SNA and blood pressure in normal animals, and (c) transgenic orexin deficient animals have lower resting blood pressure, have led two independent groups to test the hypothesis that orexin may participate in the development of neurogenic hypertension in spontaneously hypertensive rats (SHRs) (Lee et al., 2013; Li et al., 2013a). The SHR is one of the most studied animal models of neurogenic hypertension. As in human essential hypertension, the blood pressure of the SHR rises with age, starting at about 6 weeks, accompanied by an overactive sympathetic nervous system (Smith and Hutchins, 1979; Zicha and Kunes, 1999; Simms et al., 2009). We found (Li et al., 2013a,b) in unanesthetized freely moving adult SHRs that: (1) there is a strong trend toward a significant increase in orexin-A mRNA expression in the RVLM (Figure 5A), a projection site for orexinergic LHA neurons; (2) blocking both orexin receptors by oral administration of an antagonist, Almxt: (a) significantly lowers blood pressure in wakefulness and sleep during both the dark and light periods of the diurnal cycle, (b) the largest average decrease of ABP after blocking orexin receptors was in wakefulness during the dark period (−37 mmHg) and the smallest average change in NREM sleep during the light period (−25 mmHg) relative to the pretreatment baseline, (c) one dose of Almxt produced a remarkable and long-lasting (~8 h) reduction of ABP in SHRs (Figure 6); (3) the anti-hypertensive effect was accompanied by: (a) a significantly decreased SNA assessed by power spectral analysis of systolic ABP, and (b) decreased noradrenaline levels in cerebrospinal fluid and plasma (Figures 5B,C); (4) antagonizing orexin receptors had no effect on resting blood pressure in normotensive WKY rats (Figure 6B). Our findings are supported by a recent publication (Lee et al., 2013), which showed that blocking OX2R centrally by microinjection of an OX2R antagonist, TCS-OX2-29, into either the cerebral ventricle (icv) or the RVLM in anesthetized SHRs significantly decreased blood pressure (Figure 7) (Lee et al., 2013). The significant decrease in ABP following TCS-OX2-29 was observed at 3, 10, and 30 nmol doses, and the maximum reduction of ABP was ~21 or ~30 mmHg at 30 nmol with icv or RVLM injection respectively. It is important to note that in both studies antagonism of orexin receptor(s) with either Almxt or TCS-OX2-29 had no significant effect on ABP in conscious or anesthetized normotensive Wistar- Kyoto (WKY) control rats.

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