Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

Kim, Seung Jae; Pilowsky, Paul M.; Farnham, Melissa M.J.

doi:10.1124/jpet.116.234443

Cited by 6 publications

(10 citation statements)

References 65 publications

(77 reference statements)

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“…Also, activation of spinal orexin receptors is critical for enhancing chemoreflex phrenic responses to hypoxia after AIH (Kim et al . ).…”

Section: Discussionmentioning

confidence: 97%

“…This is reminiscent of the role of 5-HT and adenosine receptors in the maintenance of phrenic LTF, for which 5-HT and/or adenosine receptor activation is necessary to initiate but not maintain phrenic LTF following episodic hypoxia (Fuller et al 2001;Fields & Mitchell, 2015). Also, activation of spinal orexin receptors is critical for enhancing chemoreflex phrenic responses to hypoxia after AIH (Kim et al 2016b).…”

Section: Role Of Hypercapnia In Sensory Ltf In the Naïve Cbmentioning

confidence: 98%

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Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

Roy

Farnham

Derakhshan

et al. 2018

The Journal of Physiology

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Apnoeas constitute an acute existential threat to neonates and adults. In large part, this threat is detected by the carotid bodies, which are the primary peripheral chemoreceptors, and is combatted by arousal and acute cardiorespiratory responses, including increased sympathetic output. Similar responses occur with repeated apnoeas but they continue beyond the last apnoea and can persist for hours [i.e. ventilatory and sympathetic long-term facilitation (LTF)]. These long-term effects may be adaptive during acute episodic apnoea, although they may prolong hypertension causing chronic cardiovascular impairment. We report a novel mechanism of acute carotid body (CB) plasticity (sensory LTF) induced by repeated apnoea-like stimuli [i.e. acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc)]. This plasticity did not require chronic intermittent hypoxia preconditioning, was dependent on P2X receptors and protein kinase C, and involved heat-sensitive transient receptor potential vanilloid type 1 (TRPV1) receptors. Reactive oxygen species (O ·¯) were involved in initiating plasticity only; no evidence was found for H O involvement. Angiotensin II and 5-HT receptor antagonists, losartan and ketanserin, severely reduced CB responses to individual hypoxic-hypercapnic challenges and prevented the induction of sensory LTF but, if applied after AIH-Hc, failed to reduce plasticity-associated activity. Conversely, TRPV1 receptor antagonism had no effect on responses to individual hypoxic-hypercapnic challenges but reduced plasticity-associated activity by ∼50%. Further, TRPV1 receptor antagonism in vivo reduced sympathetic LTF caused by AIH-Hc, although only if the CBs were functional. These data demonstrate a new mechanism of CB plasticity and suggest P2X-TRPV1-dependent sensory LTF as a novel target for pharmacological intervention in some forms of neurogenic hypertension associated with recurrent apnoeas.

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“…Also, activation of spinal orexin receptors is critical for enhancing chemoreflex phrenic responses to hypoxia after AIH (Kim et al . ).…”

Section: Discussionmentioning

confidence: 97%

Section: Role Of Hypercapnia In Sensory Ltf In the Naïve Cbmentioning

confidence: 98%

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

Roy

Farnham

Derakhshan

et al. 2018

The Journal of Physiology

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“…Furthermore, several neuropeptides may contribute to the sympathetic effects of AIH, such as orexin (Kim et al . 2016b), serotonin (Dick et al . ; Bautista et al .…”

Section: Discussionmentioning

confidence: 99%

“…The protocol for AIH was adopted from previous studies (Xing & Pilowsky, ; Kim et al . 2016b). Rats were subjected to 10 cycles of hypoxia lasting 45 s with 5 min of recovery between hypoxia cycles breathing 100% oxygen.…”

Section: Methodsmentioning

confidence: 99%

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Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

Kim

Fong

Pilowsky

et al. 2018

The Journal of Physiology

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Circulating angiotensin II (Ang II) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the renin-angiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.7 ± 2.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympathetic-respiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of Ang II (Int.Ang II) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.Ang II, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating Ang II, reduced the increase in SNA following AIH and Int.Ang II by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympathetic-respiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.Ang II. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO.

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Orexin-A promotes Glu uptake by OX1R/PKCα/ERK1/2/GLT-1 pathway in astrocytes and protects co-cultured astrocytes and neurons against apoptosis in anoxia/hypoglycemic injury in vitro

Shu¹,

Zhang²,

Ma³

et al. 2016

Mol Cell Biochem

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Orexin-A, which is an endogenous neuropeptide, is reported to have a protective role in ischemic stroke. High-concentration glutamic acid (Glu) induced by hypoxia injury in ischemic stroke can be inhibited by glial glutamate transporter GLT-1 which is only expressed in astroglia cells. A previous study reported that Orexin-A may regulate GLT-1 expression. However, the role of orexin-A in the regulation of GLT-1 in ischemic stroke still remains unclear. In this study, we aimed to investigate the effect and the underlying mechanism of orexin-A on Glu uptake in astrocytes in vitro and this effect on protecting the neurons from anoxia/hypoglycemic injury. The expression of GLT-1 significantly increased in the astrocytes with orexin-A treatment under anoxia/hypoglycemic conditions, promoting the uptake of Glu and inhibiting the apoptosis of co-cultured cells of astrocytes and neurons. However, these effects were significantly weakened by treatment with orexin-A receptor 1 (OX1R) antagonist. Orexin-A significantly up-regulated the expressions of PKCα and ERK1/2 under anoxia/hypoglycemic conditions in astrocytes, whereas the OX1R antagonist markedly reversed the effect. Furthermore, PKCα or ERK1/2 inhibitor significantly constrained the GLT-1 expression in astrocytes and facilitated the apoptosis of co-cultured cells, and GLT-1 overexpression could reverse those effects of PKCα or ERK1/2 inhibitor. Taken together, orexin-A promoted the GLT-1 expression via OX1R/PKCα/ERK1/2 pathway in astrocytes and protected co-cultured cells against anoxia/hypoglycemic injury.

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Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats

Cited by 6 publications

References 65 publications

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor‐dependent sensory long‐term facilitation in naïve carotid bodies

Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

Orexin-A promotes Glu uptake by OX1R/PKCα/ERK1/2/GLT-1 pathway in astrocytes and protects co-cultured astrocytes and neurons against apoptosis in anoxia/hypoglycemic injury in vitro

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