Neural Control of Blood Pressure in Chronic Intermittent Hypoxia

Shell, Brent; Faulk, Katelynn; Cunningham, J. Thomas

doi:10.1007/s11906-016-0627-8

Cited by 50 publications

(61 citation statements)

References 83 publications

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“…Hypoxia activates PVN‐projecting adrenergic neurones, particularly those in the nTS, and NE increases PVN excitation . PVN over‐activity, including that caused by long‐term hypoxic exposure such as with obstructive sleep apnoea, correlates with negative health outcomes such as hypertension, heart failure and stroke .…”

Section: Discussionmentioning

confidence: 99%

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

Milanick

Polo‐Parada

Dantzler

et al. 2019

J Neuroendocrinology

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Norepinephrine (NE) activates adrenergic receptors (ARs) in the hypothalamic paraventricular nucleus (PVN) to increase excitatory currents, depolarise neurones and, ultimately, augment neuro‐sympathetic and endocrine output. Such cellular events are known to potentiate intracellular calcium ([Ca2+]i); however, the role of NE with respect to modulating [Ca2+]i in PVN neurones and the mechanisms by which this may occur remain unclear. We evaluated the effects of NE on [Ca2+]i of acutely isolated PVN neurones using Fura‐2 imaging. NE induced a slow increase in [Ca2+]i compared to artificial cerebrospinal fluid vehicle. NE‐induced Ca2+ elevations were mimicked by the α1‐AR agonist phenylephrine (PE) but not by α2‐AR agonist clonidine (CLON). NE and PE but not CLON also increased the overall number of neurones that increase [Ca2+]i (ie, responders). Elimination of extracellular Ca2+ or intracellular endoplasmic reticulum Ca2+ stores abolished the increase in [Ca2+]i and reduced responders. Blockade of voltage‐dependent Ca2+ channels abolished the α1‐AR induced increase in [Ca2+]i and number of responders, as did inhibition of phospholipase C inhibitor, protein kinase C and inositol triphosphate receptors. Spontaneous phasic Ca2+ events, however, were not altered by NE, PE or CLON. Repeated K+‐induced membrane depolarisation produced repetitive [Ca2+]i elevations. NE and PE increased baseline Ca2+, whereas NE decreased the peak amplitude. CLON also decreased peak amplitude but did not affect baseline [Ca2+]i. Taken together, these data suggest receptor‐specific influence of α1 and α2 receptors on the various modes of calcium entry in PVN neurones. They further suggest Ca2+ increase via α1‐ARs is co‐dependent on extracellular Ca2+ influx and intracellular Ca2+ release, possibly via a phospholipase C inhibitor‐mediated signalling cascade.

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Section: Discussionmentioning

confidence: 99%

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

Milanick

Polo‐Parada

Dantzler

et al. 2019

J Neuroendocrinology

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“…The role of angiotensinergic activation in the PVN and systemic circulation has long been described in the cause and progression of hypertension in humans and rodent experimental models alike (Shell et al . ; Takesue et al . ,b).…”

Section: Discussionmentioning

confidence: 99%

“…; Shell et al . ). Projections from the paraventricular hypothalamic nuclei (PVN) to the nucleus of solitary tract and rostral ventrolateral medulla (RVLM) constitutes the pre‐autonomic sympathetic system which in turn projects to the intermediolateral grey column to reach the cardiac sympathetic plexus (Affleck et al .…”

mentioning

confidence: 97%

Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

Ogundele

Lee

Francis

2016

Journal of Neurochemistry

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Modifications to neural circuits of the paraventricular hypothalamic nucleus (PVN) have been implicated in sympathoexcitation and systemic cardiovascular dysfunction. However, to date, the role of insulin-like growth factor 1 receptor (IGF-1R) expression on PVN pathophysiology is unknown. Using confocal immunofluorescence quantification and electrophysiological recordings from acute PVN slices, we investigated the mechanism through which age-dependent IGF-1R depletion contributes to the progression of inflammation and sympathoexcitation in the PVN of spontaneously hypertensive rats (SHR). Four and twenty weeks old SHR and Wistar Kyoto (WKY) rats were used for this study. Our data showed that Angiotensin I/II and pro-inflammatory high mobility box group protein 1 (HMGB1) exhibited increased expression in the PVN of SHR versus WKY at 4 weeks (p<0.01), and were even more highly expressed with age in SHR (p<0.001). This correlated with a significant decrease in IGF-1R expression, with age, in the PVN of SHR when compared with WKY (p<0.001) and were accompanied by related changes in astrocytes and microglia. In subsequent analyses, we found an age-dependent change in the expression of proteins associated with IGF-1R signaling pathways involved in inflammatory responses and synaptic function in the PVN. MAPK/ErK was more highly expressed in the PVN of SHR by the 4th week (p<0.001; vs WKY), while expression of neuronal nitric oxide synthase (nNOS; p<0.001) and calcium-calmodulin dependent kinase II alpha (CamKIIα; p<0.001) were significantly decreased by the 4th and 20th week respectively. Age-dependent changes in MAPK/ErK expression in the PVN correlated with an increase in the expression of vesicular glutamate transporter (VGLUT2) (p<0.001 vs WKY), while decreased levels of CamKIIα was associated with a decreased expression of tyrosine hydroxylase (p<0.001) by the 20th week. In addition, reduced labeling for GABA in the PVN of SHR (p<0.001) correlated with a decrease in nNOS labeling (p<0.001) when compared with the WKY by the 20th week. Electrophysiological recordings from neurons in acute slice preparations of the PVN of 4 weeks old SHR revealed spontaneous post-synaptic currents of higher frequency when compared with neurons from WKY PNV slices of the same age (p<0.001; n=14 cells). This also correlated with an increase in post-synaptic densities (PSD-95) in the PVN of SHR when compared with the WKY (p<0.001). Overall, we found an age-dependent reduction of IGF-1R, and related altered expression of associated downstream signaling molecules that may represent a link between the concurrent progression of synaptic dysfunction and inflammation in the PVN of SHR.

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“…Experimental data suggest that peripheral renin–angiotensin system (RAS) activation and circulating angiotensin II (Ang II) contribute to hypertension in CIH‐treated rodents (Shell et al . ). For example, plasma renin is elevated in CIH‐treated rats (Fletcher et al .…”

Section: Introductionmentioning

confidence: 97%

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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Neural Control of Blood Pressure in Chronic Intermittent Hypoxia

Cited by 50 publications

References 83 publications

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

Activation of alpha‐1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus

Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

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

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