CrossTalk proposal: a central hypoxia sensor contributes to the excitatory hypoxic ventilatory response

Funk, Gregory D.; Gourine, Alexander V.

doi:10.1113/jp275707

Cited by 19 publications

(28 citation statements)

References 29 publications

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“…Both Kir5.1 2/2 mice (21) and SS Kcnj162/2 rats also exhibit reduced responses to hypoxia. This is an intriguing result given that Kir5.1-containing Kir channels have not been implicated in hypoxia-sensing mechanisms within the glomus cells of the carotid bodies or the recently proposed astrocytemediated hypoxia-sensing mechanisms in the brain (31)(32)(33). However, Kir5.1 expression has been detected in the carotid bodies (34) and brainstem astrocytes and glia (6,9), and both have known pH sensitivity (10,35).…”

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confidence: 95%

Genetic mutation of Kcnj16 identifies Kir5.1‐containing channels as key regulators of acute and chronic pH homeostasis

et al. 2019

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Acute and chronic homeostatic pH regulation is critical for the maintenance of optimal cellular function. Renal mechanisms dominate global pH regulation over longer time frames, and rapid adjustments in ventilation compensate for acute pH and CO2 changes. Ventilatory CO2 and pH chemoreflexes are primarily determined by brain chemoreceptors with intrinsic pH sensitivity likely driven by K+ channels. Here, we studied acute and chronic pH regulation in Kcnj 16 mutant Dahl salt‐sensitive (SSKcnj16−/−) rats; Kcnj16 encodes the pH‐sensitive inwardly rectifying K+ 5.1 (Kir5.1) channel. SSKcnj16−/− rats hyperventilated at rest, likely compensating for a chronic metabolic acidosis. Despite their resting hyperventilation, SSKcnj16−/−) rats showed up to 45% reduction in the ventilatory response to graded hypercapnic acidosis vs. controls. SSKcnj16−/− rats chronically treated with bicarbonate or the carbonic anhydrase inhibitor hydrochlorothiazide had partial restoration of arterial pH, but there was a further reduction in the ventilatory response to hypercapnic acidosis. SSKcnj16−/− rats also had a nearly absent hypoxic ventilatory response, suggesting major contributions of Kir5.1 to O2‐ and CO2‐dependent chemoreflexes. Although previous studies demonstrated beneficial effects of a high‐K+ diet (HKD) on cardiorenal phenotypes in SSKcnj16−/− rats, HKD failed to restore the observed ventilatory phenotypes. We conclude that Kir5.1 is a key regulator of renal H+ handling and essential for acute and chronic regulation of arterial pH as determinants of the ventilatory CO2 chemoreflex.—Puissant, M. M., Muere, C.., Levchenko, V., Manis, A. D., Martino, P., Forster, H. V., Palygin, O., Staruschenko, A., Hodges, M. R. Genetic mutation of Kcnj16 identifies Kir5.1‐containing channels as key regulators of acute and chronic pH homeostasis. FASEB J. 33, 5067–5075 (2019). http://www.fasebj.org

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confidence: 95%

Genetic mutation of Kcnj16 identifies Kir5.1‐containing channels as key regulators of acute and chronic pH homeostasis

et al. 2019

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“…Second, CB denervation studies are historically important, but, as discussed at length from both sides (Gourine & Funk, ; Funk & Gourine, ; Teppema, ), unlikely to ever be conclusive. Thus, the focus of our colleague on data from anaesthetized or conscious peripherally chemodenervated animals (Gourine et al .…”

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Rebuttal from Gregory D. Funk and Alexander V. Gourine

Funk

Gourine

2018

The Journal of Physiology

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“…In contrast to Funk and Gourine (2018), I do not consider the literature concerning the HVR after carotid body denervation (CBD) confusing. The small stimulation that is sometimes observed has a time profile indicating a peripheral, not central, origin, likely the aortic bodies (Swanson et al 1978;Honda et al 1979).…”

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“…In the view of this author, it is confusing to state that the only CNS contribution to the isocapnic HVR is depression of ventilation (Funk & Gourine, 2018). The term decline may be preferred over depression (hypoxic ventilatory decline; HVD; Teppema & Dahan, 2010).…”

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“…While carotid body stimulation does not influence CBF, there is also no evidence for a CB role in the hypoxaemia-induced cerebral vasodilatation (Heistad et al 1976;Myabe et al 1989;Awar et al 1990), so in this respect a confounding effect of CBD is minimal. Rather than ascribing the maintenance of ventilation during hypoxia in CBD patients to a central stimulation (Funk & Gourine, 2018), it may be preferable to circumscribe it as resulting from an absence of both an increased CB activity and HVD. Due to the abolishment of a peripheral-central interaction and the known decrease in central CO 2 sensitivity, hypoxia in these patients results in only a limited change (if any, but sometimes decrease) in ventilation despite an intact CBF response.…”

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confidence: 99%

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