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Background and Aims: There is a lack of basic science data on the effect of dexmedetomidine on the hypoxic chemosensory reflex with both depression and stimulation suggested. The primary aim of this study was to assess if dexmedetomidine inhibited the cellular response to hypoxia in rat carotid body glomus cells, the cells of the organs mediating acute hypoxic ventilatory response (AHVR). Additionally, we used a small sample of mice to assess if there was any large influence of subsedative doses of dexmedetomidine on AHVR., Material and Methods: In the primary study, glomus cells isolated from neonatal rats were used to study the effect of 0.1 nM ( n = 9) and 1 nM ( n = 13) dexmedetomidine on hypoxia-elicited intracellular calcium [Ca 2% ]i influx using ratiometric fluorimetry. Secondarily, whole animal unrestrained plethysmography was used to study AHVR in a total of 8 age-matched C57BL6 mice, divided on successive days into two groups of four mice randomly assigned to receive sub-sedative doses of 5, 50, or 500 μg.kg -1 dexmedetomidine versus control in a crossover study design (total n = 12 exposures to drug with n = 12 controls)., Results: There was no effect of dexmedetomidine on the hypoxia-elicited increase in [Ca 2% ]i in glomus cells (a mean ± SEM increase of 95 ± 32 nM from baseline with control hypoxia, 124 ± 41 nM with 0.1 nM dexmedetomidine; P = 0.514). In intact mice, dexmedetomidine had no effect on baseline ventilation during air-breathing (4.01 ± 0.3 ml.g -1 .min -1 in control and 2.99 ± 0.5 ml.g -1 .min -1 with 500 μg.kg -1 dexmedetomidine, the highest dose; P = 0.081) or on AHVR (136 ± 19% increase from baseline in control, 152 ± 46% with 500 μg.kg -1 dexmedetomidine, the highest dose; P = 0.536)., Conclusion: Dexmedetomidine had no effect on the cellular responses to hypoxia. We conclude that it unlikely acts via inhibition of oxygen sensing at the glomus cell. The respiratory chemoreflex effects of this drug remain an open question. In our small sample of intact mice, hypoxic chemoreflex responses and basal breathing were preserved., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Anaesthesiology Clinical Pharmacology.)

Background: The degree to which different volatile anesthetics depress carotid body hypoxic response relates to their ability to activate TASK potassium channels. Most commonly, volatile anesthetic pairs act additively at their molecular targets. We examined whether this applied to carotid body TASK channels., Methods: We studied halothane and isoflurane effects on hypoxia-evoked rise in intracellular calcium (Ca2+i, using the indicator Indo-1) in isolated neonatal rat glomus cells, and TASK single-channel activity (patch clamping) in native glomus cells and HEK293 cell line cells transiently expressing TASK-1., Results: Halothane (5%) depressed glomus cell Ca2+i hypoxic response (mean ± SD, 94 ± 4% depression; P < 0.001 vs. control). Isoflurane (5%) had a less pronounced effect (53 ± 10% depression; P < 0.001 vs. halothane). A mix of 3% isoflurane/1.5% halothane depressed cell Ca2+i response (51 ± 17% depression) to a lesser degree than 1.5% halothane alone (79 ± 15%; P = 0.001), but similar to 3% isoflurane alone (44 ± 22%; P = 0.224), indicating subadditivity. Halothane and isoflurane increased glomus cell TASK-1/TASK-3 activity, but mixes had a lesser effect than that seen with halothane alone: 4% halothane/4% isoflurane yielded channel open probabilities 127 ± 55% above control, versus 226 ± 12% for 4% halothane alone (P = 0.009). Finally, in HEK293 cell line cells, progressively adding isoflurane (1.5 to 5%) to halothane (2.5%) reduced TASK-1 channel activity from 120 ± 38% above control, to 88 ± 48% (P = 0.034)., Conclusions: In all three experimental models, the effects of isoflurane and halothane combinations were quantitatively consistent with the modeling of weak and strong agonists competing at a common receptor on the TASK channel., (Copyright © 2020, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

In humans the intravenous anaesthetic propofol depresses ventilatory responses to hypoxia and CO 2 . Animal studies suggest that this may in part be due to inhibition of synaptic transmission between chemoreceptor glomus cells of the carotid body and the afferent carotid sinus nerve. It is however unknown if propofol can also act directly on the glomus cell. Here we report that propofol can indeed inhibit intracellular Ca 2+ responses to hypoxia and hypercapnia in isolated rat glomus cells. Neither this propofol effect, nor the glomus cell response to hypoxia in the absence of propofol, were influenced by GABA receptor activation (using GABA, muscimol and baclofen) or inhibition (using bicuculline and 5-aminovaleric acid). Suggesting that these effects of propofol are not mediated through GABA receptors. Propofol inhibited calcium responses to nicotine in glomus cells but the nicotinic antagonists vecuronium and methyllycaconitine did not inhibit calcium responses to hypoxia. TASK channel activity was not altered by propofol. The glomus cell Ca 2+ response to depolarisation with 30 mM K + was however modestly inhibited by propofol. In summary we conclude that propofol does have a direct effect upon hypoxia signalling in isolated type-1 cells and that this may be partially due to its ability to inhibit voltage gated Ca 2+ v channels. We also note that propofol has the capacity to supress glomus cell excitation via nicotinic receptors and may therefore also interfere with paracrine/autocrine cholinergic signalling in the intact organ. The effects of propofol on chemoreceptor function are however clearly complex and require further investigation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BK C a ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca 2+ ] i -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell [Ca 2+ ] i . These [Ca 2+ ] i responses were abolished in Ca 2+ -free solution and greatly attenuated by Ni 2+ (2 mM) suggesting that depolarization and voltage-gated Ca 2+ -entry mediated the rise in [Ca 2+ ] i. Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca 2+ ] i. . We also tested the effects of combined inhibition of BK C a and TASK channels. TEA (5 mmol/L) slightly increased [Ca 2+ ] i in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca 2+ ] i in the presence of A1899 but not in the presence of PK-THPP. In general [Ca 2+ ] i responses to TASK inhibitors, alone or in combination with BK C a inhibitors, were smaller than the [Ca 2+ ] i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca 2+ -entry but suggest that this, even with concomitant inhibition of BK C a channels, may be insufficient to account fully for the [Ca 2+ ] i -response to hypoxia., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Ketonuria (on standard urine testing) is a frequent finding in children presenting to emergency departments. With the advent of hand-held ketone meters, blood ketone levels can now be rapidly quantified., Hypothesis: Point of care testing (POCT) of blood ketone levels could provide clinically useful information on severity of illness in children and risk of hospital admission., Methods: A prospective study using POCT of blood ketone levels in a convenience sample of children <13 years old, with a typical case mix of medical problems., Findings: 186 children were studied. The range of ketone levels varied widely among this study population depending on the presenting complaint. Higher levels were noted in those presenting with anorexia or vomiting and fever. The median ketone level of the total study population was 0.2 (range 0-6.0, interquartile range 0.1-0.9) mmol/l. Ketone levels correlated poorly with discharge destination and duration of admission. However, receiver-operator characteristics for ketones as a predictor of admission were comparable to Pediatric Risk of Admission scores (area under the curve 0.64 and 0.72, respectively) and may represent an independent risk factor for admission. A ketone level >1.2 mmol/l has a positive predictive value of 66.7% for admission. Ketone levels correlated well with decreased oral intake (R2 = 0.25; p<0.001)., Conclusions: A strong association was found between ketone levels, decreased oral intake and fever. Although ketone levels do not correlate well with more traditional markers of illness severity, they can help to predict the requirement for admission to hospital when interpreted in the context of the presenting illness. They may have applications in both the emergency department and primary care settings. Further prospective testing is required to validate these findings.