Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response

There is considerable interindividual variation in ventilatory response to hypoxia in humans but the mechanism remains unknown. To examine the potential contribution of variable peripheral chemorecptor function to variation in hypoxic ventilatory response (HVR), we compared the peripheral chemoreceptor and ventilatory response to hypoxia in 51 anesthetized cats. We found large interindividual differences in HVR spanning a sevenfold range. In 23 cats studied on two separate days, ventilatory measurements were correlated (r = 0.54, P less than 0.01), suggesting stable interindividual differences. Measurements during wakefulness and in anesthesia in nine cats showed that although anesthesia lowered the absolute HVR it had no influence on the range or the rank of the magnitude of the response of individuals in the group. We observed a positive correlation between ventilatory and carotid sinus nerve (CSN) responses to hypoxia measured during anesthesia in 51 cats (r = 0.63, P less than 0.001). To assess the translation of peripheral chemoreceptor activity into expiratory minute ventilation (VE) we used an index relating the increase of VE to the increase of CSN activity for a given hypoxic stimulus (delta VE/delta CSN). Comparison of this index for cats with lowest (n = 5, HVR A = 7.0 +/- 0.8) and cats with highest (n = 5, HVR A = 53.2 +/- 4.9) ventilatory responses showed similar efficiency of central translation (0.72 +/- 0.06 and 0.70 +/- 0.08, respectively). These results indicate that interindividual variation in HVR is associated with comparable variation in hypoxic sensitivity of carotid bodies. Thus differences in peripheral chemoreceptor sensitivity may contribute to interindividual variability of HVR.

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Ventilatory Response to Hypoxia in Humans

Anesthesiology ◽

10.1097/00000542-199607000-00009 ◽

1996 ◽

Vol 85 (1) ◽

pp. 60-68 ◽

Cited By ~ 34

Author(s):

Albert Dahan ◽

Elise Sarton ◽

Maarten van den Elsen ◽

Jack van Kleef ◽

Luc Teppema ◽

...

Keyword(s):

Carbon Dioxide ◽

Partial Pressure ◽

Ventilatory Response ◽

Minute Ventilation ◽

Carbon Dioxide Concentration ◽

Detectable Effect ◽

Hypoxic Ventilatory Response ◽

Anesthetic Agents ◽

Carotid Bodies ◽

End Tidal

Background At low dose, the halogenated anesthetic agents halothane, isoflurane, and enflurane depress the ventilatory response to isocapnic hypoxia in humans. In the current study, the influence of subanesthetic desflurane (0.1 minimum alveolar concentration [MAC]) on the isocapnic hypoxic ventilatory response was assessed in healthy volunteers during normocapnia and hypercapnia. Methods A single hypoxic ventilatory response was obtained at each of 4 target end-tidal partial pressure of oxygen concentrations: 75, 53, 44, and 38 mmHg, before and during 0.1 MAC desflurane administration. Fourteen subjects were tested at a normal end-tidal partial pressure of carbon dioxide (43 mmHg), with 9 subjects tested at an end-tidal carbon dioxide concentration of 49 mmHg (hypercapnia). The hypoxic sensitivity (S) was computed as the slope of the linear regression of inspired minute ventilation (V1) on (100-SPO2). Values are mean +/- SE. Results Sensitivity was unaffected by desflurane during normocapnia (control: S = 0.45 +/- 0.07 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.43 +/- 0.09 l.min-1.%-1). With hypercapnia S decreased by 30% during desflurane inhalation (control: S = 0.74 +/- 0.09 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.53 +/- 0.06 l.min-1.%-1; P < 0.05). Conclusions On the basis of the data, subanesthetic desflurane has no detectable effect on the normocapnic hypoxic ventilatory response sensitivity. However, the carbon dioxideinduced augmentation of the hypoxic response was reduced. This indicates that subanesthetic desflurane effects the chemoreceptors at the carotid bodies.

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Living high-training low increases hypoxic ventilatory response of well-trained endurance athletes

Journal of Applied Physiology ◽

10.1152/japplphysiol.00381.2002 ◽

2002 ◽

Vol 93 (4) ◽

pp. 1498-1505 ◽

Cited By ~ 52

Author(s):

Nathan E. Townsend ◽

Christopher J. Gore ◽

Allan G. Hahn ◽

Michael J. McKenna ◽

Robert J. Aughey ◽

...

Keyword(s):

Ventilatory Response ◽

Minute Ventilation ◽

Respiratory Control ◽

Endurance Athletes ◽

Hypoxic Exposure ◽

Dependent Manner ◽

Hypoxic Ventilatory Response ◽

Ambient Conditions ◽

Altitude Exposure ◽

End Tidal

This study determined whether “living high-training low” (LHTL)-simulated altitude exposure increased the hypoxic ventilatory response (HVR) in well-trained endurance athletes. Thirty-three cyclists/triathletes were divided into three groups: 20 consecutive nights of hypoxic exposure (LHTLc, n = 12), 20 nights of intermittent hypoxic exposure (four 5-night blocks of hypoxia, each interspersed with 2 nights of normoxia, LHTLi, n = 10), or control (Con, n = 11). LHTLc and LHTLi slept 8–10 h/day overnight in normobaric hypoxia (∼2,650 m); Con slept under ambient conditions (600 m). Resting, isocapnic HVR (ΔV˙e/ΔSpO2 , whereV˙e is minute ventilation and SpO2 is blood O2 saturation) was measured in normoxia before hypoxia (Pre), after 1, 3, 10, and 15 nights of exposure (N1, N3, N10, and N15, respectively), and 2 nights after the exposure night 20 (Post). Before each HVR test, end-tidal Pco 2(Pet CO2 ) and V˙e were measured during room air breathing at rest. HVR (l · min−1 · %−1) was higher ( P < 0.05) in LHTLc than in Con at N1 (0.56 ± 0.32 vs. 0.28 ± 0.16), N3 (0.69 ± 0.30 vs. 0.36 ± 0.24), N10 (0.79 ± 0.36 vs. 0.34 ± 0.14), N15 (1.00 ± 0.38 vs. 0.36 ± 0.23), and Post (0.79 ± 0.37 vs. 0.36 ± 0.26). HVR at N15 was higher ( P < 0.05) in LHTLi (0.67 ± 0.33) than in Con and in LHTLc than in LHTLi. Pet CO2 was depressed in LHTLc and LHTLi compared with Con at all points after hypoxia ( P < 0.05). No significant differences were observed for V˙e at any point. We conclude that LHTL increases HVR in endurance athletes in a time-dependent manner and decreases Pet CO2 in normoxia, without change inV˙e. Thus endurance athletes sleeping in mild hypoxia may experience changes to the respiratory control system.

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Potentiation of hypoxic ventilatory response by hyperoxia in the conscious rat: putative role of nitric oxide

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.1.129 ◽

1998 ◽

Vol 85 (1) ◽

pp. 129-132 ◽

Cited By ~ 31

Author(s):

David Gozal

Keyword(s):

Nitric Oxide ◽

Ventilatory Response ◽

Minute Ventilation ◽

Hypoxic Ventilatory Response ◽

Sprague Dawley ◽

Conscious Rat ◽

Adult Rats ◽

Hyperoxic Exposure ◽

Essential Components ◽

Oxide Synthase

In humans, the hypoxic ventilatory response (HVR) is augmented when preceded by a short hyperoxic exposure (Y. Honda, H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. J. Appl. Physiol. 81: 1627–1632, 1996). To examine whether neuronal nitric oxide synthase (nNOS) is involved in such hyperoxia-induced HVR potentiation, 17 male Sprague-Dawley adult rats underwent hypoxic challenges (10% O2-5% CO2-balance N2) preceded either by 10 min of room air (−O2) or of 100% O2(+O2). At least 48 h later, similar challenges were performed after the animals received the selective nNOS inhibitor 7-nitroindazole (25 mg/kg ip). In −O2 runs, minute ventilation (V˙e) increased from 121.3 ± 20.5 (SD) ml/min in room air to 191.7 ± 23.8 ml/min in hypoxia ( P< 0.01). After +O2,V˙e increased from 114.1 ± 19.8 ml/min in room air to 218.4 ± 47.0 ml/min in hypoxia (+O2 vs. −O2: P < 0.005, ANOVA). After 7-nitroindazole administration, HVR was not affected in the −O2 treatment group withV˙e increasing from 113.7 ± 17.8 ml/min in room air to 185.8 ± 35.0 ml/min in hypoxia ( P < 0.01). However, HVR potentiation in +O2-exposed animals was abolished (111.8 ± 18.0 ml/min in room air to 184.1 ± 35.6 ml/min in hypoxia; +O2 vs. −O2: P not significant). We conclude that in the conscious rat nNOS activation mediates essential components of the HVR potentiation elicited by a previous short hyperoxic exposure.

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Calcium/calmodulin-dependent kinase II mediates critical components of the hypoxic ventilatory response within the nucleus of the solitary tract in adult rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00249.2005 ◽

2005 ◽

Vol 289 (3) ◽

pp. R871-R876 ◽

Cited By ~ 4

Author(s):

Stephen R. Reeves ◽

Edwin S. Carter ◽

Shang Z. Guo ◽

David Gozal

Keyword(s):

Ventilatory Response ◽

Minute Ventilation ◽

Acute Hypoxia ◽

Respiratory Frequency ◽

Whole Body ◽

Solitary Tract ◽

Hypoxic Ventilatory Response ◽

Adult Rats ◽

Osmotic Pumps ◽

Calcium Calmodulin Dependent

Calcium/calmodulin-dependent kinase II (CaMKII) is an ubiquitous second messenger that is highly expressed in neurons, where it has been implicated in some of the pathways regulating neuronal discharge as well as N-methyl-d-aspartate receptor-mediated synaptic plasticity. The full expression of the mammalian hypoxic ventilatory response (HVR) requires intact central relays within the nucleus of the solitary tract (NTS), and neural transmission of hypoxic afferent input is mediated by glutamatergic receptor activity, primarily through N-methyl-d-aspartate receptors. To examine the functional role of CaMKII in HVR, KN-93, a highly selective antagonist of CaMKII, was microinjected in the NTS via bilaterally placed osmotic pumps in freely behaving adult male Sprague-Dawley rats for 3 days. Vehicle-loaded osmotic pumps were surgically placed in control animals, and adequate placement of cannulas was ascertained for all animals. HVR was measured using whole body plethysmography during exposure to 10% O2-balance N2 for 20 min. Compared with control rats, KN-93 administration elicited marked attenuations of peak HVR (pHVR) but did not modify normoxic minute ventilation. Differences in pHVR were primarily attributable to diminished respiratory frequency recruitments during pHVR without significant differences in tidal volume. These findings indicate that CaMKII activation in the NTS mediates respiratory frequency components of the ventilatory response to acute hypoxia; however, CaMKII activity does not appear to underlie components of normoxic ventilation.

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The hypoxic ventilatory response is facilitated by the activation of Lkb1-AMPK signalling pathways downstream of the carotid bodies

10.1101/604900 ◽

2019 ◽

Author(s):

Amira D. Mahmoud ◽

Andrew P. Holmes ◽

Sandy MacMillan ◽

Oluseye A. Ogunbayo ◽

Christopher N. Wyatt ◽

...

Keyword(s):

Carotid Body ◽

Ventilatory Response ◽

Afferent Input ◽

The Body ◽

System Level ◽

Type I ◽

Hypoxic Ventilatory Response ◽

Level Control ◽

Body Type ◽

Carotid Bodies

ABSTRACTWe recently demonstrated that the role of the AMP-activated protein kinase (AMPK), a ubiquitously expressed enzyme that governs cell-autonomous metabolic homeostasis, has been extended to system-level control of breathing and thus oxygen and energy (ATP) supply to the body. Here we assess the contribution to the hypoxic ventilatory response (HVR) of two upstream kinases that govern the activities of AMPK. Lkb1, which activates AMPK in response to metabolic stress and CaMKK2 which mediates the alternative Ca2+-dependent mechanism of AMPK activation. HVRs remained unaffected in mice with global deletion of the CaMKK2 gene. By contrast, HVRs were markedly attenuated in mice with conditional deletion of LKB1 in catecholaminergic cells, including carotid body type I cells and brainstem respiratory networks. In these mice hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, rather than hyperventilation. Attenuation of HVRs, albeit less severe, was also conferred in mice carrying ∼90% knockdown of Lkb1 expression. Carotid body afferent input responses were retained following either ∼90% knockdown of Lkb1 or AMPK deletion. In marked contrast, LKB1 deletion virtually abolished carotid body afferent discharge during normoxia, hypoxia and hypercapnia. We conclude that Lkb1 and AMPK, but not CaMKK2, facilitate HVRs at a site downstream of the carotid bodies.

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Control of breathing in Sherpas at low and high altitude

Journal of Applied Physiology ◽

10.1152/jappl.1980.49.3.374 ◽

1980 ◽

Vol 49 (3) ◽

pp. 374-379 ◽

Cited By ~ 63

Author(s):

P. H. Hackett ◽

J. T. Reeves ◽

C. D. Reeves ◽

R. F. Grover ◽

D. Rennie

Keyword(s):

High Altitude ◽

Ventilatory Response ◽

Minute Ventilation ◽

Acute Hypoxia ◽

Arterial Oxygen Saturation ◽

Carbon Dioxide Tension ◽

Arterial Oxygen ◽

Hypoxic Ventilatory Response ◽

Oxygen Administration ◽

End Tidal

Sherpas are well known for their physical performance at extreme altitudes, yet they are reported to have blunted ventilatory responses to acute hypoxia and relative hypoventilation in chronic hypoxia. To examine this paradox, we studied ventilatory control in Sherpas in comparison to that in Westerners at both low and high altitude. At low altitude, 25 Sherpas had higher minute ventilation, higher respiratory frequency, and lower end-tidal carbon dioxide tension than 25 Westerners. The hypoxic ventilatory response of Sherpas was found to be similar to that in Westerners, even though long altitude exposure had blunted the responses of some Sherpas. At high altitude, Sherpas again had higher minute ventilation and a tendency toward higher arterial oxygen saturation than Westerners. Oxygen administration increased ventilation further in Sherpas but decreased ventilation in Westerners. We conclude that Sherpas differ from other high-altitude natives; their hypoxic ventilatory response is not blunted, and they exhibit relative hyperventilation.

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Acute mountain sickness, chemosensitivity, and cardiorespiratory responses in humans exposed to hypobaric and normobaric hypoxia

Journal of Applied Physiology ◽

10.1152/japplphysiol.00319.2013 ◽

2014 ◽

Vol 116 (7) ◽

pp. 945-952 ◽

Cited By ~ 24

Author(s):

Normand A. Richard ◽

Inderjeet S. Sahota ◽

Nadia Widmer ◽

Sherri Ferguson ◽

A. William Sheel ◽

...

Keyword(s):

Ventilatory Response ◽

Minute Ventilation ◽

Acute Mountain Sickness ◽

Blood Oxygenation ◽

Normobaric Hypoxia ◽

Hypoxic Exposure ◽

Hypoxic Ventilatory Response ◽

Before And After ◽

Mountain Sickness ◽

Normobaric Normoxia

We examined the control of breathing, cardiorespiratory effects, and the incidence of acute mountain sickness (AMS) in humans exposed to hypobaric hypoxia (HH) and normobaric hypoxia (NH), and under two control conditions [hypobaric normoxia (HN) and normobaric normoxia (NN)]. Exposures were 6 h in duration, and separated by 2 wk between hypoxic exposures and 1 wk between normoxic exposures. Before and after exposures, subjects ( n = 11) underwent hyperoxic and hypoxic Duffin CO2 rebreathing tests and a hypoxic ventilatory response test (HVR). Inside the environmental chamber, minute ventilation (V̇e), tidal volume (Vt), frequency of breathing ( fB), blood oxygenation, heart rate, and blood pressure were measured at 5 and 30 min and hourly until exit. Symptoms of AMS were evaluated using the Lake Louise score (LLS). Both the hyperoxic and hypoxic CO2 thresholds were lower after HH and NH, whereas CO2 sensitivity was increased after HH and NH in the hypoxic test and after NH in the hyperoxic test. Values for HVR were similar across the four exposures. No major differences were observed for V̇e or any other cardiorespiratory variables between NH and HH. The LLS was greater in AMS-susceptible than in AMS-resistant subjects; however, LLS was alike between HH and NH. In AMS-susceptible subjects, fB correlated positively and Vt negatively with the LLS. We conclude that 6 h of hypoxic exposure is sufficient to lower the peripheral and central CO2 threshold but does not induce differences in cardiorespiratory variables or AMS incidence between HH and NH.

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Development of the ventilatory response to hypoxia in Swiss CD-1 mice

Journal of Applied Physiology ◽

10.1152/jappl.2000.88.5.1907 ◽

2000 ◽

Vol 88 (5) ◽

pp. 1907-1914 ◽

Cited By ~ 23

Author(s):

Dean M. Robinson ◽

Henry Kwok ◽

Brandon M. Adams ◽

Karen C. Peebles ◽

Gregory D. Funk

Keyword(s):

Tidal Volume ◽

Body Mass ◽

Breathing Pattern ◽

Ventilatory Response ◽

Minute Ventilation ◽

Developmental Changes ◽

Hypoxic Exposure ◽

Hypoxic Ventilatory Response ◽

Expiratory Time ◽

Ventilatory Response To Hypoxia

We examined developmental changes in breathing pattern and the ventilatory response to hypoxia (7.4% O2) in unanesthetized Swiss CD-1 mice ranging in age from postnatal day 0 to 42(P0–P42) using head-out plethysmography. The breathing pattern of P0 mice was unstable. Apneas were frequent at P0 (occupying 29 ± 6% of total time) but rare by P3 (5 ± 2% of total time). Tidal volume increased in proportion to body mass (∼10–13 ml/kg), but increases in respiratory frequency (f) (55 ± 7, 130 ± 13, and 207 ± 20 cycles/min for P0, P3, and P42, respectively) were responsible for developmental increases in minute ventilation (690 ± 90, 1,530 ± 250, and 2,170 ± 430 ml ⋅ min− 1 ⋅ kg− 1for P0, P3, and P42, respectively). Between P0 and P3, increases in f were mediated by reductions in apnea and inspiratory and expiratory times; beyond P3, increases were due to reductions in expiratory time. Mice of all ages showed a biphasic hypoxic ventilatory response, which differed in two respects from the response typical of most mammals. First, the initial hyperpnea, which was greatest in mature animals, decreased developmentally from a maximum, relative to control, of 2.58 ± 0.29 in P0 mice to 1.32 ± 0.09 in P42mice. Second, whereas ventilation typically falls to or below control in most neonatal mammals, ventilation remained elevated relative to control throughout the hypoxic exposure in P0 (1.73 ± 0.31), P3 (1.64 ± 0.29), and P9 (1.34 ± 0.17) mice but not in P19 or P42 mice.

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Ventilatory responses to hypercapnia and hypoxia during continuous aspirin ingestion

Journal of Applied Physiology ◽

10.1152/jappl.1977.43.6.971 ◽

1977 ◽

Vol 43 (6) ◽

pp. 971-976 ◽

Cited By ~ 14

Author(s):

D. J. Riley ◽

B. A. Legawiec ◽

T. V. Santiago ◽

N. H. Edelman

Keyword(s):

Ventilatory Response ◽

Minute Ventilation ◽

Normal Subjects ◽

Carbon Dioxide Tension ◽

Base Line ◽

Hypoxic Ventilatory Response ◽

Ventilatory Responses ◽

Hypercapnic Ventilatory Response ◽

The Central Nervous System ◽

End Tidal

Hypercapnic and hypoxic ventilatory responses were serially measured in nine normal subjects given 3.9 g aspirin (ASA) per day for 9 days. Minute ventilation (VE), end-tidal carbon dioxide tension (PETCO2), venous bicarbonate concentration [HCO3-], oxygen consumption (VO2), hypercapnic ventilatory response (deltaVE/deltaPCO2), and isocapnic hypoxic ventilatory response (A) were determined before, 2 h after the first dose, and at 72-h intervals during the next 14 days. Serum salicylate levels averaged 18.6 +/- 2.0 mg/dl. VE increased (P less than 0.05, PETCO2 decreased (P less than 0.05), and [HCO3-] did not change significantly during drug ingestion. deltaVE/deltaPCO2 increased gradually to a value 37% greater than control by day 3 and remained constant (P less 0.01). A increased by 251% and VO2 by 18% within 2 h and remained constant for the remainder of the ASA period (P less than 0.01). All values returned to base line within 24 h following cessation of ASA. We conclude that during continuous ASA ingestion there is a gradual increase of hypercapnic ventilatory response. This may reflect slow entrance of ASA into the central nervous system. In contrast, there is a rapid rise in hypoxic ventilatory response which may be mechanically linked to changes in metabolic rate.

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