Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2

We studied the arousal and ventilatory responses to hypoxia during sleep in three trained dogs, before and 1–4 wk after carotid body denervation (CBD). During the studies the dogs breathed through a cuffed endotracheal tube inserted via a chronic tracheostomy. Eucapnic progressive hypoxia was induced by a rebreathing technique, and arterial O2 saturation (Sao2) was measured with an ear oximeter. Sleep stage was determined by electroencephalographic and behavioral criteria. Following CBD, all dogs exhibited hypoventilation under resting conditions; hypoxic ventilatory responses during wakefulness, slow-wave sleep (SWS), and rapid-eye-movement (REM) sleep were less than 10% of control. Prior to CBD, hypoxic arousal occurred at Sao2 of 83.2 +/- 4.6% (mean +/- Se) during SWS and 70.6 +/-2.2% in REM sleep. Following CBD, arousal failed to occur during progressive desaturation to 60% in SWS and 50% in REM sleep, at which levels hypoxia was arbitrarily terminated. In a few studies following CBD where rebreathing was allowed to continue, the dogs occasionally failed to arouse at all and require active resuscitation. The results indicate a critical role for the carotid chemoreceptors in mediating the arousal response to hypoxia.

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The essential role of carotid body chemoreceptors in sleep apnea

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y03-056 ◽

2003 ◽

Vol 81 (8) ◽

pp. 774-779 ◽

Cited By ~ 42

Author(s):

Curtis A Smith ◽

Hideaki Nakayama ◽

Jerome A Dempsey

Keyword(s):

Sleep Apnea ◽

Carotid Body ◽

Respiratory Acidosis ◽

Periodic Breathing ◽

Peripheral Chemoreceptors ◽

Carotid Chemoreceptors ◽

Ventilatory Responses ◽

Carotid Bodies ◽

The Difference ◽

Carotid Body Chemoreceptors

Sleep apnea is attributable, in part, to an unstable ventilatory control system and specifically to a narrowed "CO2 reserve" (i.e., the difference in PaCO2 between eupnea and the apneic threshold). Findings from sleeping animal preparations with denervated carotid chemoreceptors or vascularly isolated, perfused carotid chemoreceptors demonstrate the critical importance of peripheral chemoreceptors to the ventilatory responses to dynamic changes in PaCO2. Specifically, (i) carotid body denervation prevented the apnea and periodic breathing that normally follow transient ventilatory overshoots; (ii) the CO2 reserve for peripheral chemoreceptors was about one half that for brain chemoreceptors; and (iii) hypocapnia isolated to the carotid chemoreceptors caused hypoventilation that persisted over time despite a concomitant, progressive brain respiratory acidosis. Observations in both humans and animals are cited to demonstrate the marked plasticity of the CO2 reserve and, therefore, the propensity for apneas and periodic breathing, in response to changing background ventilatory stimuli.Key words: sleep apnea, carotid bodies, hypocapnia, apneic threshold, periodic breathing.

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Exercise intolerance in volume overload heart failure is associated with low carotid body mediated chemoreflex drive

Scientific Reports ◽

10.1038/s41598-021-93791-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

David C. Andrade ◽

Esteban Díaz-Jara ◽

Camilo Toledo ◽

Karla G. Schwarz ◽

Katherin V. Pereyra ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Training Program ◽

Carotid Body ◽

Exercise Tolerance ◽

Systolic Function ◽

Volume Overload ◽

Exercise Intolerance ◽

Ventilatory Responses ◽

Cardiac Systolic Function

AbstractMounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands, and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in heart failure (HF) patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses, and exercise tolerance were assessed at the end of a 6 week exercise training program. At the conclusion of the training program, exercise tolerant HF rats (HF + EX-T) exhibited improvements in cardiac systolic function and reductions in HCVR, sympathetic tone, and arrhythmias. In contrast, HF rats that were exercise intolerant (HF + EX-inT) exhibited worse diastolic dysfunction, and showed no improvements in cardiac systolic function, HCVR, sympathetic tone, or arrhythmias at the conclusion of the training program. In addition, HF + EX-inT rats had impaired HVR which was associated with increased arrhythmia susceptibility and mortality during hypoxic challenges (~ 60% survival). Finally, we observed that exercise tolerance in HF rats was related to carotid body (CB) function as CB ablation resulted in impaired exercise capacity in HF + EX-T rats. Our results indicate that: (i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and (ii) loss of CB chemoreflex sensitivity contributes to EX-inT in HF.

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Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI)

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.1.292 ◽

1998 ◽

Vol 84 (1) ◽

pp. 292-302 ◽

Cited By ~ 3

Author(s):

R. Gelfand ◽

C. J. Lambertsen ◽

J. M. Clark ◽

E. Hopkin

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Adverse Effects ◽

Exposure Time ◽

Carotid Body ◽

Exposure Limits ◽

Peripheral Chemoreceptors ◽

Human Organ ◽

Ventilatory Responses ◽

Before And After

Gelfand, R., C. J. Lambertsen, J. M. Clark, and E. Hopkin.Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI). J. Appl. Physiol. 84(1): 292–302, 1998.—Potential adverse effects on the O2-sensing function of the carotid body when its cells are exposed to toxic O2 pressures were assessed during investigations of human organ tolerance to prolonged continuous and intermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxic ventilatory responses (HVR) were determined at 1.0 ATA before and after severe hyperoxic exposures: 1) continuous O2 breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and 2) intermittent O2 breathing at 2.0 ATA (30 min O2-30 min normoxia) for 14.3 O2 h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared with preexposure controls. The hyperbolas were temporarily elevated to higher ventilations than controls due to increments in respiratory frequency that were proportional to O2 exposure time, not O2 pressure. In humans, prolonged hyperoxia does not attenuate the hypoxia-sensing function of the peripheral chemoreceptors, even after exposures that approach limits of human pulmonary and central nervous system O2 tolerance. Current applications of hyperoxia in hyperbaric O2therapy and in subsea- and aerospace-related operations are guided by and are well within these exposure limits.

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Ventilatory responses to hypocapnic vertebral artery perfusion in intact and carotid body denervated dogs

Respiration Physiology ◽

10.1016/0034-5687(81)90052-9 ◽

1981 ◽

Vol 45 (1) ◽

pp. 97-110 ◽

Cited By ~ 1

Author(s):

Paul J. Feustel ◽

J.Milton Adams ◽

David F. Donnelly ◽

Robert E. Dutton

Keyword(s):

Vertebral Artery ◽

Carotid Body ◽

Ventilatory Responses ◽

Artery Perfusion

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Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse

Journal of Applied Physiology ◽

10.1152/japplphysiol.00025.2004 ◽

2004 ◽

Vol 97 (4) ◽

pp. 1401-1407 ◽

Cited By ~ 26

Author(s):

Masahiko Izumizaki ◽

Mieczyslaw Pokorski ◽

Ikuo Homma

Keyword(s):

Tidal Volume ◽

Carotid Body ◽

Minute Ventilation ◽

Respiratory Frequency ◽

Whole Body ◽

Sudden Increase ◽

Ventilatory Responses ◽

Carotid Bodies ◽

Before And After ◽

Carotid Body Denervation

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.

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Carotid body function and ventilatory responses in intermittent hypoxia. evidence for anomalous brainstem integration of arterial chemoreceptor input

Journal of Cellular Physiology ◽

10.1002/jcp.22528 ◽

2011 ◽

Vol 226 (8) ◽

pp. 1961-1969 ◽

Cited By ~ 31

Author(s):

M.C. Gonzalez-Martín ◽

M.V. Vega-Agapito ◽

S.V. Conde ◽

J. Castañeda ◽

R. Bustamante ◽

...

Keyword(s):

Carotid Body ◽

Intermittent Hypoxia ◽

Body Function ◽

Ventilatory Responses ◽

Arterial Chemoreceptor

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Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.022634199 ◽

2002 ◽

Vol 99 (2) ◽

pp. 821-826 ◽

Cited By ~ 202

Author(s):

D. D. Kline ◽

Y.-J. Peng ◽

D. J. Manalo ◽

G. L. Semenza ◽

N. R. Prabhakar

Keyword(s):

Carotid Body ◽

Chronic Hypoxia ◽

Hypoxia Inducible Factor ◽

Body Function ◽

Ventilatory Responses ◽

Hypoxia Inducible Factor 1

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Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat

Antioxidants ◽

10.3390/antiox10060840 ◽

2021 ◽

Vol 10 (6) ◽

pp. 840

Author(s):

Agnieszka Swiderska ◽

Andrew M. Coney ◽

Abdulaziz A. Alzahrani ◽

Hayyaf S. Aldossary ◽

Nikolaos Batis ◽

...

Keyword(s):

Carotid Body ◽

Ex Vivo ◽

Acute Hypoxia ◽

Whole Body ◽

Dimethyl Malonate ◽

Peripheral Chemoreceptor ◽

Ventilatory Responses ◽

Mitochondrial Ros ◽

O2 Sensing

Reflex increases in breathing in response to acute hypoxia are dependent on activation of the carotid body (CB)—A specialised peripheral chemoreceptor. Central to CB O2-sensing is their unique mitochondria but the link between mitochondrial inhibition and cellular stimulation is unresolved. The objective of this study was to evaluate if ex vivo intact CB nerve activity and in vivo whole body ventilatory responses to hypoxia were modified by alterations in succinate metabolism and mitochondrial ROS (mitoROS) generation in the rat. Application of diethyl succinate (DESucc) caused concentration-dependent increases in chemoafferent frequency measuring approximately 10–30% of that induced by severe hypoxia. Inhibition of mitochondrial succinate metabolism by dimethyl malonate (DMM) evoked basal excitation and attenuated the rise in chemoafferent activity in hypoxia. However, approximately 50% of the response to hypoxia was preserved. MitoTEMPO (MitoT) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SKQ1) (mitochondrial antioxidants) decreased chemoafferent activity in hypoxia by approximately 20–50%. In awake animals, MitoT and SKQ1 attenuated the rise in respiratory frequency during hypoxia, and SKQ1 also significantly blunted the overall hypoxic ventilatory response (HVR) by approximately 20%. Thus, whilst the data support a role for succinate and mitoROS in CB and whole body O2-sensing in the rat, they are not the sole mediators. Treatment of the CB with mitochondrial selective antioxidants may offer a new approach for treating CB-related cardiovascular–respiratory disorders.

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Exercise Intolerance in Volume Overload Heart Failure Is Associated With Low Carotid Body Chemosensitivity

10.21203/rs.3.rs-192470/v1 ◽

2021 ◽

Author(s):

David Andrade ◽

Esteban Diaz ◽

Camilo Toledo ◽

Karla Schwarz ◽

Katherin Pereyra ◽

...

Keyword(s):

Cardiac Function ◽

Carotid Body ◽

Exercise Tolerance ◽

Systolic Function ◽

Volume Overload ◽

Sympathetic Tone ◽

Exercise Intolerance ◽

Ventilatory Responses ◽

Exercise Training Program ◽

Cardiac Systolic Function

Abstract Mounting an appropriate ventilatory response to exercise is crucial to meeting metabolic demands during exercise and abnormal ventilatory responses may contribute to exercise-intolerance (EX-inT) in HF patients. We sought to determine if abnormal ventilatory chemoreflex control contributes to EX-inT in volume-overload HF rats. Cardiac function, hypercapnic (HCVR) and hypoxic (HVR) ventilatory responses and exercise tolerance were assessed at the end of a 6 weeks exercise training program. Exercise tolerant HF rats (HF+EX-T) completed all training sessions and benefit from exercise as evidenced by improvements in cardiac systolic function and reductions in HCVR, sympathetic tone and arrhythmias. Contrarily, HF rats that failed to complete training sessions (HF+EX-inT) showed no improvements in cardiac systolic function nor in HCVR, sympathetic tone, or arrhythmias but displayed a further compromise in cardiac diastolic function when compared to HF-sedentary rats. In addition, HF+EX-inT rats showed impaired HVR which was associated with increased arrhythmias susceptibility and mortality during hypoxic challenges (~60% survival). Finally, exercise tolerance was closely dependent on carotid body (CB) function since their selective ablation impaired exercise capacity in HF. Our results indicate that: i) exercise may have detrimental effects on cardiac function in HF-EX-inT, and ii) reduced CB chemoreflex contributes to EX-inT in HF.

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