Carotid body hypercapnia does not elicit ventilatory acclimatization in goats

doi:10.1016/0034-5687(86)90010-1

Respiration Physiology

Volume 65, Issue 1, July 1986, Pages 113-125

Respiration Physiolo...

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Abstract

The carotid body (CB) perfusion model utilizes surgical vascular ligations to allow isolated blood supply to a single in situ CB in awake goats. The contralateral CB was excised. By use of an extracorporeal pump-oxygenator system the blood gas composition perfusing the CB can be controlled independently from that of the systematic arterial system including the brain. Using this model we compared the responses of systemically normoxic goats to CB hypercapnia and CB hypoxia. In 6 goats CB sitmulation with hypercapnic-normoxic blood (mean Pcb_CO₂ = 78Torr, mean Pcb_O₂ ≅ 100 Toor) produced acute hyperventillation (mean decrease in Pa_CO₂ of 5.2 Torr, P < 0.05) which remained constant over the 4-h perfusion period, Lack of a progressively increasing hyperventilation indicates that ventilatory acclimatization did not occur with hypercapnic CB perfusion. Hypoxic-normocapnic CB stimulation (mean Pcb_O₂ = 40 Torr, mean PcB_CO₂ = 39 Torr) produced an acute mean in Pa_CO₂ of 5.5 Torr (P < 0.05) in 6 additional goats. In contrast to CB hypercapina, the acute hyperventilation induced by CB hypoxia was followed by a progressive time-dependent additional mean decrease in Pa_CO₂ of 5.6 Torr (P < 0.05) over a 4-h period (ventilatory acclimatization).

These data are compatible with the concept of separate mechanisms for hypercapnia and hypoxia in the CB suggest that the early phase of ventillatory acclimatization to hypoxia in goats may result from a time-dependent increase in CB afferent output.

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Perfusion of carotid bodies with hypoxic blood (PaO2 ~ 40 mmHg) for 4 to 6 h, while maintaining normoxia to brain, produced time-dependent stimulation of breathing similar to that elicited by short-term systemic hypoxia (Busch et al., 1985; Bisgard et al., 1986b; Engwall and Bisgard, 1990). In contrast, perfusing brain with hypoxic blood, while maintaining normoxia at the carotid bodies did not elicit VAH (Bisgard et al., 1986a). Selective perfusion of the carotid body with hypercapnic blood (elevated arterial blood CO2) failed to produce VAH.
This chapter reviews cardiorespiratory adaptations to chronic hypoxia (CH) experienced at high altitude and cardiorespiratory pathologies elicited by chronic intermittent hypoxia (CIH) occurring with obstructive sleep apnea (OSA). Short-term CH increases breathing (ventilatory acclimatization to hypoxia) and blood pressure (BP) through carotid body (CB) chemo reflex. Hyperplasia of glomus cells, alterations in ion channels, and recruitment of additional excitatory molecules are implicated in the heightened CB chemo reflex by CH. Transcriptional activation of hypoxia-inducible factors (HIF-1 and 2) is a major molecular mechanism underlying respiratory adaptations to short-term CH. High-altitude natives experiencing long-term CH exhibit blunted hypoxic ventilatory response (HVR) and reduced BP due to desensitization of CB response to hypoxia and impaired processing of CB sensory information at the central nervous system. Ventilatory changes evoked by long-term CH are not readily reversed after return to sea level. OSA patients and rodents subjected to CIH exhibit heightened CB chemo reflex, increased hypoxic ventilatory response, and hypertension. Increased generation of reactive oxygen species (ROS) is a major cellular mechanism underlying CIH-induced enhanced CB chemo reflex and the ensuing cardiorespiratory pathologies. ROS generation by CIH is mediated by nontranscriptional, disrupted HIF-1 and HIF-2-dependent transcriptions as well as epigenetic mechanisms.
Update on Chemoreception: Influence on Cardiorespiratory Regulation and Pathophysiology
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The ventilatory response to carotid chemoreceptor CO2, in the absence of concomitant changes in PaO2, appears to be relatively sluggish, as best demonstrated in awake goats and awake or sleeping dogs using extracorporeal perfusion of the isolated carotid chemoreceptor. In these animals, the raising of the isolated carotid chemoreceptor Pco2 more than 15 to 20 mm Hg above eupneic air-breathing levels was required to elicit a significant hyperventilatory response.5,6 The hypoventilatory response to hypocapnic blood delivered to the isolated carotid chemoreceptor was more sensitive , as transient reductions in PCBCO2 during NREM sleep over the 3-14 mmHg range elicited immediate, dose-dependent reductions in Vt and mean inspiratory flow - but no alteration in breath timing.7
Determination of the minimum infusion rate of propofol required to prevent purposeful movement of the extremities in response to a standardized noxious stimulus in goats
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The present study demonstrated a clinically significant reduction in fR during the induction and maintenance of anaesthesia in comparison with baseline readings taken just prior to anaesthesia, but no apnoea was observed. Partial pressure of arterial CO2 is generally indicative of ventilation performance, and the subtle but persistent increase in PaCO2 in conjunction with the persistent decrease in pHa observed in this study supports descriptions in the previous literature of propofol-mediated respiratory depression in goats (Bisgard et al. 1986; Pablo et al. 1997). Similarly, decreases in PaO2, SaO2 and the PaO2/FiO2 ratio were consistent clinical observations noted directly after the induction of anaesthesia and resolved by the initiation of oxygen supplementation.
To determine the minimum infusion rate (MIR) of propofol required to prevent purposeful movement in response to a standardized stimulus in goats.
Prospective, experimental study.
Eight healthy goats (four does, four wethers).
Anaesthesia was induced with 4 mg kg⁻¹ propofol intravenously (IV). A continuous IV infusion of propofol at 0.6 mg kg⁻¹ minute⁻¹ was initiated immediately to maintain anaesthesia. Following endotracheal intubation, goats breathed spontaneously via a circle breathing system delivering supplementary oxygen. The initial propofol infusion rate was maintained for 30 minutes before responses to noxious stimulation provided by clamping the proximal part of the claw with a Vulsellum forceps for 60 seconds were tested. In the presence or absence of purposeful movements of the extremities, the infusion rate was increased or reduced by 0.1 mg kg⁻¹ minute⁻¹ and held constant for 30 minutes before claw clamping was repeated. The propofol MIR for each goat was calculated as the mean of the infusion rates that allowed and abolished movement. Basic cardiopulmonary parameters were monitored, recorded and tested for statistical significance using Wilcoxon's signed rank test with Bonferroni adjustment for multiple testing. The quality of recovery from anaesthesia was assessed and scored.
The median MIR of propofol was 0.45 mg kg⁻¹ minute⁻¹ (range: 0.45–0.55 mg kg⁻¹ minute⁻¹). Induction and recovery were free of adverse behaviour. No statistically significant cardiopulmonary changes in comparison with baseline were observed, but clinically relevant hypoxaemia at 2 minutes after induction of anaesthesia was consistently observed. Chewing during anaesthesia was observed in three goats. Median times to extubation and standing were 3 minutes (range: 2–6 minutes) and 10 minutes (range: 7–21 minutes), respectively.
Propofol induction and maintenance of general anaesthesia minimally compromise cardiopulmonary function when oxygen is supplemented in goats.
An interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control
2010, Respiratory Physiology and Neurobiology
In this review we discuss the implications for ventilatory control of newer evidence suggesting that central and peripheral chemoreceptors are not functionally separate but rather that they are dependent upon one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the carotid body chemoreceptors and vice versa i.e., they are interdependent. We examine potential interactions of the interdependent central and carotid body (CB) chemoreceptors with other ventilatory-related inputs such as central hypoxia, lung stretch, and exercise. The limitations of current approaches addressing this question are discussed and future studies are suggested.
Role of the peripheral chemoreflex in the early stages of ventilatory acclimatization to altitude
2007, Respiratory Physiology and Neurobiology
This review of ventilatory acclimatization to altitude/hypoxia (VAH) emphasizes the widely differing timescales that VAH is considered to encompass. The review concludes: (1) that early (24–48 h) VAH is unlikely to arise as a reaction to the respiratory alkalosis that is normally associated with exposure to hypoxia; (2) that changes in peripheral chemoreflex function may be sufficiently rapid to explain early VAH; (3) that alterations in gene expression induced by hypoxia through the hypoxia-inducible factor (HIF) signalling pathway may underlie a major component of VAH; and (4) that compensatory adjustments to acid–base balance in response to the initial respiratory alkalosis may have more significance for the slower changes observed later in VAH.
The influence of chronic hypoxia upon chemoreception
2007, Respiratory Physiology and Neurobiology
Carotid body chemoreceptors are essential for time-dependent changes in ventilatory control during chronic hypoxia. Early theories of ventilatory acclimatization to hypoxia focused on time-dependent changes in known ventilatory stimuli, such as small changes in arterial pH that may play a significant role in some species. However, plasticity in the cellular and molecular mechanisms of carotid body chemoreception play a major role in ventilatory acclimatization to hypoxia in all species studied. Chronic hypoxia causes changes in (a) ion channels (potassium, sodium, calcium) to increase glomus cell excitability, and (b) neurotransmitters (dopamine, acetylcholine, ATP) and neuromodulators (endothelin-1) to increase carotid body afferent activity for a given $P_{O_{2}}$ and optimize O₂-sensitivity. O₂-sensing heme-containing molecules in the carotid body have not been studied in chronic hypoxia. Plasticity in medullary respiratory centers processing carotid body afferent input also contributes to ventilatory acclimatization to hypoxia. It is not known if the same mechanisms occur in patients with chronic hypoxemia from lung disease or high altitude natives.

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Carotid body hypercapnia does not elicit ventilatory acclimatization in goats

Abstract

Respir. Physiol.

Respir. Physiol.

Neuroscience

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

The distribution of carotid and vertebral blood in the brain and spinal cord of the goat

Q. J. Exp. Physiol.

The frequency of nerve impulses in single carotid body chemoreceptor afferent fibers recorded in vivo with intact circulation

J. Physiol. (London)

Depression of ventilation by dopamine in goats; effects of carotid body excision

Respir. Physiol.

Ventilatory acclimatization to hypoxia is not dependent upon cerebral hypoxia is not dependent upon cerebral hypocapnic alkalosis

J. Appl. Physiol.

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

J. Appl. Physiol.

Mediation of ventilatory adaptations

Physiol. Rev.

Composition of cerebral fluids in goats adapted to high altitude

J. Appl. Physiol.