Specific Carotid Body Research Articles

Contribution of carotid body chemoreceptors to the eupneic drive to breathe in the intact awake canine

We used extracorporeal perfusion of the reversibly isolated carotid sinus to determine the effects of specific carotid body (CB) chemoreceptor inhibition on eupneic ventilation (VI) in the resting, awake, unanesthetized, intact dog. 4 female dogs were studied when CB was perfused with 1) normoxic and normocapnic blood, and 2) hyperoxic (> 500 mmHg) and hypocapnic (20 mmHg) blood to maximally inhibit the CB tonic activity. We found that perfusion per se (normoxic ‐ normocapnic) had no effect on VI. In contrast, CB inhibition caused an immediate and substantial reduction in VI which reached a nadir (‐56%) within 29 sec and a steady state (‐24%) within 100 sec. At steady state, this VT‐induced (‐17%) hypoventilation persisted throughout continued CB perfusion (up to 25 min) despite a marked CO2 retention (+9 mmHg) and respiratory acidosis (pHa = 7.27). Consistent with hypoventilation, mean electrical activity of diaphragm EMG was also reduced (‐24%) during CB inhibition. Ventilation returned toward control values within ∼27 sec when exogenous CB perfusion was terminated. We interpret these data to mean that CB chemoreceptor contributes as much as one‐half or more to the total drive to eupnea in the normoxic, intact, awake animal, and that this contribution consists of both a tonic sensory input to respiratory controller as well as a strong modulatory effect on the central chemoreceptor responsiveness to CO2. NHLBI/NIH ‐ AHA

Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog

We used extracorporeal perfusion of the reversibly isolated carotid sinus region to determine the effects of specific carotid body (CB) chemoreceptor inhibition on eupneic ventilation (Vi) in the resting, awake, intact dog. Four female spayed dogs were studied during wakefulness when CB was perfused with 1) normoxic, normocapnic blood; and 2) hyperoxic (>500 mmHg), hypocapnic ( approximately 20 mmHg) blood to maximally inhibit the CB tonic activity. We found that CB perfusion per se (normoxic-normocapnic) had no effect on Vi. CB inhibition caused marked reductions in Vi (-60%, range 49-80%) and inspiratory flow rate (-58%, range 44-87%) 24-41 s following the onset of CB perfusion. Thereafter, a partial compensatory response was observed, and a steady state in Vi was reached after 50-76 s following the onset of CB perfusion. This steady-state tidal volume-mediated hypoventilation ( approximately 31%) coincided with a significant reduction in mean diaphragm electromyogram (-24%) and increase in mean arterial pressure (+12 mmHg), which persisted for 7-25 min until CB perfusion was stopped, despite a substantial increase in CO(2) retention (+9 Torr, arterial Pco(2)) and systemic respiratory acidosis. We interpret these data to mean that CB chemoreceptors contribute more than one-half to the total eupneic drive to breathe in the normoxic, intact, awake animal. We speculate that this CB contribution consists of both the normal tonic sensory input from the CB chemoreceptors to medullary respiratory controllers, as well as a strong modulatory effect on central chemoreceptor responsiveness to CO(2).

A negative interaction between brainstem and peripheral respiratory chemoreceptors modulates peripheral chemoreflex magnitude

Interaction between central (brainstem) and peripheral (carotid body) respiratory chemosensitivity is vital to protect blood gases against potentially deleterious fluctuations, especially during sleep. Previously, using an in situ arterially perfused, vagotomized, decerebrate preparation in which brainstem and peripheral chemoreceptors are perfused separately (i.e. dual perfused preparation; DPP), we observed that the phrenic response to specific carotid body hypoxia was larger when the brainstem was held at 25 Torr P(CO(2)) compared to 50 Torr P(CO(2)). This suggests a negative (i.e. hypo-additive) interaction between chemoreceptors. The current study was designed to (a) determine whether this observation could be generalized to all carotid body stimuli, and (b) exclude the possibility that the hypo-additive response was the simple consequence of ventilatory saturation at high brainstem P(CO(2)). Specifically, we tested how steady-state brainstem P(CO(2)) modulates peripheral chemoreflex magnitude in response to carotid body P(CO(2)) and P(O(2)) perturbations, both above and below eupnoeic levels. We found that the peripheral chemoreflex was more responsive the lower the brainstem P(CO(2)) regardless of whether the peripheral chemoreceptors received stimuli which increased or decreased activation. These findings demonstrate a negative interaction between brainstem and peripheral chemosensitivity in the rat in the absence of ventilatory saturation. We suggest that a negative interaction in humans may contribute to increased controller gain associated with sleep-related breathing disorders and propose that the assumption of simple addition between chemoreceptor inputs used in current models of the respiratory control system be reconsidered.

Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation

Inputs from central (brainstem) and peripheral (carotid body) respiratory chemoreceptors are coordinated to protect blood gases against potentially deleterious fluctuations. However, the mathematics of the steady-state interaction between chemoreceptors has been difficult to ascertain. Further, how this interaction affects time-dependent phenomena (in which chemoresponses depend upon previous experience) is largely unknown. To determine how central P(CO2) modulates the response to peripheral chemostimulation in the rat, we utilized an in situ arterially perfused, vagotomized, decerebrate preparation, in which central and peripheral chemoreceptors were perfused separately (i.e. dual perfused preparation (DPP)). We carried out two sets of experiments: in Experiment 1, we alternated steady-state brainstem P(CO2) between 25 and 50 Torr in each preparation, and applied specific carotid body hypoxia (60 Torr P(O2) and 40 Torr P(CO2)) under both conditions; in Experiment 2, we applied four 5 min bouts (separated by 5 min) of specific carotid body hypoxia (60 Torr P(O2) and 40 Torr P(CO2)) while holding the brainstem at either 30 Torr or 50 Torr P(CO2). We demonstrate that the level of brainstem P(CO2) modulates (a) the magnitude of the phrenic responses to a single step of specific carotid body hypoxia and (b) the magnitude of time-dependent phenomena. We report that the interaction between chemoreceptors is negative (i.e. hypo-additive), whereby a lower brainstem P(CO2) augments phrenic responses resulting from specific carotid body hypoxia. A negative interaction may underlie the pathophysiology of central sleep apnoea in populations that are chronically hypocapnic.

Specific carotid body chemostimulation is sufficient to elicit phrenic poststimulus frequency decline in a novel in situ dual-perfused rat preparation

Time-dependent ventilatory responses to hypoxic and hypercapnic challenges, such as posthypoxic frequency decline (PHxFD) and posthypercapnic frequency decline (PHcFD), could profoundly affect breathing stability. However, little is known about the mechanisms that mediate these phenomena. To determine the contribution of specific carotid body chemostimuli to PHxFD and PHcFD, we developed a novel in situ arterially perfused, vagotomized, decerebrate rat preparation in which central and peripheral chemoreceptors are perfused separately (i.e., a nonanesthetized in situ dual perfused preparation). We confirmed that 1) the perfusion of central and peripheral chemoreceptor compartments was independent by applying specific carotid body hypoxia and hypercapnia before and after carotid sinus nerve transection, 2) the PCO(2) chemoresponse of the dual perfused preparation was similar to other decerebrate preparations, and 3) the phrenic output was stable enough to allow investigation of time-dependent phenomena. We then applied four 5-min bouts (separated by 5 min) of specific carotid body hypoxia (40 Torr PO(2) and 40 Torr PCO(2)) or hypercapnia (100 Torr PO(2) and 60 Torr PCO(2)) while holding the brain stem PO(2) and PCO(2) constant. We report the novel finding that specific carotid body chemostimuli were sufficient to elicit several phrenic time-dependent phenomena in the rat. Hypoxic challenges elicited PHxFD that increased with bout, leading to progressive augmentation of the phrenic response. Conversely, hypercapnia elicited short-term depression and PHcFD, neither of which was bout dependent. These results, placed in the context of previous findings, suggest multiple physiological mechanisms are responsible for PHxFD and PHcFD, a redundancy that may illustrate that these phenomena have significant adaptive advantages.

Increased propensity for apnea via dopamine-induced carotid body inhibition in sleeping dogs

We determined the effects of specific carotid body chemoreceptor inhibition on the propensity for apnea during sleep. We reduced the responsiveness of the carotid body chemoreceptors using intravenous dopamine infusions during non-rapid eye movement sleep in six dogs. Then we quantified the difference in end-tidal Pco(2) (Pet(CO(2))) between eupnea and the apneic threshold, the "CO(2) reserve," by gradually reducing Pet(CO(2)) transiently with pressure support ventilation at progressively increased tidal volume until apnea occurred. Dopamine infusions decreased steady-state eupneic ventilation by 15 +/- 6%, causing a mean CO(2) retention of 3.9 +/- 1.9 mmHg and a brief period of ventilatory instability. The apneic threshold Pet(CO(2)) rose 5.1 +/- 1.9 Torr; thus the CO(2) reserve was narrowed from -3.9 +/- 0.62 Torr in control to -2.7 +/- 0.78 Torr with dopamine. This decrease in the CO(2) reserve with dopamine resulted solely from the 20.5 +/- 11.3% increase in plant gain; the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal. We conclude that specific carotid chemoreceptor inhibition with dopamine increases the propensity for apnea during sleep by narrowing the CO(2) reserve below eupnea. This narrowing is due solely to an increase in plant gain as the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal control. These findings have implications for the role of chemoreceptor inhibition/stimulation in the genesis of apnea and breathing periodicity during sleep.

Ventilatory effects of specific carotid body hypocapnia and hypoxia in awake dogs.

Specific carotid body (CB) hypocapnia in the-10-Torr (less than eupneic) range reduced ventilation in the awake and sleeping dog to the same degree as did CB hyperoxia [CB PO2 (PCBO2); > 500 Torr; C.A. Smith, K.W. Saupe, K. S. Henderson, and J. A. Dempsey. J. Appl. Physiol. 79:689-699, 1995], suggesting a powerful inhibitory effect of hypocapnia at the carotid chemosensor over a range of PCO2 encountered commonly in physiological hyperpneas. The primary purpose of this study was to assess the ventilatory effect of CB hypocapnia on the ventilatory response to concomitant CB hypoxia. The secondary purpose was to assess the relative gains of the CB and central chemoreceptors to hypocapnia. In eight awake female dogs the vascularly isolated CB was perfused with hypoxic blood (mild, PCBO2 approximately equal to 50 Torr or severe, PCBO2 approximately equal to 36 Torr) in a background of normocapnia or hypocapnia (10 Torr less than eupneic arterial PCO2) in the perfusate. The systemic (and brain) circulation was normoxic throughout, and arterial PCO2 was not controlled (poikilocapnia). With CB hypocapnia, the peak ventilation (range 19-27 s) in response to hypoxic CB perfusion increased 48% (mild) and 77% (severe) due to increased tidal volume. When CB hypocapnia was present, these increases in ventilation were reduced to 21 and 27%, respectively. With systemic hypocapnia, with the isolated CB maintained normocapnic and hypoxic for > 70 s, the steady-state poikilocapnic ventilatory response (i.e., to systemic hypocapnia alone) decreased 15% (mild CB hypoxia) and 27% (severe CB hypoxia) from the peak response, respectively. We conclude that carotid body hypocapnia can be a major source of inhibitory feedback to respiratory motor output during the hyperventilatory response to hypoxic carotid body stimulation.

This Month in the Journal

This Month in the Journal

Invited editorial on "Ventilatory effects of specific carotid body hypocapnia in dogs during wakefulness and sleep"

Invited editorial on "Ventilatory effects of specific carotid body hypocapnia in dogs during wakefulness and sleep"

Ventilatory effects of specific carotid body hypocapnia in dogs during wakefulness and sleep.

We used extracorporeal perfusion of the vascularly isolated carotid sinus region to determine the effects of specific carotid body chemoreceptor hypocapnia-alkalosis on ventilatory control in the unanesthetized dog. Eight female dogs were studied during wakefulness, non-rapid-eye-movement (NREM) sleep, and rapid eye movement (REM) sleep. Carotid body perfusions lasted from 1 to 2 min, and each trial was preceded by a 1-min control period. Two levels of carotid body hypocapnia were employed, approximately 7 and 14 Torr below eupneic levels in a given dog. We found that 1) During wakefulness and NREM sleep, carotid body hypocapnia caused reduced tidal volume (VT) but not apnea or expiratory time prolongation. 2) The inhibition of ventilation in response to carotid body hypocapnia was graded below normocapnia, showing the highest sensitivity at carotid body PCO2 near 7 Torr below eupneic values. Inhibition reached a maximum near 14 Torr below the eupneic level; VT, inspiratory minute ventilation (VI), and VT-to-inspiratory time ratio fell 31, 23, and 27% in wakefulness and 30, 23, and 30% in NREM sleep. 3) Reductions in ventilation in response to carotid body hypocapnia are lessened but still persist throughout perfusion (up to at least 130 s) despite significant systemic hypercapnia. 4) During REM sleep, carotid body hypocapnia had no consistent inhibitory effect on ventilation until carotid body PCO2 was reduced to values near 14 Torr below the eupneic level, at which point ventilation was similar to wakefulness and NREM. 5) Moderate carotid body hypocapnia was as effective as carotid body hyperoxia in reducing VT and VI. We conclude that carotid body hypocapnia-alkalosis can significantly inhibit eupneic VT and ventilation during wakefulness and NREM sleep and, if the hypocapnia is severe enough, during REM sleep.

Effects of specific carotid body and brain hypoxia on respiratory muscle control in the awake goat.

1. We assessed the effects of specific brain hypoxia on the control of inspiratory and expiratory muscle electromyographic (EMG) activities in response to specific carotid body hypoxia in seven awake goats. We used an isolated carotid body perfusion technique that permitted specific, physiological, steady-state stimulation of the carotid bodies or maintenance of normoxia and normocapnia at the carotid bodies while varying the level of systemic, and therefore, brain oxygenation. 2. Isolated brain normocapnic hypoxia of up to 1.5 h duration increased inspired minute ventilation (VI) by means of increases in both tidal volume (VT) and respiratory frequency (fR). Electromyographic activities of both inspiratory and expiratory muscles were augmented as well. These responses were similar to those produced by low levels of whole-body normoxic hypercapnia. We conclude that moderate levels of brain hypoxia (Pa,O2 approximately 40 mmHg) in awake goats caused a net stimulation of ventilatory motor output. 3. Hypoxic stimulation of the carotid bodies alone caused comparable increases in VT and fR, and EMG augmentation of both inspiratory and expiratory muscles whether the brain was hypoxic or normoxic. These responses were quite similar to those obtained over a wide range of whole-body normoxic hypercapnia. We conclude that the integration of carotid body afferent information is not affected by moderate brain hypoxia in awake goats. 4. We found no evidence for an asymmetrical recruitment pattern of inspiratory vs. expiratory muscles in response to carotid body hypoxia or in response to brain hypoxia alone. 5. Our data support the concept that moderate brain hypoxia results in a net stimulation of respiratory motor output. These findings question the significance of 'central hypoxic depression' to the regulation of breathing under physiological levels of hypoxaemia in the awake animal.

The influence of carotid body chemoreceptors on expiratory muscle activity

Respiratory muscle EMG responses to transient, specific carotid body excitation (NaCN, hypoxia) and inhibition (dopamine, hyperoxia) were studied in 7 unanesthetized standing dogs while intact ( N = 7) and during bilateral cold block of the vagi ( N = 3). In all dogs carotid body excitation augmented the EMG activities of both expiratory muscles (triangularis sterni, TS; transversus abdominis, TA) and the (inspiratory) crucal diaphragm (CR); carotid body inhibition significantly reduced phasic EMG activities in all muscles. With vagal blocckade the response of the TS to carotid body stimulation was increased; that of the TA was essentially unchanged from the intact state. In all dogs expiratory muscle recruitment in response to carotid body excitation/inhibition could either precede or follow that of the CR. We conclude that in response to specific, transient carotid body excitation or inhibition: (1) Changes in CR, TS and TA EMGs are qualitatively similar. (2) Vagal feedback is strongly inhibitory to TS and excitatory to TA. (3) Changes in expiratory muscle EMGs do not require preceding changes in the CR. Carotid body stimulation contributes significantly to the generation of phasic expiratory activity during eupnea.

Carotid bodies and expiratory muscle recruitment

\ e have reported previously (FASEB J 1989; 3:A401) that specific carotid body stimulation/inhibition tended to recruit/derecruit expiratory muscles in the same direction, and with similar time course, as the diaphragm in unanesthetized dogs (N = 5). One limitation of that study was the presence of pulmonary vagal afferent traffic that could have had an effect on expiratory muscle recruitment independent of the direct carotid body effects. To address this question, we blocked the pulmonary stretch receptor afferent traffic by bilateral cooling ofexteriorized (skin loops) cervical vagi in 3 awake, tracheotomized dogs. Excitatory (NaCN, 3-5 breaths N2) and inhibitory (dopamine, 3-5 breaths O ) stimuli of the carotid bodies during vagal blockade produced effects similar to those seen in nonblocked dogs; recruitment/derecruitment ofexpiratory musdes (triarigularis sterni, transversus abdominis) was in the same direction and had the same time course as changes in the crural diaphragm. We conclude that pulmonary stretch receptor afferents are not required for inspiratory or expiratory muscle recruitment/derecruitment in response to carotid body stimuli.

Carotid Bodies and Expiratory Muscle Recruitment

e have reported previously (FASEB J 1989; 3:A401) that specific carotid body stimulation/inhibition tended to recruit/derecruit expiratory muscles in the same direction, and with similar time course, as the diaphragm in unanesthetized dogs (N = 5). One limitation of that study was the presence of pulmonary vagal afferent traffic that could have had an effect on expiratory muscle recruitment independent of the direct carotid body effects. To address this question, we blocked the pulmonary stretch receptor afferent traffic by bilateral cooling ofexteriorized (skin loops) cervical vagi in 3 awake, tracheotomized dogs. Excitatory (NaCN, 3-5 breaths N2) and inhibitory (dopamine, 3-5 breaths O ) stimuli of the carotid bodies during vagal blockade produced effects similar to those seen in nonblocked dogs; recruitment/derecruitment ofexpiratory musdes (triarigularis sterni, transversus abdominis) was in the same direction and had the same time course as changes in the crural diaphragm. We conclude that pulmonary stretch receptor afferents are not required for inspiratory or expiratory muscle recruitment/derecruitment in response to carotid body stimuli.

Local flow velocities in the cat carotid body tissue.

With the aid of a new three-dimensional mathematical model local flow velocities in the specific carotid body tissue of the cat measured by hydrogen clearances were calculated to have a mean value of 0.006 cm/s at a perfusion pressure of 50 mm Hg, 0.014 cm/s at a perfusion pressure of 120 mm Hg, and 0.018 cm/s at a perfusion pressure of 170 mm Hg. These results indicate that the carotid body specific tissue possesses a distinct flow heterogeneity with normal capillary flow velocities and a high shunt flow. During hypoxia, the smallest decrease in tissue PO2 was significantly correlated with the highest decrease in flow velocity. This suggests that the carotid body capillary network itself exhibits a PO2 sensor mechanism amplifying the chemoreceptive process in the specific cell elements.

Distribution of oxygen partial pressure in the carotid body region and in the carotid body (rabbit).

In the specific tissue of the rabbit carotid body as well as in the connective tissue surrounding the organ, pO2 distribution was measured with membrane-covered needle electrodes (tip diameter 1-2 microns). The histograms resulting from measurements in the specific tissue were shifted to low pO2 values as compared to other tissues. The oxygen blowing test, i.e. exposure of the carotid body to humidified 100% oxygen was employed to decide upon the site of measurement: pO2 increased when the electrode measured in the surrounding tissue (type 1 response); pO2 remained stable or slightly decreased when the electrode sampled in the specific carotid body tissue (type 2 response). After the experiment, the electrode track was reconstructed from histological serial sections and the type of reaction was related to the type of tissue. Low pO2 values were found to prevail in the specific carotid body tissue, which leads to the conclusion that the amount of low pO2 values determines the degree of chemoreceptor activity.