Carotid Body Perfusion Research Articles

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2.

We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the central chemoreceptors to CO2 . The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body PCO2 ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of central chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with PCO2 of 19-75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO2 response slopes were increased 303% for minute ventilation (V̇I)(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT /TI ) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO2 response slopes for tidal volume (VT ), breathing frequency (fb ) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO2 response slopes were also increased 237% for V̇I(P ≤ 0.01) and 249% for VT /TI (P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body chemoreceptors are driven by a wide range of O2 and/or CO2 .

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2

We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.

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).

Can carotid body perfusion act as a respiratory controller?

The carotid bodies contain chemoreceptor cells that respond to hypoxia and hypercapnia/acidosis of the arterial blood. Since the carotid bodies receive exceptionally high blood perfusion through branches of the external carotid artery, their impulse activity to the respiratory center is thought to be determined mainly by the arterial partial pressures of oxygen (O 2) and carbon dioxide (CO 2). However, this paradigm explains the observed increase in ventilation neither during mentally agitated states nor physical exercise. The objective of the work was to test whether physiologically feasible reductions in carotid body perfusion could explain such respiratory overdrive using a flow-sensitive mathematical model of the carotid body chemoreception. The model is based on the law of mass balance and on the description of the chemical reactions in the arterial blood and inside the receptor cells. The neural response to the arterial O 2 and CO 2 levels is assumed to be mediated via the controller's intracellular O 2 partial pressure and pH. The model predicts that the O 2 response is affected even by moderate changes in blood flow, whereas the CO 2 response is not altered until blood flow is severely limited. Reducing blood flow increases neural stimulus but decreases sensitivity to changes in the partial pressures of arterial O 2 and CO 2. An example is given in which relatively small changes in blood flow significantly modify the carotid body sensitivity to CO 2. These results suggest that limiting perfusion of the carotid bodies through vasoconstriction can offer a powerful mechanism to drive breathing beyond metabolic needs. This observation may provide important insight into the control of ventilation, e.g., during transition from wakefulness to sleep, before physical exercise or during panic attack.

Ventilatory responses to specific CNS hypoxia in sleeping dogs.

Our study was concerned with the effect of brain hypoxia on cardiorespiratory control in the sleeping dog. Eleven unanesthetized dogs were studied; seven were prepared for vascular isolation and extracorporeal perfusion of the carotid body to assess the effects of systemic [and, therefore, central nervous system (CNS)] hypoxia (arterial PO(2) = 52, 45, and 38 Torr) in the presence of a normocapnic, normoxic, and normohydric carotid body during non-rapid eye movement sleep. A lack of ventilatory response to systemic boluses of sodium cyanide during carotid body perfusion demonstrated isolation of the perfused carotid body and lack of other significant peripheral chemosensitivity. Four additional dogs were carotid body denervated and exposed to whole body hypoxia for comparison. In the sleeping dog with an intact and perfused carotid body exposed to specific CNS hypoxia, we found the following. 1) CNS hypoxia for 5-25 min resulted in modest but significant hyperventilation and hypocapnia (minute ventilation increased 29 +/- 7% at arterial PO(2) = 38 Torr); carotid body-denervated dogs showed no ventilatory response to hypoxia. 2) The hyperventilation was caused by increased breathing frequency. 3) The hyperventilatory response developed rapidly (<30 s). 4) Most dogs maintained hyperventilation for up to 25 min of hypoxic exposure. 5) There were no significant changes in blood pressure or heart rate. We conclude that specific CNS hypoxia, in the presence of an intact carotid body maintained normoxic and normocapnic, does not depress and usually stimulates breathing during non-rapid eye movement sleep. The rapidity of the response suggests a chemoreflex meditated by hypoxia-sensitive respiratory-related neurons in the CNS.

Contribution of peripheral chemoreception to the depression of the hypoxic ventilatory response during halothane anesthesia in cats.

The effects of inhalational anesthetics on the hypoxic ventilatory response are complex. This study was designed to determine the contribution of peripheral chemoreception to the depression of hypoxic ventilatory response seen with halothane anesthesia. Cats were anesthetized with pentobarbital sodium and alpha-chloralose and artificially ventilated. Respiratory output was evaluated by phasic inspiratory activity of the phrenic nerve. In 12 cats, this activity was measured during inhalation of an hypoxic gas mixture with halothane, 0, 0.1, and 0.8%, with intact or denervated carotid bodies. In 10 cats, a carotid body was isolated from the systemic circulation and perfused with hypoxic Krebs-Ringer solution equilibrated with halothane, 0, 0.1, and 0.8%. The hypoxic ventilatory response was depressed in a dose-dependent manner during halothane anesthesia. In carotid body perfusion studies, the response was significantly depressed only with halothane, 0.80%. The hypoxic ventilatory response is depressed by a high dose of halothane through a peripheral effect at the carotid body.

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.

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.

Central-peripheral chemoreceptor ventilatory interaction in awake goats

This study was designed to characterize the ventilatory interaction between central and carotid body (CB) chemoreceptor stimulation in awake goats undergoing selective CB perfusion. This model allowed us to expose central and CB chemoreceptors to separate blood gas conditions in an animal that is conscious and not systemically hypoxic. Systemic CO 2 ventilatory response curves, performed by progressively increasing FI CO2 in systemic hyperoxia, were completed in 7 goats during CB perfusion with hypercapnic-hypoxic blood and normocapnic-normoxic blood, and in 3 goats without CB perfusion. The slopes of the curves done with perfusion were not significantly different ( P > 0.05) in CB hypercapnic hypoxia and CB normocapnic normoxia for V̊ E, V T, f and V T/T I, and the coefficients of variation of slopes generated with and without perfusion were similar. Our data indicate there is addition of central and CB chemoreceptor input in respiratory control, and we conclude that the previously demonstrated stimulus interaction at the CB is the primary source of the hyperadditive hypercapnic-hypoxic ventilatory interaction in an animal unaffected by anesthetics or brain hypoxia.

Carotid body hypercapnia does not elicit ventilatory acclimatization in goats

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 CO 2 = 78Torr, mean Pcb O 2 ≅ 100 Toor) produced acute hyperventillation (mean decrease in Pa CO 2 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 O 2 = 40 Torr, mean PcB CO 2 = 39 Torr) produced an acute mean in Pa CO 2 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 CO 2 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.

Ventilatory acclimatization to hypoxia is not dependent on cerebral hypocapnic alkalosis.

We previously demonstrated that, in awake goats, 6 h of hypoxic carotid body perfusion during systemic normoxia produced time-dependent hyperventilation that is typical of ventilatory acclimatization to hypoxia (VAH). The hypocapnic alkalosis that occurred could have produced VAH by inducing cerebral vasoconstriction and brain lactic acidosis even though systemic arterial normoxia was maintained. In the present study we tested the hypothesis that hypocapnic alkalosis is a necessary component of VAH. Goats were prepared so that one carotid body could be perfused, from an extracorporeal circuit, with blood in which gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Using this preparation we carried out 4 h of hypoxic carotid body perfusion while maintaining systemic arterial (and brain) normoxia in awake goats. Expired minute ventilation (VE) was measured while CO2 was added to inspired air to maintain normocapnia. Carotid body PCO2 and PO2 were maintained near 40 Torr during the 4-h carotid body perfusion. Control mean VE was 8.65 +/- 0.48 l/min (mean +/- SE). With acute carotid body hypoxia (30 min) VE increased to 21.73 +/- 2.02 l/min (P less than 0.05); over the ensuing 3.5 h of carotid body hypoxia, VE progressively increased to 39.14 +/- 4.14 l/min (P less than 0.05). These data indicate that neither cerebral hypoxia nor hypocapnic alkalosis are required to produce VAH. After termination of the 4-h carotid body stimulation, hyperventilation was not maintained in these studies, i.e., there was no deacclimatization. This suggests that acclimatization and deacclimatization are produced by different mechanisms.

Mathematical analysis and digital simulation of the respiratory control system.

Abstract : The report expresses the basic material balance relationships for the lung-blood-tissue gas transport and exchange system in a set of differential- difference equations containing a number of dependent time delays. Additional equations define the chemical details of transport and acid-base buffering, concentration equilibria, and blood flow behavior. Finally, a control function is included defining the dependence of ventilation upon CSF (H(+)), and arterial (H(+)) and PO2 at the carotid chemoceptors. A Fortran program was written for convenient digital simulation of the responses of the system to a wide variety of forcings, including CO2 inhalation, hypoxia at sea level, altitude hypoxia, and metabolic disturbances in acid-base balance. Both dynamic and steady-state behavior of the model were reasonably realistic.