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J Appl Physiol 82: 118-124, 1997;
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Journal of Applied Physiology
Vol. 82, No. 1, pp. 118-124, January 1997
CONTROL OF BREATHING, CIRCULATION, AND TEMPERATURE

Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia

M. R. Dwinell, P. L. Janssen, J. Pizarro, and G. E. Bisgard

Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Dwinell, M. R., P. L. Janssen, J. Pizarro, and G. E. Bisgard. Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia. J. Appl. Physiol. 82(1): 118-124, 1997.---Hypoxic ventilatory sensitivity is increased during ventilatory acclimatization to hypoxia (VAH) in awake goats, resulting in a time-dependent increase in expired ventilation (VE). The objectives of this study were to determine whether the increased carotid body (CB) hypoxic sensitivity is dependent on the level of CB CO2 and whether the CB CO2 gain is changed during VAH. Studies were carried out in adult goats with CB blood gases controlled by an extracorporeal circuit while systemic (central nervous system) blood gases were regulated independently by the level of inhaled gases. Acute VE responses to CB hypoxia (CB PO2 40 Torr) and CB hypercapnia (CB PCO2 50 and 60 Torr) were measured while systemic normoxia and isocapnia were maintained. CB PO2 was then lowered to 40 Torr for 4 h while the systemic blood gases were kept normoxic and normocapnic. During the 4-h CB hypoxia, VE increased in a time-dependent manner. Thirty minutes after return to normoxia, the ventilatory response to CB hypoxia was significantly increased compared with the initial response. The slope of the CB CO2 response was also elevated after VAH. An additional group of goats (n = 7) was studied with a similar protocol, except that CB PCO2 was lowered throughout the 4-h hypoxic exposure to prevent reflex hyperventilation. CB PCO2 was progressively lowered throughout the 4-h CB hypoxic period to maintain VE at the control level. After the 4-h CB hypoxic exposure, the ventilatory response to hypoxia was also significantly elevated. However, the slope of the CB CO2 response was not elevated after the 4-h hypoxic exposure. These results suggest that CB sensitivity to both O2 and CO2 is increased after 4 h of CB hypoxia with systemic isocapnia. The increase in CB hypoxic sensitivity is not dependent on the level of CB CO2 maintained during the 4-h hypoxic period.

carotid body chemoreceptors; goats; respiratory control

INTRODUCTION

VENTILATORY ACCLIMATIZATION to hypoxia (VAH) is the time-dependent increase in ventilation or decrease in arterial PCO2 (PaCO2) during exposure to hypoxia. There is good evidence that increased ventilatory drive in VAH is related, at least in part, to a time-dependent increase in carotid body (CB) sensitivity to hypoxia (6, 9, 18, 25, 24).

The role of CO2 at the CB level has been overshadowed by the distinct importance of the CB's ability to respond to hypoxia and responses of the central chemoreceptors to changes in PaCO2. However, both hypercapnia and hypocapnia occur commonly in the systemic arterial blood supply, resulting in varying levels of CB CO2 exposure. Recently, it has been established that CB hypocapnic alkalosis is a powerful inhibitory influence on normoxic ventilation in the awake goat (7) and dog (23).

Normocapnic hypoxia applied to the isolated CB elicits VAH in awake goats (6). Carotid sinus nerve (CSN) activity also increases in a time-dependent manner when anesthetized goats are exposed to hypoxia (18). In both of these studies, CB PCO2 (PcbCO2) remained constant whereas CSN activity or ventilation increased in a time-dependent manner. In addition, in the awake goat, an increased hypoxic ventilatory sensitivity to hypoxia has been demonstrated under both systemic isocapnic and poikilocapnic conditions (9). In both awake and anesthetized cats, increased hypoxic sensitivities have been observed after prolonged hypobaric hypoxia with systemic poikilocapnia (24, 25). Awake rats exposed to hypobaric hypoxia for 7 wk developed an increase in hypoxic sensitivity when isocapnia was maintained (1). These studies suggest that the CB will become more sensitive to hypoxia regardless of the systemic level of CO2 (isocapnia or poikilocapnia). However, the effects of CB hypocapnia during VAH have not been investigated.

The specific goals of the present study were 1) to ascertain whether the increased CB hypoxic sensitivity is dependent on the level of CB CO2 and 2) to determine whether the CB CO2 gain is changed during VAH. This was accomplished by using the awake goat CB perfusion model, which allows separation of the CB circulation from the systemic [including central nervous system (CNS)] arterial circulation.

METHODS

Animal preparation. Ten adult goats were used in this study [mean body weight 55.2 ± 2.5 (SE) kg]. Nine of the ten goats were studied by using the first protocol (CB normocapnia). Seven of the ten (6 of the goats were studied twice) were studied by using the second protocol (CB hypocapnia). The animals were trained to stand quietly in a stanchion while breathing through a tightly fitting face mask equipped with a low-resistance one-way breathing valve (model 2700, Hans Rudolph). The inspiratory side was connected to a pneumotachograph (T-2, Fleisch) used to measure inspired air flow, which was electronically integrated to give inspired tidal volume (VT). Expired gases were collected in a spirometer (120 liter). Inspired ventilation was used during the experiment as an index of ventilation, although expired ventilation (VE) was used to precisely measure changes in ventilation. Inspired gases (room air and CO2) were delivered to the goat via large-bore flexible tubing (3-cm ID). A CO2 monitor (PM-20, Anarad) was used to monitor end-tidal CO2 from a port in the face mask. An O2 analyzer (model S-3A, Applied Electrochemistry) was used to monitor the inspired O2 concentration. A six-channel polygraph was used to record expired CO2, systemic arterial blood pressure, CB perfusion pressure, inspiratory flow, inspired VT, and expired minute volume.

Systemic arterial and extracorporeal circuit blood samples were drawn anaerobically into heparinized syringes and immediately analyzed for pH, PCO2, and PO2 (ABL3 M, Radiometer, Copenhagen, Denmark). The blood-gas values were corrected to the goat's rectal temperature.

CB perfusion model. The CB perfusion model has been described in detail previously (6), and a brief summary follows. The anatomic characteristics of cerebral blood flow in the goat provided a basis for surgical separation of brain and CB perfusion. Brain blood supply in the goat is obtained from the bilateral internal maxillary arteries via the rete mirabile. Because the contribution of the vertebral artery is negligible, ligation of one carotid artery at its bifurcation into internal maxillary and lingual arteries prevents the blood perfusing the ipsilateral CB from also perfusing the brain.

Two surgeries were required to rearrange the vasculature to allow CB perfusion with blood of independent gas tensions and pH from blood perfusing the systemic arterial system, including the brain. Both surgeries were carried out under general anesthesia (induction with intravenous thiopental sodium and maintenance with a mixture of ~1% halothane-30% nitrous oxide-balance oxygen). The first surgery consisted of unilateral ligation of the internal maxillary and lingual arteries on the CB perfusion side and, contralaterally, excision of the CB and ligation of the occipital artery on the brain perfusion side. After a minimum of 2 wk recovery, the second surgery was completed on the CB-intact side. This surgery involved insertion of polyvinyl catheters into the proximal common carotid artery for subsequent arterial blood-gas sampling and systemic blood pressure measurement. In addition, Silastic cannulas were placed in the distal common carotid artery for perfusion of the CB and in the right atrium via the external jugular vein for drawing blood into the extracorporeal circuit. An arteriovenous shunt was formed by connecting these two cannulas so that between the surgery and study blood flowed from the ipsilateral occipital artery through the upper segment of the carotid artery and returned via the externalized shunt to the right atrium. Heparin sodium (40,000 U, subcutaneously) was administered daily after this surgery.

During the study the extracorporeal perfusion circuit drew blood from the jugular cannula into a venous reservoir (Medtronic) by means of one head of a two-headed perfusion pump (Travenol). Blood was pumped from the reservoir by the second pump head through an oxygenator (Medtronic) and blood filter (Medtronic) and into the carotid artery perfusion cannula. Perfusion blood-gas tensions were changed by adjusting the relative concentrations of O2, CO2, and N2 flowing through the oxygenator. Blood was sampled, and perfusion pressure was measured by using a T connector located just proximal to the carotid artery cannula. Perfusion pressure was maintained 15-20 mmHg above systemic arterial pressure.

Protocol. Goats were studied no sooner than 6 days after the second surgery. After a control period of normoxic-normocapnic CB perfusion with the animal breathing room air, three acute responses were performed in each goat in random order. First, the CB was perfused with hypoxic-normocapnic blood whereas systemic isocapnia was maintained by adding CO2 to the inspiratory flow. Second, the CB perfusion was adjusted to deliver hypercapnic-normoxic blood to the CB while systemic isocapnia was maintained. Last, a whole body (systemic) CO2 response was performed by switching the CB perfusion off (systemic arterial blood perfused the CB) and adjusting the inspired CO2 to an inspired CO2 fraction of 0.03 and 0.05. Arterial blood gases were taken, and VE was measured 10 min after elevation of the level of inspired CO2.

After the initial responses, after the goats had returned to baseline conditions, a prolonged CB hypoxic exposure began. The extracorporeal circuit PO2 [CB PO2 (PcbO2)] was lowered to 40 Torr while isocapnic systemic PCO2 (PaCO2) was maintained. In the first group of animals (n = 9), CB normocapnia was maintained by keeping the extracorporeal circuit PCO2 (PcbCO2) at the same level throughout the 4-h hypoxic period (CB normocapnia). In the second group of goats (n = 7), PcbCO2 was progressively lowered as necessary throughout the prolonged hypoxic period to prevent any reflex hyperventilation (CB hypocapnia). In this group, no adjustments were necessary to maintain systemic isocapnia. In both groups, perfusion circuit and arterial blood-gas samples were taken every 10-15 min and adjustments were made to keep perfusion and systemic blood-gas tensions constant.

At the end of the 4-h period of CB hypoxia, both groups returned to control steady-state conditions within 30 min while being perfused with normoxic-normocapnic blood and breathing room air. All three acute responses were repeated after the prolonged hypoxia exposure.

Statistical analysis. The pre- and post-CB hypoxia slopes for the CB hypoxic response and slopes and intercepts for the CB and systemic CO2 response curves were analyzed by using paired t-tests. The ventilatory parameters during the 4-h hypoxic exposure were compared by using repeated-measures analysis of variance and Bonferroni correction for multiple comparisons. P < 0.05 was significant for all tests.

RESULTS

Blood gases. There were no changes in the pH of the perfusion circuit [CB pH (pHcb)] or of the systemic arterial blood before and after the 4-h CB hypoxic period (Tables 1 and 2). In the CB normocapnic group, pH and PaCO2 remained constant throughout the 4-h hypoxic period. Arterial PO2 (PaO2) rose slightly during the 4-h exposure to CB hypoxia-normocapnia as a consequence of the elevated VE from the CB hypoxic stimulation. Changes in pHcb in the CB hypoxic-hypocapnic group paralleled the changes in PcbCO2 during the hypoxic period. It was necessary to progressively reduce PcbCO2 during the CB hypoxia exposure in the hypocapnic group to keep VE constant (Fig. 1). Before the start of the 4-h CB hypoxia, control PcbCO2 was 40.2 ± 0.8 Torr. After 30 min of CB hypoxia, PcbCO2 was decreased significantly by 7.7 Torr (P < 0.05) and decreased by an additional 6.2 Torr (significantly lower than the 30-min measurement) by 240 min. PaCO2 remained constant throughout the CB hypoxic period in the hypocapnic group.

Table 1. Mean blood gas and pH data before, during, and after 4 h of CB hypoxia-normocapnia

Pre 30 min 60 min 120 min 180 min 240 min Post
PaO2, Torr 92.1 ± 2.7  126.0 ± 3.5  130.2 ± 4.2  133.1 ± 3.8  134.2 ± 4.0  133.6 ± 3.8  92.9 ± 2.6 
PcbO2, Torr 106.4 ± 2.3  41.2 ± 0.6  41.8 ± 1.0  40.7 ± 0.4  40.5 ± 0.6  40.3 ± 0.5  106.7 ± 2.8 
PaCO2, Torr 41.4 ± 0.8  40.8 ± 0.8  40.6 ± 0.9  41.0 ± 0.8  40.6 ± 0.9  41.0 ± 0.9  40.3 ± 1.0 
PcbCO2, Torr 40.8 ± 0.8  40.4 ± 1.0  39.8 ± 1.1  39.9 ± 1.1  40.1 ± 1.1  40.1 ± 1.1  40.4 ± 1.0 
pHa 7.397 ± 0.01  7.403 ± 0.01  7.404 ± 0.01  7.398 ± 0.01  7.400 ± 0.01  7.391 ± 0.01  7.396 ± 0.01 
pHcb 7.392 ± 0.01  7.406 ± 0.01  7.407 ± 0.01  7.408 ± 0.01  7.400 ± 0.01  7.398 ± 0.01  7.387 ± 0.01
Values are means ± SE. CB, carotid body; PaO2, arterial PO2; PcbO2, CB PO2; PaCO2, arterial PCO2; PcbCO2, CB PCO2; pHa, arterial pH; pHcb, CB pH; Pre, immediately before start of 4-h CB hypoxia; Post, 30 min after end of 4-h CB hypoxia.

Table 2. Mean blood-gas and pH data before, during, and after 4 h of CB hypoxia-hypocapnia

Pre 30 min 60 min 120 min 180 min 240 min Post
PaO2, Torr 95.1 ± 1.6  93.6 ± 2.4  93.4 ± 2.8  90.0 ± 2.5  90.1 ± 2.0  88.4 ± 2.9  93.6 ± 2.5 
PcbO2, Torr 111.8 ± 1.9  40.2 ± 0.4  39.2 ± 0.3  39.8 ± 0.3  40.2 ± 0.5  39.4 ± 0.3  102.7 ± 2.3 
PaCO2, Torr 41.3 ± 1.1  40.3 ± 1.1  40.4 ± 1.1  41.2 ± 1.1  40.3 ± 1.1  40.5 ± 1.2  39.6 ± 1.0 
PcbCO2, Torr 40.2 ± 0.8  32.5 ± 1.3  31.0 ± 1.1  28.0 ± 0.8  26.5 ± 1.1  26.3 ± 1.5  40.4 ± 0.8 
pHa 7.402 ± 0.01  7.416 ± 0.02  7.415 ± 0.01  7.410 ± 0.01  7.413 ± 0.01  7.415 ± 0.01  7.411 ± 0.01 
pHcb 7.399 ± 0.01  7.490 ± 0.01  7.507 ± 0.02  7.537 ± 0.02  7.557 ± 0.02  7.569 ± 0.02  7.394 ± 0.01
Values are means ± SE.

Fig. 1. Carotid body (CB) PCO2 (PcbCO2) during control (C), CB hypoxic exposure (0-240 min), and return to CB normoxia (R). Values are means ± SE. bullet , PcbCO2 during CB hypoxia-normocapnia; open circle , PcbCO2 during CB hypoxia-hypocapnia. * Significantly different from C, P < 0.05. ** Significantly different from 30 min, P < 0.05. All PcbCO2 values during CB hypoxia-hypocapnia are significantly different from the corresponding CB hypoxia-normocapnia values.
[View Larger Version of this Image (13K GIF file)]

VE. VE increased in a time-dependent manner throughout the 4-h CB hypoxic period when CB normocapnia and systemic isocapnia were maintained (Fig. 2A). VE significantly increased from a control level of 10.3 ± 1.1 to 22.9 ± 1.4 l/min at 30 min of hypoxia. By 240 min, VE had increased to 32.0 ± 2.1 l/min. Both frequency and VT increased in a time-dependent manner during the hypoxic exposure. Because the goal was to keep VE constant in the CB hypocapnic group, it was found to be necessary to progressively decrease PcbCO2 to achieve this goal (Fig. 1). This indicated that a progressive increase in hypoxic gain at the CB was occurring. However, when PcbCO2 was raised to the control level at the end of the hypoxic period (240 min), VE increased to 27.3 ± 3.3 l/min (Fig. 2B; open circle ).
Fig. 2. Expired ventilation (VE) during C, CB hypoxic exposure (0-240 min), and R. A: CB normocapnia. B: CB hypocapnia. open circle , At 250 min, VE after PcbCO2 was elevated from hypocapnia to normocapnia during CB hypoxia. Values are means ± SE. * Significantly different from C, P < 0.05. ** Significantly different from 30 min, P < 0.05.
[View Larger Version of this Image (13K GIF file)]

Acute isocapnic CB hypoxia-normocapnia responses. Both groups showed a prompt increase in VE during acute exposure to CB hypoxia-normocapnia with systemic isocapnia (Fig. 3; preacclimatization slopes: -0.155 ± 0.02 l · min-1 · Torr-1, isocapnic group; -0.172 ± 0.05 l · min-1 · Torr-1, hypocapnic group). These increases were due to increases in both frequency and VT. After the 4-h hypoxic exposure, and after 30 min of normoxic-normocapnic conditions, the slope of the ventilatory response to acute isocapnic CB hypoxia was significantly greater than the slope of the response before the hypoxic period in both the CB normocapnic and CB hypocapnic groups (Fig. 3; postacclimatization slopes: -0.322 ± 0.04 l · min-1 · Torr-1, isocapnic group; -0.308 ± 0.04 l · min-1 · Torr-1, hypocapnic group). The responses of the two groups were not significantly different from each other.
Fig. 3. Changes in VE during acute exposure to isocapnic CB hypoxia. A: before and after CB hypoxia-normocapnia. B: before and after CB hypoxia-hypocapnia. PcbO2, CB PO2. bullet , Preacclimatization hypoxic re- sponse; open circle , postacclimatization response. Values are means ± SE. * Slope of postacclimatization hypoxic ventilatory response is significantly different from preacclimatization hypoxic ventilatory response slope, P < 0.05.
[View Larger Version of this Image (13K GIF file)]

CB CO2 responses. The ventilatory response to CB hypercapnia (systemic normoxia and isocapnia) was determined before and after 4 h of CB hypoxia. The CB normocapnic group had a significantly increased slope and PcbCO2 intercept (Table 3) after prolonged CB hypoxia (Fig. 4A), whereas the systemic blood-gas and acid-base values were not different (Table 4). The CB hypocapnic group demonstrated no change in slope or PcbCO2 intercept and no changes in blood-gas or acid-base values after prolonged CB hypoxia (Fig. 4B) with no changes in blood-gas or acid-base values (Table 5).

Table 3. Linear regression data for ventilatory response curves to CB CO2 before (Pre) and after (Post) 4 h of CB hypoxia while either CB normocapnia or CB hypocapnia is maintained

Slope, l · min-1 · Torr-1 PcbCO2 Intercept, Torr r2
Normocapnia (n = 7)
Pre 0.54 ± 0.1  18.7 ± 3.9  0.95 ± 0.02 
Post 0.96 ± 0.2* 26.1 ± 3.9* 0.96 ± 0.03 
Hypocapnia (n = 7)
Pre 0.40 ± 0.1  15.6 ± 3.5  0.83 ± 0.14 
Post 0.56 ± 0.2  18.3 ± 7.1  0.83 ± 0.12
Values are means ± SE; n, no. of goats. * Significantly different from preacclimatization systemic CO2 response, P < 0.05.

Fig. 4. Changes in VE during acute CB CO2-response curves. A: before and after CB hypoxia-normocapnia. B: before and after CB hypoxia-hypocapnia. bullet , Preacclimatization hypoxic response; open circle , postacclimatization response. Values are means ± SE. * Slope of postacclimatization hypercapnic ventilatory response is significantly different from preacclimatization hypercapnic ventilatory response slope, P < 0.05.
[View Larger Version of this Image (15K GIF file)]

Table 4. Mean blood-gas and acid-base values for CB CO2 response before and after 4 h of CB hypoxia-normocapnia

PaO2, Torr PcbO2, Torr PaCO2, Torr PcbCO2, Torr pHa pHcb
Pre
  Control 85.0 ± 4.1  97.8 ± 4.4  41.0 ± 1.0  39.6 ± 1.1  7.394 ± 0.01  7.397 ± 0.01 
  8% CB CO2 109.9 ± 5.0  103.4 ± 4.0  41.0 ± 1.1  49.9 ± 1.8  7.400 ± 0.01  7.322 ± 0.02 
  10% CB CO2 124.2 ± 6.1  101.8 ± 3.6  41.7 ± 1.1  62.0 ± 2.3  7.401 ± 0.01  7.249 ± 0.01 
Post
  Control 95.3 ± 2.6  103.2 ± 2.0  39.9 ± 1.3  40.7 ± 1.2  7.403 ± 0.01  7.389 ± 0.01 
  8% CB CO2 121.8 ± 5.8  103.5 ± 2.4  41.0 ± 1.0  51.4 ± 1.7  7.391 ± 0.01  7.301 ± 0.01 
  10% CB CO2 133.8 ± 4.9  101.1 ± 2.0  40.1 ± 0.9  62.3 ± 2.1  7.390 ± 0.01  7.227 ± 0.01
Values are means ± SE.

Table 5. Mean blood-gas and acid-base values for CB CO2 response before and after 4 h of CB hypoxia-hypocapnia

PaO2, Torr PcbO2, Torr PaCO2, Torr PcbCO2, Torr pHa pHcb
Pre
  Control 91.2 ± 2.5  107.7 ± 3.4  40.4 ± 1.0  40.1 ± 0.8  7.401 ± 0.01  7.394 ± 0.01 
  8% CB CO2 112.0 ± 4.3  106.4 ± 1.1  40.2 ± 0.9  52.5 ± 1.0  7.406 ± 0.01  7.303 ± 0.02 
  10% CB CO2 124.0 ± 3.5  103.1 ± 1.8  40.2 ± 1.0  64.3 ± 0.8  7.409 ± 0.01  7.233 ± 0.02 
Post
  Control 90.9 ± 2.6  104.9 ± 1.6  39.5 ± 1.2  40.3 ± 1.1  7.410 ± 0.01  7.391 ± 0.01 
  8% CB CO2 118.0 ± 5.3  105.5 ± 1.1  39.4 ± 1.0  51.3 ± 1.1  7.409 ± 0.01  7.304 ± 0.01 
  10% CB CO2 126.4 ± 5.9  100.3 ± 1.2  39.5 ± 1.2  63.5 ± 0.9  7.409 ± 0.01  7.235 ± 0.01
Values are means ± SE.

Whole body CO2 responses. The response to whole body (CB and CNS) arterial hypercapnia was determined before and after 4 h of CB hypoxia. No change in slope or PaCO2 intercept was demonstrated in either group (CB normocapnia or CB hypocapnia) after prolonged CB hypoxia (Table 6). The slopes of the ventilatory response to CO2 were similar between both groups both before and after 4 h of CB hypoxia. The proportion of the CB chemoreceptor contribution to the whole body CO2 response was calculated by subtracting the slope of the CB CO2 response from the slope of the systemic CO2 response for each animal. The additive effect of central and peripheral chemoreceptor stimulation in awake goats has been previously described (8).

Table 6. Linear regression data for ventilatory response curves to systemic CO2 before (Pre) and after (Post) 4 h of CB hypoxia while either CB normocapnia or CB hypocapnia is maintained

Slope, l · min-1 · Torr-1 PaCO2 Intercept, Torr r2 %CB
Normocapnia (n = 9)
Pre 2.60 ± 0.2  35.1 ± 1.4  0.92 ± 0.05  0.21 ± 0.2 
Post 2.55 ± 0.3  34.2 ± 1.5  0.94 ± 0.02  0.36 ± 0.06 
Hypocapnia (n = 7)
Pre 2.91 ± 0.6  35.0 ± 1.1  0.96 ± 0.02  0.17 ± 0.04 
Post 2.72 ± 0.2  34.6 ± 0.9  0.98 ± 0.01  0.20 ± 0.05
Values are means ± SE; n, no. of goats. %CB, contribution of CB chemoreceptors to systemic CO2 response.

DISCUSSION

This study demonstrates that exposure to CB hypoxia alone elicits an increase in CB sensitivity to hypoxia regardless of the level of CO2 at the CB during the prolonged exposure to hypoxia. Similar increases in sensitivity to CB hypoxia were seen in both groups after prolonged exposure to hypoxia. Exposure to CB hypoxia, while CB normocapnia is maintained, resulted in an increase in the ventilatory response to CB hypercapnia. However, no increase in CB sensitivity to hypercapnia was observed when the CB was hypocapnic (i.e., progressively lowered throughout the hypoxia to prevent reflex hyperventilation), although there was a trend toward an increased response. In addition, the present study provides no evidence that CB hypoxia alters the whole body ventilatory response to CO2.

Critique of methods. This study used the CB perfusion model to separate CB and brain blood flow to examine the effects of prolonged CB stimulation on ventilation without the effects of the central chemoreceptors. Specifically, we were interested in the effects of hypoxia and hypercapnia on the CB before and after hypoxic stimulation. Isolation of the perfused blood to the CB without mixing with blood perfusing the brain was required. Busch et al. (6) demonstrated by using various techniques (acrylic polymer casts, cerebral angiography, radiolabeled microspheres, and blood-gas tension comparison) that there is no significant mixing of blood between perfused and systemic blood. In addition, arterial blood-gas tensions and pH of samples drawn from the perfusate and from the proximal common carotid artery in the present study did not suggest that mixing was occurring.

The present study measured VE during normocapnic-hypoxic and hypocapnic-hypoxic CB perfusion. The effect of normocapnic-hyperoxic CB perfusion has been previously tested (6) by perfusing the CB for 6 h under control conditions. No time-dependent ventilatory effects or changes in blood-gas tensions during the 6 h of CB perfusion were found. The effects of prolonged CB hypocapnia-normoxia have not been investigated, although acute CB hypocapnia has been reported to have significant inhibitory influences on ventilation (7).

Acclimatization. These results are consistent with findings from several previous experiments demonstrating that VAH is nearly complete within 4 h of exposure to hypoxia in the awake goat (9, 10, 19, 20, 22). A previous experiment (6) demonstrated that CB hypoxia-normocapnia alone, without CNS hypoxia, was sufficient to elicit VAH, as seen by a time-dependent decrease in PaCO2 during the prolonged exposure to hypoxia. Bisgard et al. (3) showed that isolated CB hypoxia could elicit VAH while maintaining systemic isocapnia. The findings in the present study provide additional support that CB hypoxic stimulation alone without brain hypoxia or systemic respiratory alkalosis will elicit VAH.

In the CB hypocapnic group, the requirement to progressively decrease PcbCO2 (by 14 Torr) during 4 h of hypoxia is strong evidence that VAH occurred during CB hypocapnia. That is, there was a time-dependent increase in CB sensitivity to hypoxia that had to be counterbalanced by greater hypocapnia to keep VE constant. Additional evidence for VAH in this group was the significantly increased response to CB hypoxia after the 4-h CB hypoxia exposure. This is consistent with previous studies in which VAH has been demonstrated (9, 19, 20). Also, when PcbCO2 was elevated to the control level at the end of the 4-h hypoxic period, VE increased beyond the acute hypoxic level to nearly the level of VE seen at the end of the 4-h hypoxic period in the CB normocapnic group.

Under normal conditions at high altitude, inspired PO2 is lower than at sea level, resulting in a lower PaO2. This stimulates the carotid chemoreceptors and VE increases, resulting in a decrease in PaCO2. After the immediate response, the CB is exposed to low PaO2 but also to a lower PaCO2 than normal. The effect of the hypoxia and hypocapnia interaction would be an attenuated afferent output from the CB, although a greater output than under normoxic-normocapnic conditions. The results from the present study may suggest that the time-dependent increase in CSN activity would be inhibited by a time-dependent decrease in PaCO2, resulting in no net increase in ventilation due to the CB. Two previous studies in awake goats measuring decreases in PaCO2 as the criterion for VAH report acute decreases in PaCO2 after 30 min of hypoxia between 4.8 and 6.7 Torr below control levels (6, 9). In the present study, PcbCO2 was lowered 7.7 Torr after 30 min of hypoxia and by a total of 13.9 Torr by the end of the 4-h hypoxic exposure. These PCO2 values are lower than those described in the previous studies, indicating that carotid afferent activity would still be elevated above the control level, resulting in ventilatory acclimatization to hypoxia. Although PaCO2 values are progressively lowered through VAH when the whole animal is exposed to hypoxia, the time-dependent decrease in PaCO2 is a result of the time-dependent increase in CSN nerve afferent activity, which, in turn, is translated into a progressive increase in VE.

CO2 sensitivity. The CB CO2 response after VAH revealed different responses depending on the type of stimulus during the 4-h hypoxic period. After CB hypoxia-normocapnia, the CB response to elevated CO2 was significantly elevated, although the CB response to elevated CO2 after CB hypoxia-hypocapnia was not significantly elevated. One possible explanation for the lack of increase after CB hypoxia-hypocapnia is a persistent acid-base change during the hypocapnic perfusion that prevented the increased response. Gonzales et al. (13) suggested that a depression of the transducing mechanism for acidic stimuli may alter catecholamine release from the CBs, resulting in a reduced response to an acidic stimulus. Additional studies using isolated type I cells from rat CBs demonstrate that changes in external pH result in altered internal pH and may affect the chemotransduction process (4, 5).

The ventilatory response of the CB to change in PCO2 in the hypocapnic range may be important, especially in the CB hypocapnic group. This was not investigated in the present study, but it may have revealed a change that was not seen when only PCO2 levels were used in the hypercapnic range. We assume that there is probably no change in this slope between pre- and post-VAH measurements, based on extrapolation, which could be erroneous.

The proportion of CO2 response mediated by the CB can be determined by using the isolated CB perfusion model. In the present study, the CB is responsible for between 17% (hypocapnic group) and 21% (normocapnic group) of the systemic CO2 response. The proportion remains unchanged after 4 h of CB hypoxia-hypocapnia, whereas it increased to 36% of the systemic response after 4 h of CB hypoxia-normocapnia. A previous study estimated the contribution of the carotid chemoreceptors to be between 20 and 50% of the total response to CO2 in anesthetized cats with use of an artificial pontomedullary perfusion method (14). Another study using anesthetized cats before and after carotid chemoreceptor denervation (2) reported that the carotid chemoreceptors contributed 40% to the overall respiratory response to CO2. The present results in awake goat suggest that the proportion is somewhat lower than originally reported, although the conditions of the stimulus varied considerably. In the present study, the animals were awake and both the peripheral and central chemoreceptors were intact, although only one CB was intact. In the previous studies, the animals were anesthetized, studied before and after the CSN was cut, and, in one case, perfused with an artificial perfusate in the pontomedullary region. In addition, the method of determining the percentage of CB CO2 response in the present study was by subtraction, not by addition, of peripheral and central responses to CO2.

Results of the present study for the whole body CO2 response are in contrast to those reported in a similar study using awake goats (9). Engwall and Bisgard (9) reported an increase in the CO2 response slope when isocapnia was maintained throughout the hypoxic period. When isocapnia was not maintained (poikilocapnia), the slope did not change but a parallel leftward shift was shown. Data from the present study do not support a change in slope or PaCO2 intercept when systemic isocapnia and CB normocapnia-hypoxia were maintained or when PcbCO2 was progressively lowered during the hypoxic exposure (CB hypocapnia-hypoxia). The major difference in the present study is that the hypoxia stimulus was isolated to the CB, whereas Engwall and Bisgard exposed the whole animal to hypoxia. In humans, exposure to prolonged hypobaric hypoxia results consistently in a leftward shift of the CO2-response curve (12, 15, 21, 26), and most investigators also report an increased ventilatory response slope to CO2 (12, 15, 21). Leftward shifts and increased slopes of CO2 responses that have been reported after VAH in humans are likely associated with cerebral acid-base changes associated with brain hypocapnia. In the present study, the central chemoreceptor response to CO2 would not be expected to change because CNS oxygenation and acid-base were kept constant in all conditions in the present studies (except during the systemic CO2 response). Increased whole body CO2 response slopes and leftward shifts have also been documented in ponies (11) and in cats (24). However, although the response to CO2 in goats does shift leftward (16, 17), the increase in ventilatory response slope is not a uniform finding. Lahiri et al. (16) did report a 70% increase in slope, whereas Mines and Sorensen (17) saw no increase in slope but only a leftward shift. Engwall and Bisgard (9) reported an increased slope when isocapnia was maintained and a leftward shift with no slope change when PaCO2 was allowed to fall.

The lack of change in systemic CO2 ventilatory response in this study may be attributed to the following factors. 1) As outlined above, there was neither CNS hypoxia nor acid-base changes induced during isolated CB hypoxic acclimatization; thus there is no reason to expect a resetting or change in the central chemoreceptor responsiveness. 2) There is inherent variability in ventilatory responses to CO2 that have been documented in the goat (8). 3) Last, the CB contributes only ~20% (see above) of the systemic CO2 ventilatory response.

In conclusion, we investigated the role of CO2 at the CB during VAH. This study confirmed our previous observation that VAH can be induced by an isolated hypoxic stimulus to the CB and is evident under either normocapnic or hypocapnic conditions at the CB. The increase in CB sensitivity to hypoxia is independent of the level of CB CO2. However, the CB CO2 sensitivity appears to be dependent on the level of CB CO2 during the hypoxic stimulus. The increase in CB CO2 gain was only evident when the excitatory afferent output from the CB is maintained (CB hypoxia-normocapnia).

ACKNOWLEDGEMENTS

The authors thank Gordon Johnson for excellent technical assistance.

FOOTNOTES

   This research was supported by National Heart, Lung, and Blood Institute Grants HL-15473 and HL-07654.

Address for reprint requests: G. E. Bisgard, Dept. of Comparative Biosciences, School of Veterinary Medicine, Univ. of Wisconsin, 2015 Linden Dr. West, Madison, WI 53706.

Received 10 June 1996; accepted in final form 9 September 1996.

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