The role of brief hypocapnia in the ventilatory response to CO2 with hypoxia

Respiration Physiology (1976) 28. 333-346 0 Elsevier/North-Holland

Biomedical Press

THE ROLE OF BRIEF HYPOCAPNIA IN THE VENTILATORY TO CO, WITH HYPOXIA’

RESPONSE

L. C. OU and S. M. TENNEY Department of Physiology, Dartmouth Medical School, Hanover, N. H. 03755, U.S.A.

Abstract. In conscious cats the ventilatory response curve to physiological range of CO, is displaced upward by hypoxia (about 45 torr), but it rises, either parallel with, or convergent on, the normoxic curve. Thus, a positive interaction of hypoxia and hypercapnic stimuli is not observed under these circumstances. However, if during the hypoxic exposure, hypocapnia is allowed to develop, the subsequently determined CO, ventilatory response curve will shift to the left, rise steeply, particularly in the early phase, and demonstrate a positive hypoxic-hypercapnic interaction. A demonstrable interactive effect was dependent on a conditioning period of hypocapnia, and this was shown to be associated with an elevated level of lactic acid to a greater degree in cerebral venous blood than in CSF or arterial blood. The interpretation is discussed without reaching a firm conclusion of mechanism, but the results emphasize how a minor change of experimental protocol affects a basic phenomenon in the chemical control of breathing.

Cerebral blood flow Cerebral lactic acid CO, ventilatory response

Control of breathing Hypocapnia Hypoxic-hypercapnic

interaction

The interaction of hypoxia and CO, as stimuli to produce a multiplicative response of ventilation is generally considered a normal characteristic of the human respiratory control system (Nielsen and Smith, 1951; Loeschcke and Gertz, 1958; Lloyd et al., 1958; Cormack et al., 1961). Further, such an interactive effect is also demonstrable when measured as the neural output of the carotid body of cats (Witzleb et al., 1955; Hombein et al., 1961; Fitzgerald and Parks, 1971). In both anesthetized and unanesthetized dogs there is a slight hypoxic-hypercapnic interaction (Mitchell et al., 1966; Honda and Kreuzer, 1966; Cherniack et al., 1970/71), but in unanesthetized goats there is none, or very little (Tenney and Brooks 1966; Mines and !Sqrensen, 1970; Smith and Kellogg, 1975). In decerebrate cats there is none (Rosenstein et al., 1974)

Accepted for publication I3 September 1976.

’ This work was supported by Grant PHS HL 02888-16 of the National Heart and Lung Institute, National Institutes of Health. 333

334

L. C. OU AND S. M. TENNEY

and we have found in many studies conducted with unanesthetized cats over the past five years that a multiplicative response to combined hypoxia and CO, is rarely observed. The usual effect of hypoxia in this species is, in fact, a negative interaction (Ou et al., 1976), although Lahiri and DeLaney (1975) have recently published curves obtained from anesthetized cats that show a positive hypoxic-hypercapnic interaction. In our standard protocol with cats, when hypoxic gas mixtures are introduced, it has been customary to enrich the inspired air with enough CO, to prevent ~~~~~ from falling. One day we noted, after a period of hypoxic hypocapnia which had unwittingly been allowed to occur, that the cat had developed a response characteristic for hypoxic-hypercapnic interaction. This finding was confirmed, and the purpose of the present report is to identify its origin. The most likely explanation for a change of response brought about by a period of hypocapnic hypoxic conditioning (HH), contrasted with a period of eucapnic hypoxic (HE) conditioning, is the presence of a metabolic acidosis in the former, but not the latter. It is well known that hypocapnia, even without hypoxia, leads to an increase in CNS lactic acid production (Plum and Posner, 1967). This would provide an added respiratory drive, due to the increased cerebral and CSF [H+], but in itself, a central acidosis need not predispose to interaction of respiratory stimuli. In exploring the role of lactic acid in ventilatory responses to hypoxia and CO,, an opportunity was also provided for examining the relative importance of stimuli at different cerebral locations - CSF, arterial blood, and venous blood - since lactate will not accumulate in equal concentrations in each site. The results may also be relevant to early respiratory changes in acclimatization to high altitude.

Methods EXPERIMENTS ON UNANESTHETIZED

ANIMALS

Four cats, 2 males and 2 females, weighing 3 to 4 kg, were studied in this series. Several weeks prior to the experiments a gas sampling catheter (1 mm I.D.) was installed in the trachea (Scotto and Naitove, 1970) under ketamine hydrochloride (30 mg/kg). Ventilatory measurements were subsequently made in the awake condition with the cat sitting or lying quietly in a 27-liter (26 x 26 x 40 cm) plexiglass whole body plethysmograph. From the pressure changes in the box associated with the warming and humidifying of the inspired gas, the value of the tidal volume (VT) can be calculated, as described by Drorbaugh and Fenn (1955). Calibration was made with known volumes of air injected into the box. The respiratory frequency was taken directly from the pressure record. The details of this method and its experimental validation have been reported (Bartlett and Tenney, 1970); the characteristics of the particular plethysmograph used in the present study have also been reported (Gautier et al., 1973).

VENTILATORY

RESPONSE TO co,

IN CONSCIOUS CATS

335

The experimental protocol consisted of measuring the steady-state CO, ventilatory responses while the cats were breathing either room air or a hypoxic gas mixture. In the latter cases, CO, response was studied under two different conditions : hypoxic eucapnic (HE) and hypoxic hypocapnic (HH) conditions. Under the HE conditions, the animals were given a hypoxic inspired gas while alveolar Pco2 was controlled at the normal room air value by adding appropriately CO, into the breathing gas mixture. After twenty minutes of HE conditioning, the ventilatory response to graded CO, was studied with the degree of hypoxia controlled at the established level. In the case of HH conditioning, the animals were exposed to a hypoxic inspired mixture to produce the same alveolar PO2as in HE conditions, but no attempt was made to control CO, and the animals became hypocapnic. After 20 minutes of HH conditioning, the ventilatory response to graded CO, was studied under controlled hypoxia.

EXPERIMENTS ON ANESTHETIZED

ANIMALS

Six cats, 4 males, 2 females, weighing 3.5-5 kg, were anesthetized with an intraperitoneal injection of allobarbital (60 mg/kg) and urethane (240 mg/kg). Catheters were placed in the femoral artery, femoral vein, and in the cerebral sagittal sinus. A 20-gauge B-D longwell catheter needle was placed in the cisterna magna for CSF sampling. The sagittal sinus catheter was secured by means of dental cement to a stainless steel screw fixed to the skull. The cisterna magna catheter was secured with a stereotaxic manipulator. The free ends of both sagittal sinus and cisterna magna catheters were cemented to a plastic adapter suited for micropipettes of different sizes. The trachea was cannulated and from it gas was sampled continuously at the rate of 100 ml/min through a catheter placed in the airway. CO, was analyzed by an infrared CO, meter (Beckman LB-l) and 0, with a Westinghouse oxygen monitor. Outputs of both CO, and 0, analyzers were recorded on a polygraph (Grass Instrument Co.). The animals breathed through a low-resistance, low dead space non-rebreathing valve, inhaling from a 35-liter reservoir plastic bag and exhaling into a 9-liter water spirometer (Collins). Rectal temperature was monitored by a thermistor, connecting to a Yellow-Spring temperature controller. The body temperature was maintained at 37-38 “C by means of a heating pad. Experimental protocol was similar to that designed for the studies on unanesthetized animals. It included measuring the ventilatory CO, response under three experimental conditions, normoxic (N), hypoxic eucapnic (HE), and hypoxic hypocapnic (HH), as explained previously. The protocol for sampling and measurements is schematically illustrated in fig. 1. The curves are labeled to indicate the three basic experimental conditions. The numbers denote the loci at which measurements were made according to the protocol key. Under control and HE conditions, ventilatory response to CO, was measured only at two levels of arterial Pco2 - eucapnic (Points

336

Fig.

L. C. OU AND S. M. TENNEY

I. Schematic

(numbered

points)

the hypoxic

portrayal under

conditions

of ventilation

three experimental

as a function

of alveolar

conditions.

The normoxic

P,02 to illustrate condition

are: ‘HE’, those which did not allow any decrease

those under a comparable

degree of hypoxia

but with hypocapnia

allowed

of alveolar to develop

sampling

is labeled,

loci

‘control’;

P,,>, and ‘HH’,

in the conditioning

period.

1 and 3) and hypercapnic (Points 2 and 4). Under HH conditions, ventilatory CO, response was measured at 3 levels of Pa,, L: hypocapnic (Point 5) eucapnic (Point 6) and hypercapnic (Point 7). While the level of hypocapnia associated with hypoxic breathing was a characteristic for each cat, depending on its degree of hypoxic responsiveness, the eucapnic and hypercapnic points were experimentally controlled at a comparable level under the three conditions in all cats. Although the ventilatory CO, response under normoxic conditions was invariably studied first for each cat in the present study, the sequence of the study of the CO, response under HE and HH was alternated randomly. At the time of each ventilatory measurement, arterial and sagittal sinus (also referred to as cerebral venous) blood and CSF samples were drawn simultaneously. The arterial and venous blood samples were immediately analyzed for pH, Pco, and Po,. The CSF sample was analyzed only for total CO,. An additional 0.5 ml of arterial blood and 0.05 ml of sagittal sinus blood and CSF samples were also immediately withdrawn and quantitatively transferred into test tubes containing 0.5 ml of 6 “/, perchloric acid for subsequent lactic acid analysis. Samples for lactate determination were stored in a freezer until analysis was made.

ANALYTICAL

TECHNIQUE

All determinations of blood gas tensions and pH were made at 37 ‘C with a Radiometer pH meter. Total CO, in CSF was determined by the Natelson microgasometer, and this value was used to calculate the bicarbonate concentration. The pH of the CSF sample

was estimated

[HCO;]CSF PH,,,

= pR,,,+

log

SCSF . Pco2

indirectly

according

to the equation,

VENTILATORY

RESPONSE

TO co,

IN CONSCIOUS

CATS

337

in which [HCO;] was determined by analysis, and the value for Pco2 in CSF was estimated either as equal to that in sagittal sinus blood (method I), or as equal to (Pace,! + Pv,oz)/2 + 1 (method II), as proposed by Ponten and Siesjo (1966). Lactic acid was determined by the method of Barker and Summerson (1941).

Results UNANESTHETIZED

CATS

The results obtained from studies on the four awake cats were similar, and for illustration, fig. 2 provides the data from one of them. In all cases, the initial slopes of the ventilatory CO, response curves under HH conditions were steeper than those of the CO, response curves obtained under normoxic conditions. Although the increase of slope of the HH curves was uniformly observed at low and intermediate levels of PAco2, at higher CO, levels, the HH curve decreased in slope and became about parallel with the normoxic curve. In contrast, the slopes of the ventilatory CO, response curves under HE conditions were no different from the normoxic CO, response curves throughout. The group mean alveolar Po, under HH and HE conditions were 5 l_+ 4 and 52 + 3 torr, respectively.

ANESTHETIZED

ANIMALS

Initially, it was determined that the general character of the ventilatory responses of the anesthetized cats under N. HE and HH conditions matched the unanesthetized , PAO,=~O-48

VE L/min

1

PACO,

Fig. 2. A characteristic

experiment

illustrated

I

50

40

30

mmHg

by one cat in the series of studies

on conscious

animals.

Minute volume of ventilation is shown as a function of end tidal Pco in an awake cat under three conditions. The control study was under normoxic (PAN* > 100 torr) conditions; the middle curve was obtained under hypoxic conditions out the pre-test,

hypoxic

and with end tidal Pcol closely controlled at the control (eucapnic) level throughconditioning period; the upper curve was under the same hypoxic conditions,

but hypocapnia

was allowed

to develop

in the conditioning

period.

338

L. C. OU AND S. M. TENNEY TABLE

Average

arterial arterial

and cerebral

venous oxygen pressures

CO, following

a period

Hypoxic

of hypoxic

hypocapnic

B%*

pa,>

I .4

1 (torr

hypocapnic

(HH) pvoi

+ SD) for six cats, each studied under graded and hypoxic

eucapnic

Hypoxic _

eucapnic

conditioning (HE)

Pa,,?

Pa,:

Pvo,

Hypocapnia

23.3 +

38.3k4.2

24.2k3.Y

Normocapnia

30.6 +4.Y

46.3k4.1

29.9 + 5.0

31.5&4.1

43.1 +6.2

21.5k3.Y

Hypercapnia

42.Yk3.3

47.2k2.3

40.6k2.7

41.3k2.0

46.0 f 5.0

37.

I ) 3.9

cats. The essential fact was that normoxic (N) and hypoxic (HE) CO, response curves were either parallel or convergent. They never diverged. Once this had been established, and since the purpose of the study was to compare and contrast HE and HH conditions, the remainder of the experiments were restricted to a study of those two conditions. Practically, the number of samples that could be taken were necessarily limited, and this forced a decision to omit further close consideration of the normoxic response. Table 1 shows the mean values of the Po2 in arterial and venous bloods under hypoxic eucapnic (HE) and hypoxic hypocapnic (HH) initial conditions with samples drawn at the particular points diagrammed in fig. 1. There was no significant difference between the HH and HE arterial or cerebral venous PO2values, at comparable eucapnic and hypercapnic levels. Simultaneously determined ventilatory measurements as a function of Pco2 are plotted for each cat in fig. 3. The curves of ventilatory response as a function of arterial Pco2 under HH conditions were shifted to the left, and the initial slopes were steeper, in comparison with those obtained after HE initial conditions. The slopes of the HH curves in the higher Pco2 range diminished, with the result that they were terminally either parallel to, or sometimes converged towards, the HE curve, more often the former. Thus, the 9~ : Paco2 curves from anesthetized animals reflect consistently the VE : PACT>curves of awake animals, and suggest that analysis of relevant events made under anesthesia will be pertinent to the unanesthetized state. Comparing the ventilatory response as a function of cerebral venous Pco, rather than as a function of arterial Pco2 emphasizes an important difference in the shape of curves, most notably under HH conditions. In all cats studied, the CO, ventilatory response curves under HH conditions more closely approximated a straight line relationship if the Pco2 of the cerebral venous blood was plotted as the stimulus index (independent variable). The two-phase character of the \i : Paco2 plot is less apparent, the reason being that the cerebral veno-arterial Pco2 difference narrows in the high Pco2 range. Figure 4 shows that the pattern of ventilatory response to [Hf] of the arterial blood under HH and HE conditions was similar to that observed on the arterial CO, plots (cJ fig. 3) viz., the initial sensitivity of the ventilatory response to [H+] of the

VENTILATORY

LL30

20

RESPONSE

40

50

60

TO co,

70

P

co2

20

IN CONSCIOUS

30

40

50

60

CATS

339

70

torr

Fig. 3. Minute volume of ventilation is shown as a function of Pco,, under two hypoxic (Pa,* = 50 torr) conditions: eucapnic (HE) and hypocapnic (HH) (see text). Each graph portrays the experimental results from a single cat, and each data point indicates the mean of three experiments. The data are grouped in the HE series with dotted connecting lines, and for the HH series with solid connecting lines. Solid points (A and 0) are arterial values, and open points (A and 0) are cerebral venous values. Horizontal lines connecting arterial and venous points in each series are drawn to emphasize the arterio-venous Pco2 differences.

arterial blood was greater under HH than under HE conditions. In contrast, the ventilatory response as a function of the [H+] of the cerebral venous blood, or [H+] of CSF, under HH and HE conditions, generally tended more closely to be described by a single relationship. Exceptions are noted in one cat in the case of the cerebral venous [H+], and two cats in the CSF [H ‘1 plot. These data are also shown on fig. 4. The changes in the [H’] of the cerebral venous and arterial bloods, and of CSF, with the rise of arterial Pco2, are shown in fig. 5. In the cerebral venous and arterial bloods the curves of [H’] under HH conditions were displaced upward, i.e., there was a higher [H’] for the same Pea, than for the HE conditions. In the CSF the curves (methods I and II for the calculation of CSF gave similar results) for the data obtained under HH and HE conditions overlay one another. The [HCO;] in the HH condition was lower in all compartments than under HE condition (2 mM less in the blood and 1 mM less in CSF). The fact that the increase in P,, 2 of the CSF and of cerebral venous blood under HH conditions was less, at the established arterial hypercapnic level, than under HE conditions (probably

340

L. C. OU AND S. M. TENNEY

I

1

30 40

,

I

50 60

70

80

[H+l nM Fig. 4. Minute volume ofventilation as a function of [H’], under the two hypoxic conditions, HE shown by triangles and HH by circles. The key for symbols is as follows: arterial, A@ ; cerebral venous, 80 ; CSF, 00.

explained by the difference in cerebral blood flow rate) explains how, in these compartments, there was a difference of [HCO,] but not of [H+] (fig. 5). Table 2 summarizes the data concerning lactic acid concentrations in three compartments and under the various experimental conditions. In each compartment TABLE 2 Lactic acid concentrations Condition

Pa,ol (torr)

Normoxic Hypoxic-eucapnic Hypoxic-hypocapnic

(HE) (HH)

HE-N; HH-HE all compartments condition.

34.3+4.1 45.4k4.9 31.5k4.1 41.9k2.0 23.3fl.4 30.6k4.9 42.9k3.3

(mM/liter)

Cerebral lactate Arterial

Venous

0.69 + 0.43 0.65 +0.24 1.30+0.41 1.57kO.42 2.10+0.55 2.18kO.47 2.36 kO.72

I.01 +0.%3 1.18kO.19 1.93 *0.69 I .93 kO.67 3.07 +0.92 3.13*1.19 3.48k1.47

P i 0.05; SS-Art. under HE and HH conditions;

CSF lactate

1.24kO.52 I .25,0.32 l.84+0.35 1.74+0.37 2.48 kO.38 2.51 kO.21 2.35 +0.28 SS-CSF under HH

VENTILATORY

RESPONSE

TO co,

v csF

o---,

IN CONSCIOUS

CATS

1 1 H+l / PssCOz

30

40

50

60

30

40

50

60

30

40

50

60

30

40

50

60

Pa, ss

341

CO,

Fig. 5. [H+] in arterial blood (od), cerebral venous blood (*A) and CSF (OA) as a function of P,02 at the relevant site. The data shown by circles are from HH experiments, and those shown by triangles are from HE experiments. Subscripts for Pco, refer to arterial (a) or sagittal sinus (ss) blood, the latter referable to both CSF and cerebral venous PC,,*.

and under each condition, the lactic acid concentration did not change significantly with a change in Pco2. However, when two lactate values, obtained at a similar Pacoz 7 but under different breathing conditions (N; HH; HE) were compared, the following order of concentrations was obtained: HH > HE > N. The present results therefore indicate that the level of hypoxia employed in this study stimulated lactic acid production, and hypocapnia, in the presence of hypoxia, further enhanced this metabolic process. The data also showed that under HH and HE conditions, the mean lactate concentration of the cerebral venous blood was significantly higher than that of the arterial blood. Further, under HH conditions, when the lactate production was

342

L. C. OU AND

S. M. TENNEY

3.0-

,0 x N

2.0-

00

--I

8

z/

N

‘0” 0 A 0”

LO-

I.

3oP,co,4o

Fig. 6. Reciprocal of cerebral veno-arterial CO, content difference (as an index of cerebral blood flow rate) shown as a function of arterial Pco,, under the three experimental conditions. The points represent data from 126 experiments on 6 cats.

most activated, the concentration of lactic acid in the cerebral venous blood was signi~cantly higher than in CSF. Cerebral veno-arterial CO, concentration differences (Cv,02- Ca,02) were estimated by using the CO, dissociation curve of Bartels and Harms (1959) together with measured blood gas pressures. Assuming that, in the cat as in man, cerebral oxygen consumption was unaffected by hypoxic, hypoxic hypocapnic and hypercapnic conditions (Kety and Schmidt, 1948) the reciprocal of which is shown in fig. 6, is taken to be an index of cerebral cerebral (Cvco, -Ca,oJ blood flow. Although curves under both HH and HE conditions were displaced upward from the normoxic conditions, the difference between HE and normoxic conditions was not significant. The effect of CO, on cerebral blood flow under HH conditions was significantly greater in the higher CO, range than under either HE or normoxic conditions.

Discussion The experiments reported here represent but a few of a large number of studies performed in this laboratory using unanesthetized cats, all of which are consistent in showing that it has been very rare to find a multiplicative interaction between hypoxia and CO, on ventilation in that species, if the alveolar Pco2 is never allowed to fall below normal, particularly during the period of hypoxic exposure. Since there is good evidence which favors the peripheral chemoreceptor as the site of multiplicative ventilatory response in man (Bemards ef al., 1966; Torrance, 1968; Swanson and Belkille, 1974) and direct measurements of carotid body activity definitely show a multiplicative response (Hombein et al., 1961; Eyzaguirre and Levin, 1961; Fitzgerald and Parks, 1971) and most of these experiments have used

VENTILATORY

RESPONSE TO co,

IN CONSCIOUS

CATS

343

cats, it is surprising not to find consistently a hypoxic-hypercapnic ventilatory interaction in this species. Our results do differ from those of Lahiri and Delaney (1975) in this regard, and Edelman et al. (1969) have also postulated a central site as important for the genesis of the interactive effect. It may well be significant that their studies have all been with anesthetized animals, while the majority of ours have been with fully conscious animals. Still, the experiments reported in this paper include some studies on anesthetized cats and there was no positive interaction. What is clear from these experiments is the fact that, in a study of the effect of hypoxia on 9~ : ~~~~~ curves, if hypocapnia occurs during the initial hypoxic period in one (HH), but not in the other (HE), two quite different results will follow. First, there will be in the HH series a higher VE, for a given ~~~~~ and PAN*,than in the HE; and second, the slope (~~E/PA~~,) of the line in the HH case will be steeper, most notably in the range of PA,-~>roughly bridging the hypocapnic to eucapnic interval. If the ~~~~~ was increased further, the HH and HE lines were most often found to be parallel, but sometimes HH converged on HE. The data show, without a doubt, that the lactic acid concentration of the blood and CSF was higher in the HH than in the HE series. This was to be expected (Plum and Posner, 1967). The cerebral venous blood concentration was always higher than the arterial, thus establishing the brain as a principal site of lactate production; and also, the increase of blood lactate concentrations was greater than of CSF, probably indicating slower diffusion into the CSF space. Referring back to the ventilatory response curves (figs. 3 and 4) several questions come immediately to mind. Is the upward displacement of the HH, 9~ : Pacoz line from the HE line (figs. 3 and 4) to be explained by a greater arterial [H+] in the HH series? Figure 4 shows that this is not the case generally. otherwise the HH and HE lines ought to overlap, although for one cat this is nearly the case. A comparable question with reference to venous PcoZ or [H ‘1 might be more revealing, because cerebral venous values are likely to be more nearly in equilibrium with cerebral tissue than are the arterial. Figure 4 suggests that plotting cerebral venous [H ‘1 unifies the HH and HE series, at least for half of the animals. Of course, if the conditions of the experiments are such that cerebral blood flow has been altered, then that also will affect the cerebral venous values and the interpretation of ventilatory response (Lambertsen, 1968). From fig. 3 it is seen that the cerebral (Pvco2 -PacoJ difference is, in fact, smaller in the HH than the HE series, particularly in the hypercapnic range. The effect of narrowing the veno-arterial Pco, difference is to diminish slightly the curvilinearity of the HH plots of %‘E as a function of Pvco>, in comparison with $‘E as a function of Paco2. Finally, using the CSF [H’] as index of stimulus intensity does not improve much on the cerebral venous data in a search for a unifying relationship. Recapitulating, the arterial [H’J data (fig. 4) do not lead to any improvement of understanding of the reasons for the displacements of HH over HE curves in fig. 3, but the CSF and cerebral venous [H’] data do bring the HH and HE series closer together and thus establish that the relevant site of the problem is central. In brief, there was a central metabolic acidosis with hypoxia of the degree studied, and it was more severe

344

L. C. OU AND S. M. TENNEY

if the hypoxia was initially attended by hypocapnia, and the effect was to cause a greater ventilatory response. Hence, the displacement of the curves. The increase of slope (d\j~/dP~~~~) in the HH series of experiments, over the HE series, was demonstrable (see fig. 2) into the hypercapnic range, but not to its limit. In the conscious cats (fig. 2) the ventilatory increments began to wane as Paco2 rose above about 40 mm Hg, and in the anesthetized cats (fig. 3) the increase of slope in the hypocapnic range of HH series, reverted to the HE slope once the eucapnic point was passed. Although we observed a well-defined ‘hockey stick’ in one of the conscious cats, we were unable to demonstrate this phenomenon in other conscious or anesthetized cats. Since there was no significant further increase of lactic acid concentration in arterial or cerebral venous bloods, or in CSF, when the Pcol was raised from hypocapnic to eucapnic levels, the ventilatory response must have been solely due to the APco2. It appears that the metabolic state has enhanced the ventilatory response to CO,, but this is supported neither by the majority of experiments performed to test this very possibility (Kellogg, 1964), nor by the observed fact in these experiments that, beyond the normal PACT>,the HH curves become either parallel with, or even converged on, the HE curves. In other words, if there were an interaction of CO, and metabolic acidosis it ought not to be restricted to the hypocapnic range. Hence, although the rise of CNS lactate accounts for the upward displacement of the ventilatory response curves in the HH series, it is not a satisfactory explanation of the increase of slope. To some extent, it must be concluded that the problem of explaining the interaction is not one of mechanism, but is rather one of being misled by convention. If most of the ventilatory drive originates centrally, then cerebral venous is a more apt index of stimulus than is arterial Pco2 (or, [H+]); and, if cerebral blood flow is changing during the experiment, it would be easy to infer a change of ‘response’ to the arterial value when, in fact, nothing of the sort occurred if examined against the ‘true’, say cerebral venous, stimulus intensity. The curves of fig. 3 show a general, but by no means uniform, tendency for the 9~ : Pvco2 curves to be straighter than the \j~ : Paco2 curves, and this is the predicted effect of changing cerebral blood flow. Using central [H+], expressed in CSF or cerebral venous blood, leads to some further straightening of the response curves, and this also would be expected. Even though these manipulations lead to a considerable resolution of the problem, there still remains, no matter how expressed, a steeper ventilatory response in the HH series, in the hypocapnic, than in the hypercapnic, zone. The data do not permit a conclusion as to whether this is a true hypoxic-hypercapnic interaction, restricted to the hypocapnic zone, or whether the question should be asked the other way around. Does a rise of CO,, above eucapnic levels, attenuate the reception of some information centrally (Gesell et al., 1940) as well as stimulate the generation of a central respiratory drive?

VENTILATORY

RESPONSE

TO co,

IN CONSCIOUS

345

CATS

Acknowledgement

The authors acknowledge with thanks the expert professional assistance provided in certain phases of this work by Drs. D. Bartlett, Jr. and E. E. Nattie.

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