The ventilatory and metabolic response to hypercapnia in newborn mammalian species

ELSEVIER

Respiration Physiology 103 (1996) 263-270

The ventilatory and metabolic response to hypercapnia in newborn mammalian species Jacopo P. Mortola a,*, Clement Lanthier

b

a Department of Physiology, McGill University, 3655 Drummond Street, Montreal, Quebec. tt3G I Y6. Canada b Soci~t~ Zoologique de Granby. Granby. Quebec, Canada

Accepted 13 November 1995

Abstract Conscious newborns of 12 species from 4 mammalian orders, ranging in body mass (M) from 1 g (mouse) to 5 kg (deer), were studied during air and during 5% CO 2 breathing. The interspecies relationship between oxygen consumption (X/o2) and M was the same in air and hypercapnia, in both cases Vo2 ct M°'9°; on average, hypercapnic "Qo2 was 101% of the air value. In 5% CO 2, ventilation ('QE) increased in all newborns, mostly because of the increase in tidal volume (178%), whereas breathing rates averaged 98% of the air values. The hyperpnea during CO 2 was slightly greater in the larger newborns. Body temperature was not altered by CO 2 breathing. We conclude that the average respiratory response of the newborn to moderate hypercapnia is a hyperventilation different from that of the neonatal mammal in acute hypoxia (Mortola et al., Respir. Physiol. 78: 31-43, 1989). In fact, hypercapnic hyperventilation resulted only from the hyperpnea, with no hypometabolic contribution, and the hyperpnea reflected the increase in tidal volume, with no change in rate. It is also concluded that the neonatal hypometabolic response is specific to hypoxia, and not an undifferentiated response to chemoreceptors stimulation. Keywords: Allometry; Hypercapnia; Mammals, 12 species; Neonate; 02 consumption

1. Introduction In acute hypoxia, hyperventilation represents the most frequent, and probably most immediate, response. Its magnitude, reflected by the drop in arterial PCO 2, depends on the degree of hyperpnea and the metabolic change. A m o n g adult mammals, the hypometabolic response is c o m m o n in the smallest species, which have the highest normoxic metabolic

* Tel.: 1 514/398-4335; Fax: I 514/398-7452.

rates (Frappell et al., 1992b). In newborn mammals, the decrease in metabolic rate during hypoxia is also very common, and is often even more prominent than the increase in ventilation (Mortola et al., 1989). To what extent the neonatal response to acute hypercapnia is similarly characterized by a change in metabolic rate is not completely clear. In fact, only a few studies have addressed the issue of a metabolic effect of CO 2 in newborn mammals, and the results are mixed (Vfirnai et al., 1970, Vfirnai et al., 1971; Mortola and Matsuoka, 1993; Saiki and Mortola, 1996). However, differences in experimental conditions preclude meaningful interspecies comparisons

0034-5687/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0034-5687(95)00093-3

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J.P. Mortola, C. Lanthier / Respiration Physiology 103 (1996) 263-270

porcupine, gerbil, hamster, rat), Carnivora (cat, dog, arctic fox), Lagomorpha (rabbit), Artiodactyla (pig, deer, african goat). Between 2 and 20 animals were studied per species, except for the african goat of which only one specimen was available. All newborns were about 1 month old or less, most being within a week after birth. Details about the age and the weight of the animals studied are provided in Table 1. The experiments consisted of measurements of breathing pattern and oxygen consumption in normoxia (21% 02, air) and hypercapnia (5% CO 2, 21% O z, balance N2). Measurements of breathing pattern were performed individually by the barometric method, in which case they were combined with the metabolic measurements, or by flow plethysmography (rats, mice, hamsters, rabbits, gerbils). With the barometric method, the newborn is resting in a chamber through which a steady flow of gas is delivered. For short periods of time, the flow is interrupted and the chamber sealed; the oscillations in air temperature determined by breathing can be measured as pressure oscillations, and converted into lung volume changes by appropriate correction factors. The flow plethysmograph permits a direct measurement of lung ventilation, by recording airflow via a pneumotachograph connected to a body plethysmograph, and integrating the signal to measure the changes in lung volume. Both methodologies have been previously described in detail (Mortola, 1984; Mortola and Piazza, 1987; Saetta

and generalizations; in fact, the numerous factors potentially involved in determining the metabolic response, including the heat loss of the hyperpnea, the metabolic stimulus of the hypothermia, catecholamine release and the depressant effect of the acidosis, can vary depending upon the amount of inspired CO 2. With the present study we attempted an interspecies analysis of the ventilatory and metabolic responses to a moderate degree of hypercapnia (5% inspired CO 2) in conscious newborn mammals. By studying specimens from 12 species of 4 mammalian orders, ranging in size from just above 1 gram to about 5 kg, we tested the hypothesis of a body-mass dependency of the metabolic response to hypercapnia and of its similarity to that of hypoxia. Therefore, the goal has not been that of describing the response of a particular species, rather that of obtaining insights into the general pattern of the mammalian response in the early postnatal period. Confirmation or rejection of the hypothesis would, respectively, give support or deny the idea that hypometabolism is an undifferentiated response to chemoreceptors stimulation.

2. Methods

Experiments were conducted on conscious newborns of 4 mammalian orders, Rodentia (mouse, Table 1 Number of animals, mean age, body weight, and ambient temperature Species

Mouse (Mus musculus) Hamster (Mesocricetus auratus) Gerbil (Meriones unguiculatus) Rat (Rattus norvegicus) a Rabbit (Oryctolagus cuniculus) Cat (Felis catus) b Dog ( Canis familiaris) a Arctic fox ( Alopex lagopus) Porcupine (Erethizon dorsatum) Pig (Sus scrofa) Goat ( Capra aegagrus blythi) Deer (Odocoileus virginianus)

Age (days)

No. of animals

VE

9o~

2 3 4 10 3 20 6 2~ 2 2 1 2

12 8 8 10 3 12 6 2 2 2

6 3 9 6 3 5 5 32 20 5

I

5

2

5

a From the data of Saiki and Mortola (1996). b From the data of Mortola and Matsuoka (1993).

Body weight (g)

1

5 7 13 84 102 444 376 1050 1675 1900 4900

Tamb (°C)

33 32 31 33 31 28 28 25 23 27 26 25

J.P. Mortola, C. Lanthier / Respiration Physiology 103 (1996) 263-270

played on a computer monitor during on-line acquisition. V'o: was computed as the product of the inflow-outflow difference of the 0 2 concentration, averaged over several minutes, multiplied by the flow rate, therefore neglecting the small error introduced by a respiratory exchange ratio less than unity (Frappell et al., 1992a). Measurements were conducted first in normoxia (21% O2), then in hypercapnia (5% CO 2, 21% 0 2, balance N2), in each case between 30 to 60 rain from the onset of the exposure, when the animal was quiet and the recorded trace showed a steady plateau. Of the smallest five species in which breathing patte .rn was measured by flow plethysmography, Vo2 and VE were measured simultaneously in newborn rats (Saiki and Mortola, 1996); in the other species Vo2 was measured separately, a few hours before or after the VE measurements, either individually (rabbits) or in groups of a few animals (mice, gerbils, hamsters), this latter approach to increase the signal. Even in this latter case, in the metabolic chamber the pups were kept separated by a metal mesh, to avoid the effect of huddling on metabolic rate (Alberts, 1978; Saiki and Mortola, 1996). In all cases, data were normalized by the weight of the animal(s).

and Mortola, 1987). Between 50 to 200 breaths were continuously recorded on paper by a Gould pen recorder at a speed of 5 or 10 mm/sec, during air or hypercapnia, after the animal was exposed to the desired gas for about 30-60 min. The records were later analysed with the help of a graphics tablet connected to a minicomputer for calculation of inspiratory and expiratory times (T I and T E, sec), breathing frequency [f = 6 0 / ( T 1 + TE), breaths/min], tidal volume (V T, mlBTPS), and minute ventilation (VE, ml BTPS/min). Oxygen consumption (Vo:, mlsTpD/min) was measured by an open-flow system (Frappell et al., 1992b). The metabolic chamber consisted of a transparent Plexiglas chamber, chosen from a size range between 40 ml to 36 liters. The flow was maintained constant at a rate of 100 ml-3600 mlSTPD/min, depending upon the size of the chamber, and controlled by a calibrated flowmeter. The inflowing and outflowing concentrations of the gas were passed through a drying column (Drierite) before being monitored by a calibrated infrared CO 2 analyser (Beckman model LB-2, Anaheim,CA,USA) and a polarographic 0 2 analyser (Beckman model OM-11, Anaheim,CA, USA). Gas concentrations were dis-

100

• 0

".~

265

t b fdeer ~oig

Hypereapnia: slope 0.90

. . ~ ~ ~r~.goat porcupine

G9

~a

Q~ E

1

~

~

~ 0.1

~

rabbit

r~t

7 g erbil J @. , ~J Vhamster j mouse

,. . O Normocapnia: slope 0.90

I

t

i

i

I

i0

I00

I000

Bod:y zveigh~, g Fig. 1. Body weight-oxygen consumption relationship (in logarithmic scale) of newborn mammalian species during normoeapnia (open symbols) and hypercapnia (5% CO 2, filled symbols). Values represent the mean of the animals studied for each species. The slopes of the corresponding allometric relationships are indicated; the two curves did not significantly differ from each other.

J.P. Mortola, C. Lanthier / Respiration Physiology 103 (1996) 263-270

266

Table 2 Equations of ventilation and oxygen consumption in normocapnia and hypercapuia Y

X

Slope

a

Sb

r2

P

Normocapnia Vo2

M

0.90 a.b

0.038

0.028

0.995

~'z

M

0.98 ~'

0.986

0.035

0.993

VE

Oz

1.07 a.t,

35.7

0.035

0.994

M

0.08 a,b

25.5

0.032

0.602

VE/~'O 2 5% CO 2 Vo2

M

0.90 a.b

0.038

0.027

0.995

ns

VE

M

1.05 a.t,

0.082

0.016

0.992

< 0.001

~/E

~QO2

1.14 a.b

54.6

0.034

0.995

< 0.001

~rE/fJo2

M

0,145 a,t,

31.0

0.03

0.825

< 0.001

Regression equations of the form log Y = log a + b - log X (log-transformed version of the exponential Y = a. X b). Sb, standard deviation of the slope. I)o2, oxygen consumption, mls.rPt>/min. VE, minute ventilation, mlBTps/min. M, body mass, g• In all cases N = 12. a Significantly different from unity. b Significantly different from 0. P = slope differs significantly from that of the corresponding normocapnic curve, ns, slope does not significantly differ from the corresponding normocapnic curve ( P > 0.05).

For both the ventilatory and metabolic measurements, ambient temperature (Tamb) was controlled by use of heating lamps, and continuously monitored by tungsten-constantan thermocouples (Omega model DP30, Stamford, CT, USA); the value of Tamb chosen for the measurements corresponded to the most common temperature which the newborn was exposed to when under maternal care (Table 1); this value, ranging between 31-33°C in newborn rodents to about 23-25°C in the newborn porcupine and deer (Table 1) was usually higher than environmental temperature, and invariably lower than thermoneutrality. Colonic or oropharyngeal temperature, taken as representative of body temperature (Tb), was also measured by fine tungsten-constantan thermocoupies, calibrated with a mercury thermometer, in air and immediately upon termination of the CO 2 exposure. The equations relating a variable to body mass (allometric equations) or to Vo2 were calculated using the mean values of each species, in order to avoid a bias toward those species with a larger number of specimens. The exponents and intercepts were derived from the least-squares regression analysis of the logarithm of the basic data. The critical level of the correlation coefficients (r) and differences in slope (b, the exponent of the log-transformed equation Y = a. X b) were tested for a P <

0.05 level of significance of a two-tailed t-test. A significant difference between two sets of data (air versus hypercapnia) was assessed by paired twotailed t-test. In all cases significance was considered at a level of P < 0.05.

3. Results and discussion

3.1. Oxygen consumption The relationship between resting 02 and body mass (M) for the 12 species studied was "Qo2ct M °9° (Fig. 1). This exponent is higher than the familiar 0.75 exponent of the adult allometric relationship, as previously noticed for newborn species of a larger range in body mass (Mortola, 1987). In hypercapnia, the exponent remained the same (Fig. 1); in fact, the regression function was almost identical to the normocapnic relationship (Table 2). On an individual basis, most values were within + 10% of the air value; the only exceptions were the deer, which during hypercapnia increased Vo2 by 13%, and the kitten (-14%). Averaging all the species, hypercapnic Vo2 was 101% ( + 2 SEM) of the air value, and not significantly different from it. Hence, the conclusion can be drawn that, in general, in the newborn moderate hypercapnia has no major effects on aerobic

J.P. Mortola, C. Lanthier /Respiration Physiology 103 (1996) 263-270

metabolic rate. This conclusion agrees with the resuits of a detailed analysis of "Qo: in newborn rats, studied at different ambient temperatures between 40 and 20°C, individually or in groups, during 2% or 5% CO 2 breathing (Saiki and Mortola, 1996). Also, V~rnai et al. (1970, 1971) reported no changes in Vo: in newborn rats and in rabbits breathing 6% CO 2 in cold conditions. On the other hand, in the kitten during 5% CO 2 breathing, CO 2 production decreased by ~ 25% (Mortola and Matsuoka, 1993), and in the adult cat breathing 4% CO 2 9o~ drastically dropped ( - 4 0 % , Sachdeva and Jennings, 1994), a response which was quantitatively and to a large extent also qualitatively different from that of many other adult species; hence, it would seem that Fells catus, whether newborn or adult, has an uncommon metabolic sensitivity to hypercapnia. The newborn species that increased ~'o: the most (the deer) was also the one with the greatest hyperpneic response, and this may suggest that, in this species, during hypercapnia the cost of breathing had sizable effects on the total Vo:. However, the observation that, on average among species, X}o~ did not

267

change despite the hyperpnea confirms the notion that in newborns, as in adults, the cost of breathing represents a minimal component of 'qo.. 3.2. Hyperpnea

During hypercapnia X?E increased in all species, but by very different amounts. In fact, there was a small, yet significant, trend for the larger newborns to increase VE more than the smaller species, as shown by the significantly higher exponent of the "rE allometric curve during CO 2 breathing than in air (1.05 versus 0.98, Table 2), and the tendency of the "QE "QO ratio to increase with animal size (VE/'qo, M °14p, Table 2). The physiological meaning of these tiny deviations from strict proportionality are difficult to assess. In fact, the neonatal period is characterised by rapid changes in specific Vo~ and VOE; in the smallest animals during the early postnatal days 'qo: at first increases, and later decreases gradually toward the adult value (Mortola and Gautier, 1995), along a temporal pattern which is not necessarily the same among species. The metabolic -

-

H y p e r c a p n i a (5% COz) '

J125% 5"

~=i00~/" /"

~J

250 arctic fox • • O r~bbit

-~'"z'"~ dog/" -" ,.

•

-"

200 C3

cat / -"

•

rat

75~ iZ /J/" j/ • (deer, 417%,294%

. j

.//

//j.

///

150 , ," . - / " • g e r b i l ~p~c~upine f hams~--~ .J

•

/" /'/ "/ 50

• m°u~'J

. . . . . . . . . . . . .~ ...... ~- . . . . . . . . . .

iO0

[

50

~ ...........................................................

/ /

j-f/Ii /~"

J",

!

i t

I00

,

i

150

,

I

,

200

I

,

250

Tidal votume, % Fig. 2. Tidal volume (VT)-ventilation (VE) during 5% CO 2 breathing, expressed in percent of the air values. Values are the mean of each species. To avoid clustering of data points, that pertinent to the deer (X/e = 294%, VT = 417%), which increased VT more than twice the other species, has been misplaced. Dotted isopleths are isofrequency lines, indicating 75%, 100%, and 125% of the air value. In hypercapnia, '¢E increased in all species by very variable amounts; this mostly resulted from the increase in VT, since the change in breathing rate was small and inconsistent ( +_25%).

J.P. Mortola, C. Lanthier / Respiration Physiology 103 (1996) 263-270

268

and ventilatory responses to changes in Tamb and chemical stimuli also vary with postnatal development, rapidly changing within days in a small species like the rat (Eden and Hanson, 1987; Mortola and Dotta, 1992; Matsuoka and Mortola, 1996; Saiki and Mortola, 1995). Hence, it is possible that the values of ~'o2 and ~QE could have been different had the animals been examined at postnatal ages even slightly different from those of this study, but it seems unlikely that this could have had major effects on the allometric relations. In adult mammals, a comparative study which combined data from various sources (Williams et al., 1995) suggested that the ~rE response to hypercapnia was less in smaller species, whereas the hypercapnic '(,rE response was found to be body mass-independent among marsupials studied under the same experimental conditions (Frappell and Baudinette, 1995). Among newborns, the slightly greater hyperpneic response to CO 2 in the largest

species may have some relationship with their precocity at birth. In fact, the smallest species tend to be less developed (altricial), and in some of these, like the rat, the ventilatory response to CO 2, almost absent at birth, increases during the first postnatal days (Matsuoka and Mortola, 1995). The hypercapnic hyperpnea was invariably the result of an increase in VT (Fig. 2), on average to 178% ( + 2 3 ) of the air value, the largest increase occurring in the deer (417%). On the other hand, the response in f was variable, in most species being within + 25% of the air value (in the deer, f decreased to 74% of normocapnia); on average, hypercapnic f was 98% ( + 7) of, and not significantly different from, the air value. Hence, the conclusion can be made that the average breathing pattern of the newborn mammal during acute hypercapnia is characterized by an increase in VT , with minimal changes in f. This agrees with data in conscious neonatal

Hypoxia (10% 02)

Hypercapnia (5% COz) -

5 kg)

(3g

300

ov.

I

I-

I

9

kg) I

I

I

I-

250 AI •

cf

zoo Fc

•Oc

•i "

Rn

Mm0

_;

15o

oSs

i•Cab Po

....,............ii.....

loo

OOv /

•

LC0 • Cp

Mp

uob /

. . . . . . . . . . . . . . . . . . . .

. . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Q)

-~

50

25

50

75

100

125

OXYGEN

150

CONS

25

50

75

100

125

150

UMPTION

(percent of air breathing) Fig. 3. Oxygen consumption-ventilation relations during hypercapnia (left panel) or hypoxia (right panel) in newborn mammals. Values are the mean of each species, identified by generic and specific initials (Table 1), represented in percent of the corresponding air value. Values in hypoxia are derived from the data of Trippenbach (1994) (rabbit, Oc), and Mortola et al. (1989) (all other species). In both hypercapnia and hypoxia all species hyperventilated (values are above the oblique continuous line), but hypometabolism was not common during hypercapnia, whereas it was an important contributor of the hyperventilatory response to hypoxia.

J.P. Mortola, C. Lanthier / Respiration Physiology 103 (1996) 263-270

species subjected to increased inspired CO 2 (Guthrie et al., 1985; Saetta and Mortola, 1987; Mortola and Matsuoka, 1993), including the human infant (Brady and Dunn, 1970; Martin et al., 1985), whereas it sharply contrasts with the neonatal pattern in acute hypoxia, which is commonly characterized by an increase in f, with variable changes in Vv (Mortola et al., 1989). In conscious hypoxic newborn rats and kittens, moderate hypercapnia reversed their rapid and shallow pattern into a deep and normo-frequency breathing (Saetta and Mortola, 1987; Mortola and Matsuoka, 1993). The differences in VT and f response between hypoxia and hypercapnia have been recognized also in awake adult cats, and interpreted as differences in the central effects of these stimuli on the termination of inspiration (Gautier, 1976).

3.3. Body temperature During air breathing Tb averaged 37.3°C ( + 0 . 7 SEM), with some interspecies variation not related to body size. In hypercapnia Tb averaged 37.1°C ( + 0.6), not significantly different from the air value (P > 0.05). In adult mammals, hypercapnia is associated with a drop in Tb (Mortola and Gautier, 1995), but in newborns this was previously noticed not to be the case (VS,rnai et al., 1970; Saiki and Mortola, 1996). Presumably, this difference reflects the lower vasodilating effects of CO 2 on peripheral circulation, and therefore less heat loss, during the neonatal period. In the adult, the drop in Tb was considered a possible factor in the maintenance of metabolic rate during acute hypoxia, on the assumption that the fall in Tb may act as a thermogenic stimulus (Mortola and Gautier, 1995). In the newborn, the absence of hypothermia rules out this mechanism as a factor in the maintenance of 'qo, during acute hypercapnia.

3.4. Hypercapnic hyperventilation Fig. 3 summarizes the hypercapnic metabolic and ventilatory values, expressed in percent of the values during air breathing, in the format of "Qo, - ~'E plot. For comparative purposes, values previously obtained during acute hypoxia in the same and other newborn species are also represented (right hand panel, Fig. 3) (Mortola et al., 1989; Trippenbach,

269

1994). Although the hyperventilatory response is common to both hypoxia and hypercapnia, as indicated by the data points falling above the oblique line, in hypercapnia the hyperventilation is strictly due to the hyperpnea, whereas in hypoxia the hypometabolic component is important; in fact, in some species, hypometabolism is the only contributor to hypoxic hyperventilation. Several considerations can be made from the comparison of the average neonatal responses to moderate hypoxia and hypercapnia (Fig. 3). The high levels of VE during CO z breathing indicate that, in hypoxia, the small hyperpneic response cannot be contributed by mechanical constraints or limits in the performance of the respiratory muscles (Mortola, 1987). In hypoxia, metabolic acidosis could be one mechanism for the hypometabolic response, but probably only when the acidemia is severe, since hypometabolism did not occur with moderate hypercapnia; blood lactic acid does not necessarily increase during hypoxic hypometabolism (Frappell et al., 1991). Both hypercapnia and hypoxia stimulate the chemoreceptors; the fact that hypometabolism occurs only with the latter suggests that activation of the chemoreceptors is not by itself a cause of the hypometabolic manifestation. This agrees with conclusions from experiments on conscious adult rats and cats, and anesthetized newborn rabbits, by use of experimental anaemia, CO-poisoning or carotid sinus denervation, in which hypoxic hypometabolism occurred without activation of the carotid bodies (reviewed in Mortola and Gautier, 1995). In conclusion, the average respiratory response of the newborn to moderate hypercapnia, derived from a comparison of several mammalian species, is an hyperventilation which, differently from acute hypoxia, is contributed to only by the hyperpnea, with no hypometabolic component, and with minimal changes in breathing rate. Hypometabolism appears to be specific to hypoxia, and theretbre is not a neonatal undifferentiated response to chemoreceptors stimulation.

Acknowledgements We are very grateful to the Granby Zoological Society for granting permission to perform the exper-

270

J.P. Morwla, C. Lanthier / Respiration Physiology 103 (1996) 263-270

iments, to the personnel of the Granby Zoo and to Lina Naso for the technical assistance. The study was supported by MRC Canada.

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Mortola, J.P. (1984). Breathing pattern in newborns. J. Appl. Physiol. 56: 1533-1540. Mortola, J.P. (1987). Dynamics of breathing in newborn mammals. Physiol. Rev. 67: 187-243. Mortola, J.P. and T. Piazza (1987). Breathing pattern in rats with chronic section of the superior laryngeal nerves. Respir. Physiol. 70: 51-62. Mortola, J.P., R. Rezzonico and C. Lantier (1989). Ventilation and oxygen consumption during acute hypoxia in newborn mammals: a comparative analysis. Respir. Physiol. 78: 31-43. Mortola, J.P. and A. Dotta (1992). Effects of hypoxia and ambient temperature on gaseous metabolism of newborn rats. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R267-R272, 1992. Mortola, J.P. and T. Matsuoka (1993). Interaction between CO, production and ventilation in the hypoxic kitten. J. Appl. Physiol. 74: 905-910. Mortola, J.P. and H. Gautier (1995). Interaction between metabolism and ventilation: effects of respiratory gases and temperature. In Regulation of Breathing, edited by J.A. Dempsey and A.I. Pack, Marcel Dekker, New York, NY, USA, pp. 1011-1064. Sachdeva, U. and D.B. Jennings (1994). Effects of hypercapnia on metabolism, temperature, and ventilation during heat and fever. J. Appl. Physiol. 76: 1285-1292. Saetta, M. and J.P. Mortola (1987). Interaction of hypoxic and hypercapnic stimuli on breathing pattern in the newborn rat. J. Appl. Physiol. 62: 506-512. Saiki, C. and J.P. Mortola (1996). Effect of CO~ on the metabolic and ventilatory responses to ambient temperature in conscious adult and newborn rats. J. Physiol. (London), 491: 261-269. Trippenbach, T. (1994). Ventilatory and metabolic effects of repeated hypoxia in conscious newborn rabbits. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): RI584R1590. Vfimai, I., M. Farkas and S.Z. Donhoffer (1970). Thermoregulatory effects of hypercapnia in the new-born rat. Comparison with the effect of hypoxia. Acta Physiol. Acad. Sci. Hung. 38: 225-235. V~irnai, I., M. Farkas and S.Z. Donhoffer (1971). Thermoregulatory responses to hypercapnia in the new-born rabbit. Comparison with the effect of hypoxia. Acta Physiol. Acad. Sci. Hung. 40: 145-172. Williams, B.R.,Jr., D.F. Boggs and D.L. Kilgore, Jr. (1995). Scaling of hypercapnic ventilatory responsiveness in birds and mammals. Respir. Physiol. 99: 313-319.