Adenosine stimulates breathing in fetal sheep with brain stem section BRIAN

J. KOOS,

Department University

ANDREW

of Obstetrics of California

CHAO,

AND

Koos, BRIAN J., ANDREWCHAO, AND WALEED DOW. Adenmine stimulates breathing in fetal sheep with brain stem section, J. Appl. Physiol. 72(l): 94-99, 1992.-Breathing responsesto adenosinewere determined in 12 chronically catheterized fetal sheep(>0.8 term) in which hypoxic inhibition of breathing had been eliminated by brain stem section. The caudal extent of transection varied from the rostra1 midbrain to the pontomedullary junction. Isocapnic hypoxia [Aarterial PO, (Paoz) of -12 Torr] doubledthe incidence and depth of breathing activity and increasedthe incidence of eye movements. Intra-arterial infusion of adenosine(0.30 t 0.03mg min-’ kg fetal wt-‘) increasedthe incidenceand amplitude of breathing without affecting blood gases.Adenosine did not significantly alter the incidence of eye activity. Intra-arterial injection of oligomycin (120 t 26 pg/kg fetal wt), an inhibitor of mitochondrial oxidative phosphorylation, also stimulated breathing activity. In four fetuseswith brain stemsection, peripheral arterial chemodenervation blunted the stimulatory effects of hypoxia on breathing activity and abolished altogether the excitatory effects of adenosine.It is concluded that I) hypoxia and adenosinelikely inhibit breathing in normal fetusesby affecting similar areasof the brain stem and 2) in fetuseswith brain section, hypoxic hyperpnea dependson peripheral and central mechanisms,whereasadenosinestimulatesbreathing via the peripheral arterial chemoreceptors. l

l

chemoreceptors;hypoxia; respiration

ACUTE REDUCTIONSin arterial

0, tensions (>6 Torr) inhibit fetal breathing in a dose-dependent manner (13). These depressing effects of hypoxia appear to be generated centrally because they pe rsist in fetuses with carotid body denervation and vagal section (11) and because they are eliminated by suprapontine brain stem section (6,8). Although the exact mechanism underlying this fetal response is not fully understood, it may be a consequence of an 0, limitation in brain mitochondrial oxidative phosphorylation (10, 12). During hypoxia, adenosine monophosphate is metabolized to adenosine, increasing tissue concentrations of this purine nucleoside. Recent evidence suggests that these raised levels of adenosine have an important role in hypoxic inhibition. For example, intra-arterial infusions of adenosine mimic the inhibitory effects of hypoxia on fetal breathing (9), and the depressing effects of hypoxia on fetal breathing activity

are significantly

blunted or

eliminated altogether by the intravenous administration of an adenosine receptor antagonist (2,9). Adenosine presumably modulates breathing through 94

WALEED

DOANY

and Gynecology, Nichulus S. Assali Perinutul Research Laboratory, at Los Angeles School of Medicine, Los Angeles, California 90025

effects on the brain stem; however, its exact site of action is unknown. Therefore, this study was carried out to help determine whether adenosine’s inhibitory effects on fetal breathing likely involve brain stem areas known to be important for hypoxic inhibition. METHODS

Under halothane anesthesia, 12 pregnant Western ewes were operated on at 119-125 days gesta tion (0.8 term). Polyvinyl catheters were inserted in the right carotid artery and advanced 7 cm toward the aortic arch, the external jugular vein, and the amniotic sac. Bipolar stainless steel electrodes were implanted on the dura to record electrocortical activity and on a lateral orbital ridge to record eye movements. In some fetuses, bipolar electrodes were also placed in nuchal muscle. A 3-mmwide blunt spatula was inserted through a trephine hole in the interparietal bones, and the brain stem was transected between the rostra1 pons and midbrain. All pressures were measured with pressure transducers (Cobe Laboratories, Lakewood, CO). Tracheal and a rteria 1 pressures (minus amniotic fluid p ressure 1? heart rate, electrooculogram, electrocorticogram (ECoG 3? and nuchal muscle electromyogram (EMG) were displayed on a Grass chart recorder. Heart rate, blood pressure, and tracheal pressure were sampled every 0.01 s by an IBM-AT compatible computer using data acquisition software (5). Breathing movements were identified on line, and minute averages of inspiratory time, breath interval (TT), and tracheal pressure amplitude as well as heart rate and blood pressure were stored on disk. Because of the skewed distribution of TT, the mean value was determined from the log transformation of TT for values ~20 s. Fetal records were analyzed in one-min epochs, and breathing was considered present if the epoch contained at least four breaths. Blood gas electrodes (model 1304, Instrumentation Laboratories) were used to measure blood gas tensions and pH, with values corrected to fetal temperature (39.5”C). Hemoglobin concentration and 0, saturation were determined on a hemoximeter (OSM, Radiometer, Copenhagen), Experiments were started 24 days after surgery. In eight fetuses, isocapnic hypoxia was induced by having the ewe breathe a hypoxic gas mixture (9% 02-3% CO,88% N2) from a large plastic bag for 1 h. On the following

day, adenosine

in saline (3.6 mg/ml)

was infused (0.19

0161-7567192 $2.00 Copyright 0 1992 the American Physiological Society

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ADENOSINE

Midbrain

I

I1

AND BRAIN

I

Pons

I

Medulla

FIG. 1. Caudal extent of brain stem section determined by histology. Nos. indicate no. of fetuses with each specified lesion (dashed lines).

ml/min) into the arch of the fetal aorta via the right carotid artery for 1 h. This dose of adenosine has been found to inhibit breathing in normal fetuses (9). The hypoxia and adenosine studies were repeated on subsequent days to determine whether the breathing responses were reproducible. On completion of the above studies, oligomycin B (0.28 mg/0.5 ml ethanol), an inhibitor of mitochondrial oxidative phosphorylation, was injected into the right carotid artery of three fetuses. This dose of oligomycin inhibits breathing in normal fetuses (12). Chemodenervation. In four fetuses, breathing responses to hypoxia and adenosine were determined after denervation of the peripheral arterial chemoreceptors. The fetuses were operated on at 118-120 days’ gestation for catheter placement and brain stem section. Fetal breathing responses to hypoxia and adenosine infusion were determined 5-7 days later. The same protocols were followed as described previously, except the experiments lasted 10 min rather than 1 h. Seven to 8 days after the first surgery, the peripheral arterial chemoreceptors were denervated by cutting the carotid sinus nerves and stripping the fascia from the external wall of the carotid artery from the lingual branch to 0.5 cm below the occipital artery. The fascia was also stripped from the first 0.5 cm of the occipital artery. The aortic chemoreceptors were denervated by bilateral cervical vagotomy. The hypoxia and adenosine experiments were repeated 2-7 days after the second surgery. No other studies were performed in these fetuses. On completion of the studies, the fetal brains were fixed in situ with a buffered Formalin solution. The brain stems were cut in sagittal sections of 50 pm, and every fifth section was stained with cresyl violet. Repeated experiments in the same animal were averaged for analysis. Log transformation of the data was performed before data analysis when indicated. Significant differences for repeated measurements were determined using two- and three-way analysis of variance with Duncan’s test. Student’s t test was used to determine significant differences for single comparisons. The results are expressed as means t SE. RESULTS

Histological examination of the brain stem was performed in nine fetuses (Fig. 1). The site of section in one fetus was the midbrain-diencephalon junction, which left

STEM

95

SECTION

most of the mesencephalon intact. The transection was at the junction of the midbrain and pons in seven fetuses, leaving the pons intact in three fetuses, but the destruction extended caudally into the rostra1 pons in the other four fetuses. The cut was through the pons in one fetus with caudal damage extending to the pontomedullary junction. In three fetuses, the site of section was determined by visual inspection. The pons appeared to be intact in two fetuses, but only the caudal half of the pons was present in the third. The transections were incomplete in 5 of 12 fetuses with intact tissue laterally. Good recordings of the ECoG were obtained for six fetuses. In five animals, the ECoG cycled normally between episodes of low- and high-voltage states; however, eye movements and breathing activity were dissociated from electrocortical state. Breathing and rapid eye movements in one fetus occurred only in episodes associated with low-voltage electrocortical activity. The site of section in this animal was the midbrain-diencephalic junction with intact brain tissue laterally. Breathing activity was recorded for 214 days after surgery in four fetuses with brain stem section and intact peripheral arterial chemoreceptors. In these fetuses, the mean incidence of breathing was 32 t 8 min/h on postoperative day 4 and 46 t 4 min/h on day 14. Hypoxia. Isocapnic hypoxia was induced for 1 h to determine whether fetal breathing movements persisted during acute 0, deficiency. A total of 13 experiments were carried out in eight fetuses in which fetal arterial 0, tension (Pa,,) was reduced by ~12 Torr (Table 1). One fetus was unable to tolerate >0.5 h of hypoxia (arterial pH 7.16); therefore, its blood gases were not included in Table 1. During the control period, the mean incidence of breathing movements was -26 min/h (Fig. 2A). Hypoxia doubled the incidence of breathing activity and produced a nearly twofold increase in mean tracheal pressure amplitude (Table 2). Mean inspiratory time during normoxia was greater (P < 0.05) in fetuses in which the site of section was below the junction of the pons and midbrain (Table 2). Hypoxia significantly reduced mean inspiratory time only in fetuses with brain section between the pons and midbrain. The number of breaths per minute increased two- to threefold during hypoxia, and this effect was seen within 5 min of the start of the experiment (Fig. 3). The mean amplitude of fetal breathing increased progressively during the first 20 min of hypoxia and subsequently remained at relatively steady values despite a falling arterial pH (Fig. 3). Eye movements were recorded in five fetuses (8 experTABLE 1. Preductul arterial blood gasesand pH PH Hypoxia

J&O,,

Torr

(n = 7)

Control Experiment

7.36520.007

46.230.9

7.287+0.010*

46.4t0.8

Control Experiment

7.372zkO.010 7.349kO.006

Adenosine

Pao,, Tom

25.4t0.5 12.7*0.6*

(n = 8) 44.4t1.3 46.5k0.4

22.4t1.7 21.4t1.7

Values are means t SE; n, no. of fetuses. Pace, and Pao,, arterial CO, and 0, tensions, respectively. * P < 0.05.

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ADENOSINE

t*

A

60

I

J

I

-2

B

50

40 t

E

30

I

I

I1

0 2 TIME (h)

I

j

1

4

-FBM --EEOG

r

E Z .-

FBM --EEOG

T

-4

AND BRAIN

E

0 z

#

0 z

20 IO

OL

11 -4

FIG.

11 -2

11 11 1 I 2 4 0 TIME (h) 2. Effects of hypoxia (stippled bar, A) and of adenosine (stip-

pled bar, B) on breathing (solid line, FBM) and eye movements (dashed line, EOG) in fetuses with brain section (means t SE). min/h, Mean incidences per hour. *Fp < 0.05 compared with 4-h control mean.

iments). Hypoxia increased the mean incidence of rapid eye movements from 20 t 9 to 33 t 11 min/h, and after ~20 min of hypoxia the amplitude of eye activity in four fetuses was substantially greater as determined by visual inspection. Nuchal muscle activity during hypoxia (two fetuses) was slightly less than control values (control, 12 min/h; hypoxia, 6 min/h). In the three fetuses with good ECoG recordings, the mean incidence of low-voltage activity during hypoxia was 31 t 9 min/h compared with the control mean of 41 t 4 min/h. The incidence of high-voltage activity increased from a control average of 13 t 4 to 25 t 8 min/h during hypoxia. Adenosine. In eight fetuses (17 experiments), intra-arterial infusion of adenosine (0.30 t 0.03 mg min-1 . kg-l) produced no significant changes in fetal preductal arterial blood gases (Table 1). Although mean arterial pH was not significantly affected when data were averaged over 1 h (Table l), a slight but significant fall in arterial

STEM

SECTION

pH was observed 30 and 60 min after beginning the infusion (Fig. 3). During the 1 h of adenosine infusion, the mean incidence of fetal breathing increased by ~70% (Fig. 2B). The mean tracheal pressure amplitude (Table 2) and the number of breaths per minute (Fig. 3) were also greater during infusion of the purine nucleoside. This stimulation of breathing occurred within 5 min of the start of the experiment and persisted throughout the remainder of the study (Fig. 3). As with hypoxia, mean inspiratory time was reduced during adenosine infusion for fetuses in which the site of section was between the pons and midbrain (Table 2). The incidence of rapid eye movements (7 experiments in 4 fetuses) was unchanged during adenosine infusion (control, 23 t 7 min/h; adenosine, 23 t 8 min/h), and the incidence of nuchal muscle activity (3 experiments in 2 fetuses) was also not affected (control, 10 min/h; adenosine, 9 min/h). The mean incidence (32 t 3 min/h) of low-voltage electrocortical activity (5 experiments in 3 fetuses) during adenosine infusion was similar to the control value of 36 t 3 min/h. Adenosine also had little effect on the average incidence of high-voltage electrocortical activity (control, 19 t 4 min/h; adenosine, 22 t 3 min/h). Oligomycin. Oligomycin (120 t 26 pg/kg) was injected intra-arterially once in three fetuses. Mean arterial pH (7.336 t 0.025), arterial CO, tension (Pa,,,, 47.3 t 1.6 Torr), and Pa,, (24.5 t 1.4 Torr) after drug injection were not significantly different from the respective control values of 7.355 t 0.019, 46.0 t 1.6 Torr, and 25.3 + 1.2 Torr. Breathing incidence increased significantly from 24 t 6 to 48 t 11 min/h during the hour after oligomycin administration. Breath amplitude also was greater as determined by visual inspection. Chemodenervation. Figure 4 shows the effects of peripheral arterial chemodenervation on breathing responses to isocapnic hypoxia in fetuses with brain stem section (Table 3). In denervated fetuses, hypoxia (8 experiments in 4 fetuses) did not increase the number of breaths per min, and the increase in mean breath amplitude was delayed until 7 min after start of the experiment. After 3 min, the mean breath amplitude for denervated fetuses was significantly less than that for these same fetuses with intact carotid and vagal nerves (5 experiments in 4 fetuses). This difference in breathing responses to isocapnic hypoxia was not due to differences in 0, tensions, because fetal Pao, at 5 min was similar to control values for intact (16.9 t 0.9 Torr) and chemodenervated (14.8 t 1.4 Torr) fetuses. Adenosine was infused seven times in four fetuses with brain stem section and eight times in the same fetuses after peripheral arterial chemodenervation. During adenosine infusion, mean arterial pH fell slightly in both groups, but fetal Pa,, was significantly less only in fetuses with chemodenervation (Table 3). Adenosine did not stimulate breathing in transected fetuses with peripheral arterial chemodenervation (Fig. 5).

l

DISCUSSION

Hypoxic inhibition of breathing movements in normal fetuses appears to be caused by low brain 0, tensions

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ADENOSINE TABLE

AND BRAIN

STEM

97

SECTION

2. Respiratory variables Control

Site of Section

T2

TI, s

TT,

Experiment Ptr, mmHg

s

TI, s

TT,

Ptr, mmHg

s

Hypoxia Pontomedullary junction Rostra1 pons Pons-midbrain Midbrain

0.93HLO6

1.77kO.08 7.29t2.46 3.1tl.3 1.79kO.26

0.82t0.03 0.68kO.05 0.45+0.03

5.4t0.3 3.ltO.l 2.7t0.2 2.8t0.3

0.81kO.03 0.83t0.13

4.0t0.3 3.2t0.3 2.7&O. 1 2.1t0.2

0.72kO.03

0.40+0.06* 0.43t0.02

1.34t0.03* 2.67t0.57” 1.1920.28 1.17t0.09

9.3t0.6* 6.5tl.4 3.6t0.6 3.7t0.5

1.44-t0.04* 3.68t1.25 1.15t0.25* 2.3020.42

5.5,tO.2* 5.2+0.6* 3.3t0.3 4.1tO.6”

Adenosine Pontomedullary junction Rostra1 pons Pons-midbrain Midbrain

0.88zkO.07 0.80+0.11 0.66+0.07 0.54+0.05

1.84t0.09 7.62t0.12 2.79kO.68 2.29t0.35

0.91+0.06 0.51t0.07* 0.55kO.08

Values are means + SE; n, no. of fetuses. Tr, inspiratory time; TT, breath interval; Ptr, tracheal pressure amplitude. * P < 0.05.

50 z

> $ k ii! m

40 30 20 IO

5!

1

0

2

I 0

I

I

20

I

I

I

I

40 60 TIME (min.)

I

I

80

I

FIG. 3. Effects of hypoxia (solid line) and adenosine (dashed line) on number of breaths per minute, mean amplitude of breathing activity, and preductal arterial pH (pH,) in 5 fetuses with brain section (means k SE). Horizontal bar, experimental period. *p < 0.05 compared with 4-h control mean.

(10). As originally described by Dawes (6), the depressing effects of hypoxia on breathing are abolished with brain stem section as rostra1 as the midbrain, a finding indicating that hypoxic inhibition does not arise from direct effects of 0, deficiency on respiratory neurons in the medulla. Although the O,-sensitive area that triggers the response has not been identified, previous studies by

I 0

I 2

I 4

I 6

1 8

I 10

TIME (min) 4. Effects of hypoxia on breathing in fetuses with brain stem section (means t SE) before (solid line) and after denervation of peripheral arterial chemoreceptors {dashed line). *P c 0.05 compared with control mean. tP < 0.05 compared with corresponding value for denervated fetuses. FIG.

Dawes (6) and the present work suggest that it lies caudal to the diencephalon. The ventromedial mesencephalon depresses respiration in adult cats (7), and this area of the brain stem may inhibit fetal breathing during periods of acute 0, deprivation. In normal fetuses, adenosine mimics hypoxia by reducing the incidence of breathing and eye movements (9). Similar effects are also observed after intra-arterial

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98

ADENOSINE

TABLE

AND BRAIN

STEM

SECTION

3. Preductul arterial blood gasesand pH Control PH

Pace,,

10 min PQ,,

Torr

Torr

PH

pace,,

mm

Pa,,,

Torr

Hypoxia

Transection Transection and chemodenervation

7.356tO.010

46.0t1.5

7,344&0.006

47. MI.9

25.8k0.9

7.361kO.015

44.5t1.7

13.6kO.5”

24.0~1.3

7.331_tO.O08

46.0k0.4

11.9tl.O*

Adenosine

Transection Transection and chemodenervation

7.359tO.008

45.2k1.9

24.621.7

7.338tO.008”

46.3t1.3

23.621.6

7.34oto.010

47.6k1.9

25.5k1.4

7.320+0.007*

48.3t1.4

22.4H.2”

Values are means t SE. * P < 0.05.

injection of oligomycin, an antibiotic that increases adenosine production by inhibiting mitochondrial oxidative phosphorylation (12). The present study in fetuses with brain stem section shows that adenosine and oligomycin increase fetal respiratory drive. This stimulation of breathing was similar to the effects of hypoxia, and these results together suggest that the inhibitory effects of adenosine on breathing in normal fetuses likely involve

The carotid bodies are active in fetal sheep (3); consequently, the peripheral arterial chemoreceptors might be expected to mediate hypoxic stimulation of breathing in fetuses with brain stem section. However, previous studies by Dawes et al. (6) showed that hypoxia increases breath amplitude in such fetuses with denervation of the carotid bodies. Hypoxia has also been reported to increase breathing incidence in fetuses with brain stem

brain stem pathways similar to those for hypoxia. These

transection and bilateral section of carotid sinus nerves and vagosympathetic trunks (16). In the present work,

observations are consistent with the hypothesis that hypoxic inhibition arises, at least in part, from elevated levels of adenosine in the fetal brain (9).

the effects of hypoxia in fetuses with brain stem section were compared with those in the same animals after peripheral arterial chemodenervation. Our results indicate that the peripheral arterial chemoreceptors contribute to hypoxic hyperpnea in fetuses in which hypoxic inhibition has been eliminated by brain stem section. The increase in breath amplitude during hypoxia in such fetuses with peripheral arterial chemodenervation indicates that fetal breathing is also stimulated by the direct effects of hypoxia on the lower brain stem (6). Central chemoreceptor

stimulation may also contribute to this increase in breath amplitude, but this mechanism would appear to be less important, because the rate and amplitude of breathing remained constant during the last 40 min of hypoxia at a time when fetal arterial (and probably central) pH was falling rapidly.

The stimulatory effects of adenosine on fetal breathing were completely abolished by denervation of the carotid bodies and bilateral vagal section. Although these procedures eliminated afferent activity from the lungs and other organs, our results suggest that adenosine increases respiratory drive in the fetus by exciting the carotid bodies, as occurs postnatally (14,15,19,20). During hypoxia (APa,, N 10 Torr), fetal plasma adenosine levels

g-T\\,, 2-

I 0

. -&0 I

2

I

4

I

6

I

8

I

10

TIME (min) 5. Effects of adenosine on breathing in fetuses with brain stem section (means t SE) before (solid line) and after denervation of peripheral arterial chemoreceptors (dashed line). *P c 0.05 compared with control mean. tP -C 0.05 compared with corresponding value for denervated fetuses. FIG.

increase twofold (B. J. Koos and W. Doany, personal observations), suggesting that adenosine could contribute to hypoxic stimulation of the fetal carotid chemoreceptors. However, because of its high metabolic rate, the carotid body itself would probably be the major source of the rise of adenosine levels in this chemoreceptive tissue (1). Rapid irregular breathing occurs in normal fetuses -30-&O% of-the time in episodes associated with lowvoltage electrocortical activity (4, 13). In fetuses with brain stem section, mean breathing incidence has been

reported to vary from ~45% of the time right after surgery to nearly 100% of the time 2 wk after transection (6).

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ADENOSINE

AND BRAIN

We have found that breathing in fetuses with brain section may occur in isolated breaths as well as in continuous episodes; therefore, we have arbitrarily determined that breathing is present if there are at least four breaths per minute epoch. When this criterion was used, fetal breathing averaged 77% of the time in fetuses that were studied 2 wk after surgery. Other definitions of breathing incidence may give differing results. In normal fetuses, hypoxia reduces the incidence of rapid eye movements and nuchal muscle activity (13,17); in contrast, in fetuses with brain stem section, shortterm hypoxia (10 min) had little effect on eye movements or nuchal muscle activity (6). However, the longer periods of hypoxia (60 min) in the present study were associated with an increase in the incidence of eye movements and a fall in nuchal muscle activity. Apparently the rostra1 brain stem is also important for hypoxic inhibition of eye activity. However, in contrast to its effects on breathing movements, adenosine did not stimulate eye activity. These observations are consistent with denervation studies indicating that adenosine stimulates breathing by exciting the peripheral arterial chemoreceptars. In summary, the inhibitory effects of hypoxia and adenosine on fetal breathing and eye activity are eliminated by brain stem section. These results are consistent with the hypothesis that adenosine contributes to hypoxic depression of these movements and the resulting fall in fetal 0, requirements. Thus adenosine appears to have an important role in helping the fetus adapt to short periods of 0, deprivation. In fetuses with brain stem section, hypoxic stimulation of breathing was significantly blunted by denervation of the peripheral arterial chemoreceptors, whereas the excitatory effects of adenosine were completely abolished. These observations indicate that the peripheral arterial chemoreceptors modulate respiratory drive in fetuses in which hypoxic inhibition has been abolished by brain stem section. We thank Oscar Punla for technical assistance, Professors Roy M. Pitkin and Nicholas S. Assali for support, and Carolyn Houser for help in the histological examination of the fetal brains. This study was supported in part by National Institute of Child Health and Human Development Grant HD-18478. Address for reprint requests: B. J. KOOS, Dept. of Obstetrics and Gynecology, 22-132 CHS, UCLA School of Medicine, Los Angeles, California 90024. Received 14 August 1990; accepted in final form 10 August 1991. REFERENCES 1. BARDENHEIJER, H., AND J. SCHRADER. Supply-to-demand ratio for oxygen determines formation of adenosine by the heart. Am. J. PhvsioL. 250 (Heart Circ. PhvsioL. 19): Hl73-Hl80, 1986.

STEM

99

SECTION

2. BISSONNETTE, J. M., A. AND N. F. NOTOROBERTO. 3.

4.

5.

6.

7.

R. HOHIMER, C. R. CHAO, S. J. KNOPP, Theophylline stimulates fetal breathing movements during hypoxia. Pediatr. Res. 28: 83-86, 1990. BLANCO, C. E., G. S. DAWES, M. A. HANSON, AND H. B. MCCOOKE. The response to hypoxia of arterial chemoreceptors in fetal sheep and newborn lambs. J. Physiol. Lond. 351: 25-37,1984. BODDY, K., G. S. DAWES, R. FISHER, S. PINTER, AND J. S. ROBINSON. Foetal respiratory movements, electrocortical and cardiovascular responses to hypoxia and hypercapnia in sheep. J. Physiol. Lond. 243: 599-618, 1974. DALE, P. S., C. A. DUCSAY, R. D. GILBERT, B. J. Koos, AND L. D. LONGO. A microcomputer program for real-time data acquisition in the perinatal physiology laboratory. J. Dev. Physiol. 11: 185-188, 1989. DAWES, G. S., W. N. GARDNER, B. M. JOHNSTON, AND D. W. WALKER. Breathing in fetal lambs: the effects of brain stem section. J, Physiol. Lond. 335: 535-553, 1983. GALLMAN, E. J., W. L. LAWING, AND D. E. MILLORN. Mesencephalic stimulation elicits inhibition of phrenic nerve activity in cat.

J. Physiol. Lond. 436: 405-420, 1991. 8. KOOS, B. J. Central stimulation of

lambs by prostaglandin

breathing movements in fetal synthetase inhibitors. J. Physiol. Lond.

362: 455-466,1985. 9. KOOS, B. J., AND

cardiovascular

K. MATSIJDA. Fetal breathing, sleep state, and responses to adenosine in sheep. J. Appl. Physiol.

68: 489-495,199O.

10. KOOS, B. J., K. MATSUDA, AND G. G. POWER. Fetal breathing and cardiovascular responses to graded methemoglobinemia in sheep. J. Appl. Physiol. 69: 136-140, 1990. 11. Koos, B. J., AND H. SAMESHIMA. Effects of hypoxaemia and hypercapnia on breathing movements and sleep state in sinoaortic-denervated fetal sheep. J. Dev. Physiol. 10: 131-144, 1988. 12. KOOS, B. J., H. SAMESHIMA, AND G. G. POWER. Fetal breathing movement, sleep state and cardiovascular responses to an inhibitor of mitochondrial ATPase in sheep. J. Dev. Physiol. 6: 67-75, 1986. 13. Koos, B. J., H. SAMESHIMA, AND G. G. POWER. Fetal breathing, sleep state and cardiovascular responses to graded hypoxia in sheep. J. Appl. Physiol. 62: 1033-1039, 1987. 14. MCQUEEN, D. S., AND J. A. RIBEIRO. Effect of adenosine on carotid chemoreceptor activity in the cat. Br. J. Pharmacol. 74: 129-136, 1981. 15. MONTEIRO, F. C., AND J. A. RIBEIRO. Ventilatory effects of adenosine mediated by carotid body chemoreceptors in the rat. Arch. PharmacoL. 16. MOORE,

335: 143-148,1987.

P. J., M. J. PARKES, J. G. NIJHUIS, AND M. A. HANSON. The incidence of breathing movements in fetal sheep in normoxia and hypoxia after peripheral chemodenervation and brain-stem transection. J. Dev. PhysioE. 11: 147-151, 1989. 17. NATALE, R., F. CLEWLOW, AND G. S. DAWES. Measurement of fetal forelimb movements in the lamb in utero. Am. J. Obstet. Gynecol. 140: 545-551,198l. 18. RIJNOLD, M., N. S. CHERNIACK, AND N. R. PRABHAKAR. Effect of adenosine on isolated and superfused cat carotid body activity. Neurosci. 19. WATT,

Lett.

113: 111-114,

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A. H., D. C. Buss, AND P. A. ROUTLEDGE. Comparison of respiratory effects of intravenous adenosine in neonatal and adult rabbits. Life Sci. 39: 1617-1622, 1986. 20. WATT, A. H., P. G. REID, M. R. STEPHENS, AND P. A. ROUTLEDGE. Adenosine-induced respiratory stimulation in man depends upon the site of infusion. Evidence for an action on the carotid body? Br. J. CLin. Phurmucol.

23: 486-490,

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Adenosine stimulates breathing in fetal sheep with brain stem section.

Breathing responses to adenosine were determined in 12 chronically catheterized fetal sheep (greater than 0.8 term) in which hypoxic inhibition of bre...
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