Effects of carbon monoxide on avian intrapulmonary carbon dioxide-sensitive receptors

Physiology

Respiration

North-Holland

(1974) 20, 313-324;

Publishing

Cornpony. Amsterdam

EFFECTS OF CARBON MONOXIDE ON AVIAN INTRAPULMONARY CARBON DIOXIDE-SENSITIVE RECEPTORS’

R. R. TSCHORN Depurtment qf Physiological

Sciences. Kamas

Abstract.

The effects of carbon

receptors

were investigated

gas stream produced afferent

vagal

the ventilatory

stimulation

from

cyclic

movements

neurons of those rhythm

movements

of CO on intrapulmonary cannot

be induced

inhibitory

interneurons

CO,-sensitive

receptors

activated

would

neuronal

allow

pool

and induced

increases

cannot

stimulation

in HbCO

CO in 6 min to 50””

action

by intrapulmonary

CO,-sensitive high

remained

CO,

concentration

by CO on inhibitory

movements

continued

to a direct

frequency

of other chemoreceptors

if the intrapulmonary

respiratory

However,

be attributed

their discharge

from a depressing cyclic

Single-unit, O.l”,

in 15 min.

by hypoxic

even though

apnea.

by including

Rapid

because

by severe hypoxia

may have resulted

(CO,)-sensitive

from the ventilating

of the receptors.

began.

receptors

dioxide CO

was not changed

CO administration

were not caused

in the CNS that are normally of the respiratory

during

CO,-sensitive

these movements

since these movements

carbon

in P+> from 85 to 62 torr developed

decrease

Kansas 66506. U.S.A

Excluding

receptors

the CO,-sensitivity

of respiratory

is kept low. The movements

chickens.

of the C02-sensitive

respiratory

Manhattan,

on intrapulmonary

ventilated

nor did CO alter

The occurrence Further,

(CO)

receptors

with a simultaneous

unchanged.

State l~rkersity

the COZ-sensitive

gas mixture;

after CO was administered,

action

monoxide

in unidirectionally

maximal

activity

and M. R. FEDDE

receptors.

to resume

discharge

inter-

Inactivity

from

inherent

of intrapulmonary

occurred. Control

Aves Carbon

monoxide

Carboxyhemoglobin

of breathing

CO,-sensitive Pulmonary

receptors receptors

Chicken

Spontaneous

inhalation

of 0.10/o carbon

monoxide

(CO)

by the chicken

increases

tidal volume but produces no change in respiratory frequency (Tschorn and Fedde, 1974). The exact mechanism by which CO produces the response is not understood. In CO poisoning the degree of hypoxia is more severe than expected from just the formation of HbCO because the release of 0, by the remaining unbound hemoglobin is also inhibited (Stadie and Martin, 1925). However, hypoxia in the chicken increases respiratory frequency (Butler, 1967) with less effect on amplitude of breathing (Ray and Fedde, 1969). Because that response does not occur during CO intoxication, it is unlikely that peripheral chemoreceptors, such as the carotid body, are responsible for the increased tidal volume produced by inhaled CO. Accepted for publication

’ Contribution Station.

Kansas

18 January

1974.

no. 123. Department of Physiological Sciences. State University, Manhattan, Kansas 66506. 313

Kansas

Agricultural

Experiment

314

R. R. TSCHORN

AND M. R. FEDDE

Intrapulmonary CO,-sensitive receptors appear to be distributed throughout the avian lung, perhaps in the epithelium of the tubular system (Fedde and Peterson, 1970). Altering the activity of these receptors by inhaling various mixtures of CO, markedly influences amplitude of breathing with little effect on frequency (Ray and Fedde, 1969). Thus, altering the receptors activity might cause the respiratory changes observed during CO inhalation. Our objective was to determine if CO influences respiratory control by acting on intrapulmonary CO,-sensitive receptors.

in the chicken

Methods ANIMAL

PREPARATION

Adult, male, White Leghorn type chickens (Babcock strain, 1.772.0 kg) were anesthetized by injecting phenobarbital sodium (160 mg/kg) through a cannulated left, cutaneous ulnar vein. Each bird was secured in dorsal recumbency, its trachea cannulated in the midcervical region, and its thoraco-abdominal cavity exposed by a midventral incision through the skin, underlying muscles, and sternum (fig. 1). The abdominal and thoracic air sacs were incised and a warmed, humidified gas was passed into the tracheal cannula, through the lungs, and out to the atmosphere through the opened air sacs. The unidirectional ventilation procedure has been previously described (Fedde et al., 1969). A constant flow rate (4 liter/min) of gas was used. The concentration of O,, CO,, and CO in the ventilating gas stream was monitored just before it entered the trachea by an oxygen analyzer (Beckman, Model E 2) an infrared CO, analyzer (Beckman, Model LB l), and a CO Universal Sampling Pump (Mine Safety Appliance Co.).

Fig.

1. Schematic

diagram

of arrangement intrapulmonary

of the chicken for single-unit CO,-sensitive receptors.

vagal

recordings

from

CO

AND RESPIRATORY CONTROL

315

In all exp~r~m~~ts, the chickens were ~~idi~~~tio~ally ventilated with 2~.4~ 0,: balance Nz, with 0.1% CO added for 1.5mm. Body temperature, held at 40-t 0.5 ‘C, was rno~ito~~d with a rectal thermistor inserted 8 cm. EXPERIMENT

1

In experiment 1, single unit, afferent neuronal sictivity was recorded from intrapulmonary, CO,-sensitive receptors in five birds during unidirectional ventilation with 0.1% CO. The left vagus nerve in the cervical region was exposed and immersed in a mineral oil pool formed by a ring of skin. All branches of the nerve except those from the lung were transected. The epi~e~rinm was e nerve was placed on a mirror support. Small fasci~uli were divided with the aid of a dissection microscope until a single active unit couf be identified. Single unit activity was detected by placing the dissected strand of nerve on a small bipolar hook electrode (90% platinum-10% iridium, 76 p in diameter), The signal was amplified (Grass Inst. Co., Model P-5), displayed on a multichanneled oscilloscope (Tektronix, type 565), and recorded with an FM tape recorder (Hewlett-Packard, Model 3960). Impulse activity was determined to be from CO,-sensitive receptors by rapidly removing and adding CO, to the unidirectional ventilatory gas by using a solenoid valve in the CO, line. The rapid increase in impulse frequency when the intra~ulmo~~ry CO, concentration was reduced is a ~hara~teri~ti~ of those receptors (Fedde and Peterson, 1970). Vertical sternal movement was detected with a strain gauge attached ta the caudal tip of the sternum, displayed on the oscilloscope, and tape recorded. The neural activity and sternal movements were recorded on film from the tape with a kymographic camera (Grass Inst. Co., Model C-4) for analysis of data. When we found a single intrapulmonary CO,-sensitive unit, we followed the same protocol on live birds: (1) static and dynamic sensitivity curves were obtained; (2) CO, was removed from the ventilating gas stream to produce maximal static discharge frequency; (3) approximately 5 min later, 0.1% CO was introduced into the ventilatory gas stream; (4) IO min after the start of CO administration, static and dynamic COz sensitivity curves were again obtained; (5) CO was removed from the ventilatory gas stream after 15 min of ~~~os~re; (6) static and dynamic CO,-sensitivity curves were obtained I and 30 min after removing CO. Static CO,-sensitivity curves were obtained by determining the impulse discharge frequency at steady CO, concentrations of 0, 2, 4, 6 and 8% in the ventilating gas stream. Recordings were taken only when the discharge frequency had stabilized (at least 30 see) after CO, concentration was changed. Dynamic CO,-sensitivity curves were obtained by determining the change in discharge frequency as a function of time when the CO, concentration in the ventilating gas stream was abruptly reduced from 4 to UT:. The curves were used to determine whether CO

316

R. R. TSCHORN

AND M. R. FEDDE

changed the sensitivity of the receptors to their adequate stimulus, CO,. The data were analyzed for significant changes by a split-plot analysis variance

(Fryer,

EXPERIMENT

1966). Changes

were considered

significant

of

when P < 0.05.

2

In experiment 2, the effects of CO on arterial blood gas tensions and HbCO concentrations were determined in nine unidirectionally, ventilated chickens. Arterial oxygen tension, (Pao,), pHa, and carbon dioxide tensions (P+oL) were determined by withdrawing 3 ml of blood from a sciatic arterial cannula and analyzing it with a blood gas analyzer (Instrumentation Lab., Model 113). An equal volume of heated (40 “C), air-equilibrated blood was returned to the bird immediately after the sample was withdrawn. Carboxyhemoglobin concentration was determined on the sample by a modified microdiffusion method (Lambert et al., 1972). Vertical sternal displacement was continuously monitored as described in Experiment 1. We attempted to reproduce the protocol of Experiment 1 as closely as possible to correlate the respiratory response to CO observed in that experiment with any changes in arterial blood gas tensions and HbCO. One unidirectionally ventilated chicken in Experiment 2 was given 6”/, CO, after CO administration was discontinued to determine if adding CO, would increase HbCO removal from the blood. Results EXPERIMENT

1. RESPONSE

OF INTRAPULMONARY

Co2-SENSITIVE

RECEPTORS

TO co

Discharge frequency from intrapulmonary CO,-sensitive receptors was determined for 10 set each min for the first 10 min after 0.1% CO was added to the

A ,

’ j ,,,,,.,,.,.(,.I, ~,,,,,,,,,,,,,,,,1,,,,, .,,,,,,,(),,,,,.., ,,,,,,.,,...,,.,,,, .,” ,,.,.” ”

1

”

”

“‘1

”

Fig. 2. Effect of CO on discharge cyclic respiratory

movements.

administration

of CO;

including

Top

OS-set Increases

CO. intervals;

”

”

’

frequency

Unidirectional

(B), 7 min after

tracing

bottom

”

in each tracing

”

”

”

”

s j

”

including

is impulse

b

j

5

from an intrapulmonary, ventilation

record

”

discharge

from

1,

11

receptor

in the ventilating

in ventilating

movement;

in sternal movements (tracings B and C) were discharge frequency of the intrapulmonary

”

CO,-sensitive

with 0% CO,

0.1% CO

is sternal

.,,,,(,...,

”

middle

intrapulmonary

gas;

tracing

and on

gas: (A), before

(C),

10 min

after

is a time line with

CO,-sensitive

observed without significant CO,-sensitive receptor.

receptor. changes

in

co

ventilating frequency

gas

stream.

AND RESPIRATORY

A typical

for this receptor

during

response ventilation

317

CONTROL

is shown

in fig. 2. The

with Oo/ CO,

discharge

was 10.5 impulses

per

second before administering CO (fig. 2A); it was 11.0 impulses per second 7 min after (fig. 2B) and 11.5 impulses per second 10 min after (fig. 2C) CO was included in the ventilating gas. The mean discharge frequency of five receptors from five birds during CO administration is shown in fig. 3. Although the discharge frequency tended to increase as CO was administered, the change (9.4f0.6 to 11.1+0.9 SE) was not significant. The mean coefficient of variation for the discharge frequency during the lo-min period for the five receptors was 8.0%.

E i=,

8-

6-

2-

0*

Fig. 3.

Effect of 0.1%

’ 0

2 4 6 TIME [min]

8

10

CO on discharge frequency of intrapulmonary, 5 receptors (mean k SE).

CO,-sensitive

receptors

in

Ten minutes after CO administration was begun and 1 and 30 min after CO was removed, static and dynamic CO,-sensitivity curves were determined to provide information about the receptors’ response to changes in intrapulmonary CO, concentrations. The impulse frequency of the receptors decreased as the CO, concentration in the environment surrounding the receptor increased. Differences among curves did not differ significantly as a result of CO administration (figs. 4 and 5). It thus appears that CO, at the partial pressure given, does not influence the discharge frequency of intrapulmonary CO,-sensitive receptors nor their sensitivity to CO,. EXPERIMENT

2. STERNAL MOVEMENT,

HbCO,

AND

BLOOD

GAS TENSIONS

DURING

co

ADMINISTRATION

For 5 min before and during

the first 10 min of CO administration,

the chickens

328

l 5 mm before co 0 10 rnlndunng CO 1 1min aiter CD * 30 mtn after CO

Fig, 4. Effect of O.lp,; CO on static CO,-sensitivity curves determined before, during and a.fter CO was ~dmj~~st~~ed. 0, 5 min before (CO; 0, 10 min during CO; A, 1 rnin after CO; A, 30 min after CO. The mean, steady-state, impulse discharge frequency (*SE) of five receptors was plotted when 0, 2. 4, 6 and 8:~; CO2 were ~~tr~duccd into the v~n~il~t~ry gas.

Fig, 5. Effect of O.ly,, CO on dynamic CO,-sensitivity curves administered. @, 5 m& before CO; 0, 10 min during CO; A, 1 The mean ( &SE) impulse discharge Frequency from five receptors CO2 concentration in the v&Mating gas was abruptly

before, during and after CO was min after CO; a, 30 min after CO. is shown before (0 time) and after decreased from 4 to O?$

co

319

AND RESPIRATORY CONTROL

adm~nistr~tiun, cyclic respiratory motions began (fig 2). These movements were studied more carefully in 6 birds in experiment 2. They began approximateIy 6 min after CO was included in the ventilating gas and, in most birds, increased in frequency (fig. 6). Th e motions began when the HbCO concentration was approximately 2!!Q. The amplitude of the movements also increased but our recording tecb~~q~e did not permit amplitude to be q~antitated (fig. 2). Removing CO from the vexlt~lating gas stream put the birds again into apnea. 24

0

2

4 TfNE

6

8

to

~rnin)

Fig. 6. Effect of 0.17: CO on respiratory frequency during unidirectional ~~~t~l~tio~ with O?, ‘CO, in the ~~~t~latin~ gas. Mean (&SE) response of six birds is shown. The chickens were in apnea during the first 5 min of CO admjni~tr~ti~~ but they initiated cyclic re~~ir~to~~ rno~em~~ts about 6 min after CC? ~dmirlistratio~ began.

HbCO concentrations rose from 0 to 38”,;j,in only 10 min during unidirectional ventilation with 0.17; CO (fig. 7). Likewise, one-half of the HbCO was lost within 25 min after CO administration ceased. One hour after CO was removed, HbCO concentrations were only 16.8 _COJoi,(SE). ed 477;; in 10 min, died; one 10 min Two cbiek~~s~ in which HbCO exe after CO administration began and t other 15 min after CO was removed (fig. 7). In both of these birds t e rate orerise of HbCU was more rapid than in those birds that survived and the maximum HbCU was in excess of 509;. Adding CO, to the inhaled gas has been reported to reduce the affinity of hemoglobin for CO (Best and ~o~~~, 1966). To determine if the rate could be increased, we added 6% CO, to the ventilatory gas of one bird after CO was removed. The rate of removal of HbCO did not differ between that bird and the six that received 0:; COz (fig. 7). An unexpected change in P%z occurred during the experiment. One minute before CO was ~ntroduced~ P%? was 84.8 + 7.1 (SE) torr. ft decreased (61.6& 7.8 torr) within 5 min after CO administration (fig. 8) -and appeared to increase sI~~bt~y,but not to pre-exposure levels, after CO was removed from the ve~~tilatory gZK&

Because the ventilatory gas contrived Oy*,CO, when the blood samples were taken, pHa was high (approximately 8.0) and Pqoz was low (belie 110 torr)

320

R. R. TSCHORN

AND M. R. FEDDE

60 -

TIME Fig. 7. Carboxyhemoglobin and after administration six birds received

receiving 6”/, CO,

formation

[min] in unidirectionally

of 0.19; CO. Solid line represents

O.l”/O CO after

and dissociation

in the

ventilatory

CO was removed

gas.

from

ventilated

the mean (*SE)

Dotted

HbCO

line is the

the ventilatory

gas.

HbCO

Dashed

chickens, of one

bird

lines represent

concentrations

of two birds that died before the experiment ended. CO was added gas mixture at 0 min and removed at 15 min (arrow).

Fig.

on Paoi

during

concentration

of that

HbCO

to the ventilatory

TIME [min ] 8. Effects

( +SE)

of Pg,

was introduced

during

from six birds

unidirectional before

(reading

at time 0 and removed indicated

after

ventilation

with

Oq, CO,

at time 0), during, 15 min (arrow).

by the break

and

Values

and

after

O.l”,b CO.

The

CO administration.

were not obtained

during

mean CO time

in the graph.

throughout the course of the experiment. Limitations in the blood system prevented exact measurements of pHa and Paco2.

gas analyzing

Discussion Carbon monoxide poisoning seldom reduces Pg2 until respiration by pronounced central hypoxia (Root, 1965; Lambertsen, 1968). decrease in Pao2 in the chickens receiving CO in our experiments

is depressed The marked most likely

co

AND RESPIRATORY

CONTROL

321

resulted from a facet of the experimental procedure other than adding CO. Removing CO* from the ventilating gas in unidirectionally ventilated chickens has been reported to increase tracheal pressure, probably via increased pulmonary airway resistance (Ray and Fedde, 1969). It appears that low intrapulmonary COz concentration causes contraction of smooth muscle, which is abundant in the avian lung, especially surrounding the parabronchi (King and Molony, 1971). Such action could shunt gas from the parabronchi and decrease parabronchial ventilation. In recent experiments, when we unidirectionally ventilated chickens first with 5.0% CO, and 20.0% 0, then, for 15 min, with O”, CO, and 20.0% O,, Paolo, decreased from approximately 118 to 73 torr (Fedde, unpublished observations). In the current study, CO, was removed from the ventilating gas stream 4 min before Pacz was first measured. The mean Pg2, 84.8 torr, was considerably less than expected during ventilation with 20.4% 0, and it continued to drop (to a minimum of 61.6 torr) the next 5-6 min. Administration of CO was probably not involved in the response. Most probably, low intrapulmonary CO? concentration constricted parabronchial smooth muscle which decreased parabronchial ventilation and that, in turn, likely reduced PaoL. Intrapulmonary, CO,-sensitive receptor activity was not influenced by 0.10, CO in the ventilatorygas mixture. Furthermore, the receptors’ response to CO, remained unaltered in the presence of CO, as indicated by no changes in static or dynamic response curves. Thus, initiation of cyclic ventilatory motions, which began about 6 min after CO administration, could not have been caused by alterations of that receptor system’s activity. Therefore, an alternate explanation of CO action on ventilatory control is needed. The HbCO concentration reached 25% when cyclic ventilatory motions were initiated. A hypoxic stimulus sufficient to affect such peripheral chemoreceptors as the carotid body (Jones and Purves, 1970; Magno, 1973) may have been present. It is doubtful, however, that such a stimulus was responsible for cyclic ventilatory motions observed during CO administration, because the chickens were not receiving CO, in the ventilatory gas mixture during CO administration. The intrapulmonary CO,-sensitive receptors were, therefore, discharging at relatively high frequency. An increase in discharge frequency of the receptors correlates with a decrease in respiratory motoneuronal activity and apnea (Fedde and Peterson, 1970). Furthermore, that receptor system’s inhibitory influence is extremely strong. Fedde and Peterson (1970) showed that during apnea, produced by low intrapulmonary CO, concentrations, removing 0, from the ventilatory gas mixture produced lethal hypoxia but did not induce cyclic ventilatory motions. Neither are those motions induced during less hypoxia (57; 0, in the ventilating gas) nor by infusing epinephrine or norepinephrine so long as the intrapulmonary CO, concentration is low (Fedde, unpublished observations). Thus, all receptor systems, such as carotid and aortic bodies, which could be stimulated by hypoxia, cannot produce enough excitation on the central respiratory neuronal pool to overcome the strong inhibition from the intrapulmonary CO,-sensitive receptor system. Therefore,

322

R. R. TSCHORN

even if hypoxia

(due

to increased

AND M. R. FEDDE

HbCO,

decreased PaoJ was strongly stimulating their activity could have been responsible occurred

during

increased

binding

of 0,

by Hb, and

the carotid bodies, it is not likely for the cyclic ventilatory motions

that that

CO administration.

To explain the influences of CO on the respiratory control system, its effect on other regions of the body must be considered. Chiodi et nl. (1941) found that a given concentration in the hypoxia of CO that CO may depress (1969) extended that polysynaptic reflexes, concentrations of CO.

of CO, in inspired air induced less increase in ventilation poisoning than in the non-poisoned animal. They concluded centers in the CNS that control respiration. Barrios er al. idea when they found latency of many reflexes. especially increased during and after cats were exposed to various

CNS

co

I I I

I

DepreSSeS

1

I I

I 1

Inhibition

I

I

I I

I

1 l I l I I I I I

RESPIRATORY

I I I I I I I L-..--_-_______-----_----_,._~

A INTRAPULMONARY CO+ENSITIVE RECEPTORS Fig. 9. Possible

site and mode of action

+ BREATHING MOVEMENTS of CO on respiratory

control

Our results suggest a hypothesis to explain the site of depressing effect of CO on the CNS and resulting changes in ventilatory control (fig. 9). Before CO is administered, inherent respiratory rhythmicity of inspiratory and expiratory centers is modulated by peripheral receptors and possible by higher centers. When intrapulmonary CO, concentration is low, impulses from intrapulmonary CO,-sensitive receptors inhibit respiratory rhythm and cause apnea in the chicken. During CO administration, a depression of inhibitory interneurons (which are activated by the intrapulmonary CO,-sensitive receptors) would prevent the strong inhibitory influence of these receptors from reaching the respiratory centers. The action of CO must, however, be selective because generation of cyclic breathing movements shows the respiratory neuronal pool is still capable of activity. The inherent respiratory activity in the respiratory centers could then cause cyclic ventilatory motions. The cardiovascular response of the chicken to spontaneous breathing of O.lYOCO is decreased blood pressure with constant heart frequency (Tschorn and Fedde,

co

1974). Those depresses

changes

AND RESPIRATORY

are also explained

the CNS. If both

sympathetic

323

CONTROL

by the hypothesis

that

and parasympathetic

CO selectively

control

of the heart

were depressed, the result could be negligible change in heart frequency. However, because vascular tone is predominantly provided by sympathetic activity, depressed activity of sympathetic fibers may produce vasodilatation and reduce cardiac output and, rejection of interneurons effect of CO

hence, the observed decrease in blood pressure. Confirmation or the hypothesis must await single-unit recordings from inhibitory activated by intrapulmonary CO,-sensitive receptors. Perhaps a direct on these neurons may thereby be shown.

Acknowledgements We thank Dr. Arthur D. Dayton for assistance with the statistical analysis and Dr. Peter Scheid, Abteilung Physiologie, Max-Planck-Institut fur experimentelle Medizin, Gottingen, West Germany, for critique of the manuscript. Miss Ann Hurley and Mr. Wade Kuhlmann provided skillful technical assistance. This work was supported, in part, by a grant-in-aid from the Kansas Heart Association. References Barrios,

P.. W. Koll

and

G. Malorny

(1969).

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P. J. (1967).

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324 Stadie,

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K. A. Martin

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The

AND M. R. FEDDE

elimination

J. Clin. Invest. 2: 77-91. Tschorn, R. R. and M. R. Fedde (1974) Cardiopulmonary the chicken.

Respir. Physiol. 20: 303-311.

of carbon responses

monoxide

to carbon

from

monoxide

the

blood.

breathing

in