THE EFFECT OF CHANGES IN HYDROGEN ION CONCENTRATION ON THE PULMONARY CIRCULATION

THE EFFECT OF CHANGES IN HYDROGEN ION

CONCENTRATION ON THE PULMONARY

CIRCULATION

Edward H. Bergofsky, … , David E. Lehr, Alfred P. Fishman

J Clin Invest.

1962;

41(7)

:1492-1502.

https://doi.org/10.1172/JCI104604

.

Research Article

Find the latest version:

Journal of Clinical Investigation Vol. 41, No. 7, 1962

THE EFFECT OF CHANGES IN HYDROGEN ION CONCENTRATION

ON

THE

PULMONARY CIRCULATION

*

By EDWARD H. BERGOFSKY,t DAVID E.

_LEHR$

AND ALFRED P. FISHMAN

(From theDepartment of Medicine, Columbia University College of Physicians and Surgeons, and the Cardiorespiratory Laboratory of the Presbyterian Hospital, New York, N. Y.)

(Submitted for

publication January 23, 1962; accepted March 22,

1962)

Although acidosis has long been known to cause

vasodilation

in certain systemic vascular beds

(1-3), its effect

on

the

pulmonary vessels remains

unsettled.

This

uncertainty stems from the

in-consistent effects of an acute change in blood pH

on

the pulmonary circulation of the isolated lung

(4-8) and of the lung perfused

in situ (9), and

the

lack of observations on intact animals and

man.

Liljestrand,

on

the basis of experiments

involv-ing

the exposure of the isolated lung to severe

hypoxia,

recently proposed that the release of

lactic acid from the cells of the lung is responsible

for

the increase in pulmonary arterial pressure

during

acute

hypoxia

(10).

However, it is not

clear

to what extent this

hypothesis,

based on the

behavior of an artificial preparation

during

drastic

experimental

conditions,

applies to the behavior

of the normal pulmonary circulation of either the

intact animal or man

during

less severe hypoxia.

The

present

study

was

designed to assess

the

role of acidosis in

the

regulation

of

the

pulmonary

circulation

of

intact

animals and man.

We

found

that acidosis

can

increase pulmonary vascular

re-sistance.

Experiments

were

then

undertaken:

1)

to

distinguish between the effects

of

the hydrogen

ion and

the effects of

the

associated

anions

on

the

pulmonary circulation,

and

2)

to

determine

the

role

of

acidosis

in

the pulmonary arterial

pressor

responses to

acute

hypoxia

and to acute

hyper-capnia.

SUBJECTS AND METHODS

Acute acidosis. In order to avoid the increase in

min-ute ventilation which acidosis evokes in unanesthetized

*_{Supported in part by Grant H-2299}

_(C3)

_{from the}

National Heart Institute, with additional support from the American Heart Association and the New York Heart Association. Presented in part at the Conference

on In-Vitro and In-Vivo Effects of Amine Buffers, The

New York Academy of Sciences, December 12, 1960.

tSenior Fellow of the New York Heart Association.

tFellow of the American Trudeau

_Society.

animals and man, and which prevents large changes in the blood pH, the effects of acidosis were studied during controlled ventilation in anesthetized dogs. Eleven dogs were anesthetized with intravenous pentobarbital

(Nem-butal), 30 mg per kg. The minute ventilation was

con-trolled by means of an automatic, intermittent, positive

pressure breathing apparatus (Bird), connected to the trachea of the dog bymeansof acuffed endotracheal tube. The breathing apparatus was incorporated into an open circuit in such a way that expired air could be collected in a gasometer. In each doga no. 6 cardiac catheterwas

introduced into the pulmonary artery under fluoroscopic control by way of ajugular vein. An indwelling needle

was placed inonefemoral artery; ano. 6 cardiac catheter was threaded retrogradely, through the other femoral artery, into the left ventricle.

The experiments were of three types: a comparison of the effects of lactic acid with those of hydrochloric acid (four dogs) ; a comparison of the effects of lactic acid with those of acute hypercarpnia (three dogs); and the effects of lactic acid duringacute hypoxia (four dogs).

Each type of experiment consisted of four periods; each period lasted for 15 to 20 minutes. The first type of experiment, involving the comparison of the effects of lactic with hydrochloric acid, consisted of the following periods: 1) control, i.e., ambient air breathing during the intravenous infusion of normal saline at a rate of 4 ml per minute; 2) the infusion of 0.3 M lactic acid at the

same rate; 3) repeat control, 30 minutes after the second period, when the arterial blood pH had returned toward

normal; and 4) the infusion of 0.3 M hydrochloric acid

at the same rate. The second type of experiment, which compared the effects of lactic acid andacute hypercapnia,

was the same as the first, except for the fourth period, when an inspired mixture containing 5 per cent CO. in airwassubstituted for ambient air, and normal saline was infused at the standard rate of4 mlper minute. For the third typeof experiment, which tested the effects ofacute acidosis during acute hypoxia, the first two periods were the same as the first two periods of the previous experi-ments; during the third period, an inspired mixture of 12 per cent 0, in N. was substituted for ambient air; during the fourth period,an infusion of0.3 M lactic acid,

attherateof4ml permin,was substituted for the normal saline as the dog continued to breathe the hypoxic in-spired mixture.

Blood pressures were recorded, at different paper speeds, either continuously orat 1-minute intervals. For the sake ofprecise measurement, records of diastolic blood

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1494 EDWARD H. BERGOFSKY, DAVID E. LEHR AND ALFRED P. FISHMAN

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EFFECT OF PH ON THE PULMONARY CIRCULATION

pressures in the left ventricle were taken, in rapid

suc-cession, at several different gains. Expired gas for the calculation of the oxygen uptake and the respiratory

ex-change ratio was collected in a 13-L spirometer during the final 2 minutes of each period; blood samples were

drawn simultaneously from the brachial and pulmonary arteries during the middle minute of gas collection for the determination by the Fickprinciple of the cardiac output.

Acute alkalosis. The effects of acute alkalosis in

modifying the pulmonary arterial pressor response to

acute hypoxia were studied in unanesthetized normal

human subjects. The subjects were six men and three

women, ranging in age from 17to 47 years. All studies were performed in the morning after an overnight fast.

An indwellingneedle was inserted into the brachial artery and a no. 8 cardiac catheter was passed from the

ante-brachial vein into the pulmonary artery (11). An open-circuit breathing system was used to deliver either

am-bient air or the hypoxic gas and to collect expired air

in a 120-L gasometer. Each study consisted of four

periods: 1) control, ambient air breathing; 2) acute

hypoxia, during which an inspired mixture of 12 per

cent02 in N. was substituted for ambient air; 3) ambient

air breathing plus alkali; and 4) acute hypoxia plus

alkali. Throughout each study an infusion of fluid was continued at the rate of 6 ml per minute; in five subjects

normal saline was infused until 25 minutes before the start ofperiod 3 when a solution of 0.3 M Tris was sub-stituted for the saline; in four other subjects a solution

of 0.3 M sodium bicarbonate was substituted for the

saline. During periods 2 and 4 the hypoxic inspired gas mixture was administered for the last 15 to 20 minutes ofthe period. As in the animal experiments, the appro-priate blood and gas samples were collected during the final 2 minutes of each period.

Analytic techniques and calculations. The same ana-lytic techniques were used in both sets of experiments. Blood pressures were recorded from the intracardiac

cath-etersby strain gauges andanoscilloscope recorder (Elec-tronics for Medicine). Cardiac output was measured by the Fick principle during a steady state of respiration and circulation (12). The 02 and CO2 contents of expired

air were measured by the micro-Scholander technique

(13), and the 0,and CO2contents of mixed venous and arterial blood were analyzed by the method of Van Slyke

and Neill (14). The blood pH was measured at 370 C

(McInnes-Belcher glass electrode). The concentration of lactic acid in arterial blood was determined by the method of Barker and Summerson (15).

The arterial CO2 tension was calculated from the pH and the CO2 content of serum, by use of the line charts

of Van Slyke and Sendroy (16). The pulmonary

vas-cular resistance was calculated as the ratio of mean pulmonary arterial pressure minus mean left ventricular diastolic pressure to the cardiac output.

For the 22 experimental periods involving acidosis, the

constants in the best linear equations relating pulmonary vascular resistance to arterial blood pH, on the one

hand.

and to arterial blood

Pco2,

on the other, were calculated by the method of least squares; their significance was

estimated by the Fisher t test. Similar statistical anal-yses were performed for the relationship between pulmo-nary vascular resistance and arterial blood pH produced by the infusion of lactic acid, the infusion of hydrochloric acid, and the breathing of CO2, respectively.

RESULTS

Acute

acidosis

Lactic

acid versus

hydrochloric

acid.

The

ef-fects

of

these

acids

on

the

pulmonary

circulation

of four

dogs are

compared

in

Table I.

It may be

seen

that the infusion

of

HCl effected

a

slightly

greater

decrement in arterial

pH

than did the

in-fusion of

lactic acid

(- 0.27

as

compared

with

-

0.16).

The

concentration of lactic

acid in the

arterial blood increased five- to

sixfold

during

the

lactic acid

infusion

but

remained

at

control

levels

during the infusion

of

hydrochloric acid.

Despite

these dissimilarities

in

the

concentrations

of

anions

(i.e., lactate

versus

chloride) in the pulmonary

ar-terial

pressure

increased in each animal

during

acidosis.

The

average

increases

were

3

mm

Hg

during the lactic acid infusion and 5

mm

Hg

dur-ing

the HCl

infusion.

The

most

striking changes

in

pulmonary arterial

pressure

occurred

in

dog 4,

which also had

the

most

marked

changes in

ar-terial

pH. These consistent

changes

in

pulmonary

arterial

pressure

occurred

in

the

face of

unchanged

left ventricular pressure in

all

dogs

and of

un-changed cardiac

output

in three of the four

dogs;

in

the fourth animal

(dog

2),

the cardiac

output

increased

by equal

amounts

during the

two

periods

of

acidosis.

The

changes

in calculated

pulmonary vascular

resistance that occurred during

the

infusion of

the

acids

is illustrated

for

each animal in

the

upper

half

of

Figure 1.

It

can

be

seen

in

each animal that

acidosis

was

associated with

an

increase in

calcu-lated resistance.

Moreover, the

slopes of the lines

relating

arterial

pH to

resistance

were

similar for

the

two

acids.

Lactic acid

versus

5

per cent

CO2. The effects

of

infusing

lactic

acid

and of

controlled

ventila-tion with 5

per

cent

CO2

in

air

are

compared

in

the

middle portion

of Table

I.

The

two

acids had

different effects on

the

composition

of arterial

blood.

1)

The

degree

of acidosis

produced by

the

infusion

of

lactic acid exceeded that

produced

by

CO2 breathing; thus, the

average

decrement

in

EDWARD H. BERGOFSKY, DAVID E. LEHR AND ALFRED P. FISHMAN

acid and 0.19 during CO2 breathing.

2) During

CO2 breathing the CO2

content

of arterial

serum

increased,

on

the

average,

by

4 ml

per

100

ml

and

the

Pco2

increased

by 21

mm

Hg; in

contrast,

the

arterial CO2

content

fell by approximately 11 ml

per

100 ml

during

the lactic acid infusion and the

Pco2 increased by only

4

mm

Hg.

3) The

con-centration of

lactate

in the arterial blood

increased

markedly during the infusion of lactic acid but

remained

unchanged

during CO2 breathing.

De-spite these

differences,

each

dog responded

to

both

the

infusion

of lactic acid and

to

the

breathing

of

LACTIC

ACI

0.44

RMv

mmHg m I/sec

0.3

0.2

0.1

the

CO2

mixture

with

a

rise in

pulmonary

arterial

pressure.

The increases

in

pulmonary

arterial

pressurewerenot

associated with

changes

in either

the cardiac

output

or

left

ventricular

pressure.

Fi-nally,

the lower half of

Figure

1 shows

that,

de-spite

the

considerable differences between

the

con-centration of the

anions

in the arterial

blood,

simi-lar

decrements

in arterial

pH

were

associated

with

equivalent

increments

in

mean

pulmonary

vascu-lar

resistance.

Lactic acid

during

acute

hypoxia.

The effects

of

infusing

lactic

acid

during

acute

hypoxia

are

0.4

Rpv

mm Hg

mI/sec

0.3

-0.2

-0.1

LACTIC ACID

5 0/0

CO2

WA/1

I

i I I I I I

7.40 7.20 7.00 7.40 7.20 7.00

pH

pH

FIG. 1. THE EFFECTS OF A CHANGE IN PH ON MEAN PULMONARY VASCULAR

RESISTANCE (RPv) IN THE DOG. Upper half: The effects in the same animals of

infusions of 0.3 M lactic acidand 0.3 M hydrochloric acid. Lower half: The effects

in another group of animals of infusing 0.3 M lactic acid and of breathing 5 per

cent CO2.

Each symbol represents a single animal: the open symbols represent control values

before the acidosis; the solid symbols represent the corresponding values during

acidosis. Equal decrements in pH evoke similar increments in pulmonary vascular resistance, regardless ofthe acidifyingagent.

LACTIC ACID

7.00 7.20

LACTIC ACID

+

HYPOXIA

7.40

pH

7.20 7.00

pH

FIG. 2. THE EFFECTS OF 0.3 M LACTIC ACID (LEFT) AND OF HYPOXIA AND 0.3 M LACTIC ACID (RIGHT) ON THE PULMONARY VASCULAR RESISTANCE OF FOUR DOGS. As in Figure 1, each symbol represents an individual animal.

For equivalent decreases in pH, an infusion of lactic acid produces the same increase in pulmonary vascular

re-sistance during ambient air breathing as during the breathing of 12 per cent 02 in N2.

itemized for four dogs in the bottom portion of

Table

I.

In

these animals the infusion of lactic

acid

during ambient air breathing

was

associated

with

an average

increase in pulmonary arterial

pressure

of 4

mm

Hg.

Acute hypoxia elicited

an

approximately equal increase; the infusion of

lac-tic

acid during

acute

hypoxia evoked

a

further

in-crease of 3 mm

Hg.

The

change

in

pulmonary

vascular resistance that accompanies lactic acidemia

during

ambient

breathing

is

compared

with the

change

evoked

by lactic acidemia during

acute

hy-poxia

in

Figure

2.

It

may

be

seen

that

in

each

dog, lactic acidemia without hypoxia (left panel)

elicited an

increase in resistance corresponding

to

that

previously

observed in the first seven

dogs

of

Table

I.

The substitution

of

the hypoxic inspired

mixture for ambient air (right panel) elicited

a

further

increase

in

resistance.

The

increment

in

resistance

per

unit

decrement in arterial pH

was

similar, however, during

ambient air

breathing

and

during

acute

hypoxia.

Statistical analysis of data. The increase in

pul-monary

vascular resistance during the

22

periods

of

acidosis in the 11 dogs is statistically significant

(SE

=

0.019;

_p <

0.01). Moreover,

a

statistically

significant relationship exists between the

incre-ments

in pulmonary vascular resistance

_(R,)

and

the decrements in arterial blood pH

(ARP

=

-0.047

+

0.686- ApH;

p <

0.01).

With

respect to

the individual acidifying

agents,

the

relationship

between the pulmonary

vascular

resistance

and

the

decreases in arterial blood pH is statistically

sig-nificant for lactic acid experiments

_(Rep

=

0.1095

+

0.201 -ApH;

p <

0.01) and probably significant

for the CO2 experiments

(ARp

= -

0.006

+

0.581

-ApH;

p <

0.05)

and for the HCl

experiments

(ARp

=

-0.074

+

0.796-ApH;

p<

0.05).

A

statistically significant increase

in

arterial

blood

Pco2

occurred

during

the

22 periods

of

aci-dosis

(SE

=

1.74;

p<

0.01).

However,

in

con-trast to

the statistically significant relationship

be-tween

_Rp

and

pH in these animals, the linear

equation relating

increases in

pulmonary vascular

resistance

to

increases in

arterial

blood

Pco2

has

no

appreciable

slope

(ARp

=

0.104

+ 0.00022

APC0o2)

-Acute

alkalosis

Amine buffer. The effects of Tris in modifying

the

changes

induced

by

acute

hypoxia

onthe

com-0.4

-RPV

mm Hg mI/sec

0.3

-0.2

-0.1

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EFFECT OF PH ON THE PULMONARY CIRCULATION

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FIG. 3. THE AVERAGE PULMONARY HEMODYNAMIC

EF-FECTS OF 0.3 M THAM (TRIS) DURING AMBIENT AIR

BREATHING AND DURING HYPOXIA IN FIVE NORMAL HUMAN SUBJECTS. The pulmonary arterial pressure (PPA) is

represented by solid circles for systolic values, open circles formean values,andtriangles fordiastolicvalues;

PBA refers to the mean brachial arterial pressure, Q, to

cardiac output and SaO2 to arterial 02 saturation. The

pulmonary hemodynamic response to acutehypoxia is the same before andduringthe infusion of Tris.

position

of

arterial blood, the pulmonary

circula-tion, and the systemic blood

pressure

are

sum-marized for

each

of

the five

human subjects in the

upper

portion of Table

II.

Despite the alkalosis

induced by Tris, the

changes in arterial

oxygen

saturation

and

CO2 tension during

acute

hypoxia

were

approximately the

same

before and

after

the

infusion

of

the buffer.

Figure 3 summarizes the

average effects

of

acute

hypoxia

on

the

circulation

before

and

after the

infusion

of

Tris.

It may be

seen

that both the pH and the

cardiac output

con-tinued

to

increase

during the

course

of

the

experi-ments.

Nonetheless, the

magnitude and the

pat-tern

of

change of the

pulmonary arterial

pressure

were

unaffected by

the infusions.

The

brachial

arterial

pressure

remained

virtually

unchanged

during the consecutive periods.

Sodium bicarbonate.

The experiments

involv-ing the

use

of

sodium

bicarbonate instead

of

Tris

are

detailed

for the four human.

subjects

in

the

lower

half of

Table

II.

The

degrees of

hypoxemia

1499

10

Cl

1C

-.0 C')oj

QC0%0

c'-54C0)CU) .c)) (0)

Z

:11

0E

I..

co0

E 14.1

0

C

. 4,

Lo

0

CQ

Cd

0 Cd

u)

0

ad

up

v(U

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¢S!

9)n

It .- .0_m1100

I

I

0 - o.1 0

t-cialp-r- r o r

eC" -.14 .o ON -tr-U) en .o (=>

t-EDWARD H. BERGOFSKY, DAVID E. LEHR AND ALFRED P. FISHMAN

AFTER NaHCO3

30

PPA

20

7.0

L/min

5.0 PBA 105 Hmg 95 Sa2

95

Sama

85 A%

7.52--pH 7.47 7.42

INSPIRED GAS 2 1 %02 12 %02 21 % 02 12.

Oz0

FIG. 4. THE AVERAGE PULMONARY HEMODYNAMIC EF-FECTS OF 0.3 M SODIUM BICARBONATE DURING AMBIENT AIR BREATHING AND DURING HYPOXIA IN FOUR NORMAL HUMANS. Symbols as in Figure 3. The pulmonary

arterial pressor response to hypoxia is the same before andduring the infusion of sodium bicarbonate.

and

alkalosis

were

virtually identical in the Tris

and the bicarbonate experiments.

The effects of

the

two

alkalinizing

agents on

the

cardiac

output

were

also similar.

Finally,

as may

be

seen

in

Fig-ure

4, the infusion of sodium bicarbonate, just

as

the infusion

of

Tris, did

not

modify the pulmonary

arterial pressor response to acute

hypoxia.

DISCUSSION

The

present

study has shown that

acute

acidosis

in

the

anesthetized dog elicits

an

increase

in

pul-monary

arterial

pressure

without affecting either

the

pulmonary blood flow

or

the

blood

pressures in

the left ventricle; the magnitude of the

pul-monary

arterial

pressor response to

acidosis is

re-lated

to

the

change in the blood pH, rather than

to

associated

anions of the

acids; and

acute

alkalosis

in

unanesthetized human subjects does

not

modify

the

pulmonary arterial

pressor response to

hy-poxia. These results have

two

major implications:

acute

acidosis elicits pulmonary vasoconstriction,

and acute

acidosis is

not

involved

in

the

pulmo-nary

vasoconstriction of

acute

hypoxia.

These

experiments also

seem to

provide

a

rea-sonable

explanation

of the variable

effects

which

CO2 breathing is reported

to

exert

on

the

pul-monary circulation

(17, 18).

Thus, according

to

the

present

study,

both

the

infusion of

fixed

acids

and the

breathing of CO2 elicited

the same

rise

in

pulmonary arterial pressure for

equivalent

de-creases in

blood pH,

even

though

the increments

in

blood

Pco2

were

very small during the

acid

in-fusions

and

very

large during the CO2 breathing.

These

observations suggest that at least some of

the reported

variability

in

the effects

of

CO2

breathing on

the pulmonary circulation

may be

attributable to

the different degrees

of

acidosis

which

CO2 breathing evokes under

different

ex-perimental conditions:

in normal

unanesthetized

human subjects, a "compensatory" increase in

minute ventilation

minimizes

the change

in

blood

pH

so

that

CO2 breathing is without discernible

effect

on

the

pulmonary circulation

(17);

by

way

of contrast, when

ventilation is controlled

so

that

drastic

changes

in

blood pH

can occur,

CO2

breath-ing may elicit

appreciable

increments in

pulmonary

vascular resistance.

The

present

experiments

also suggest

that

the

effect

of a

change

in

blood

pH

on

the pulmonary

circulation originates in extracellular, rather

than

in

intracellular acidosis.

This

conclusion

is based

on

the observation

that

CO2

penetrates cells

more

rapidly than does

the hydrogen

ion

(19, 20);

con-sequently, during experimental

periods

of

only

20

minutes, a

comparable

degree of

extracellular

aci-dosis

is apt

to

be associated with

a

greater

degree

of

intracellular acidosis during CO2 breathing

than

during the

infusion of

fixed

acids.

The

consistent

relationship between the change

in

pulmonary

ar-terial

pressure and

the

change

in

arterial blood

pH,

regardless

of

the acidifying

agent, suggests

that

the mechanism

for

vasoconstriction

in

acidosis

originates

from

without the

cell.

On

the basis of

experiences

with

severe

hypoxia

in

the

isolated

lung,

Liljestrand proposed

that the

intrapulmonary

release

of

lactic acid

is

responsible

for the

pulmonary

pressor

response

to

hypoxia

(10).

However, in

both the

intact

animal

and

man, acute

hypoxia characteristically elicits

re-spiratory

alkalosis

as

well as

pulmonary

hyperten-sion; it does

not

evoke lactic

acidemia

(21).

Therefore, the application of Liljestrand's

hy-pothesis

to

the intact animal

presupposes

that the

lactic acid

is

produced within the vascular

smooth-muscle cells,

but is released in quantities

too small

BEFORE NoHCO3

either

to be detected in

the blood stream or to

af-fect

the

blood

pH. The use of

the

amine

buffer

to

test this possibility is

based upon three

considera-tions:

1)

the

pulmonary vascular cells, like

other

cells,

have

poorer

buffering capacity than has

ex-tracellular fluid

(22);

2) the amine buffer

ac-cumulates

rapidly

in

cells

(23)

so

that

intracellular

pH may be

expected to increase more than does

extracellular pH

(24);

and

3)

the

pKa

of

the

amine buffer

(6.10)

is such

that

it should serve

as an

efficient neutralizer of released acid

(25)

over

the usual range of intracellular or

extracellu-lar

pH

(6.5

to

7.5).

When viewed with respect

to

the extracellular

alkalosis

and the lack of

lac-tic

acidemia, the failure

of

the

amine buffer to

modify

the

pulmonary

arterial pressor response to

hypoxia suggests that

neither intracellular nor

ex-tracellular

lactic acidosis

is involved in the

pul-monary

pressor response

to hypoxia.

SUMMARY

1. The present study

was concerned with the

role of the

hydrogen

ion

in the regulation of the

pulmonary circulation.

2. We found that

acute

acidosis of

sufficient

de-gree,

whether induced by infusion of fixed acids

or

breathing carbon dioxide, consistently elicits an

increase in pulmonary arterial pressure which is,

in

turn, attributable

to

pulmonary vasoconstriction.

3.

The consistent relationship between the

de-gree of

acidosis and

the

increase

in

pulmonary

vas-cular

resistance, regardless

of

the acidifying

agent,

indicates

that the hydrogen ion,

rather than

the

as-sociated anions

of

the acids,

is involved in the

pulmonary

vasoconstriction.

4.

These

experiences

with acute acidosis in dogs

and acute

alkalosis

in man are relevant to

the

role

of the

hydrogen

ion in

the

pulmonary arterial

pres-sor

responses to acute

hypercapnia

and acute

hy-poxia;

whereas

acute

hypercapnia

seems to elicit

pulmonary vasoconstriction

through the acidosis

it

produces,

acute

hypoxia

appears to be an

inde-pendent stimulus

to

pulmonary

vasoconstriction.

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blood flow and peripheral resistance in muscular

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Effect of controlled hydrogen-ion concentration on

peripheral vascular tone and blood flow in

in-nervated hind leg of the dog. Amer. J. Physiol. 1952, 169, 678.

4. Nisell, 0. Effects of oxygen and carbon dioxide on

thecirculation of isolated and perfused lungs of the

cat. Actaphysiol. scand. 1948, 16, 121.

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1960, 153, 413.

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EDWARD H. BERGOFSKY, DAVID E. LEHR AND ALFRED P. FISHMAN

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21.

_Huckabee,

W. E.

_{Relationships}

of _pyruvate and lactate

_during

anaerobic metabolism. III. Effects of

_breathing

_low-oxygen

_gases.

_J.

_dlin.

Invest.

1958, 37,

264.

22.

_Fenn,

W. 0.

CO,

and intracellular homeostasis.

Ann. N. Y.

Acad. Sci.

1961,

92,

547.

23.

_Holmdahl,

M.

H.,

and

_Nahas,

G. .G. Volume of

distributionof

C1'

tagged

2-amino-2-hydroxymethyl-1,3-propanediol (THAM).

Fed. Proc.

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24.

Robin,

E. D. Intracellular acid-base relations and

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Ligou, J. C.,

and

Nahas,

G. G.

_Comparative

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by

acid infusion and CO2