The Role of Hydrogen Ion Concentration in

the Regulation of Pulmonary

Arterial Pressure
Observations in a Patient with Hypoventilation
and Obesity
By JoHN H. K. VOGEL, M.D., AND
THE PULMONARY circulation has been
the subject of many studies since the
original measurement of pulmonary arterial
pressure by Beutner in 1852.1 Of particular
importance were the observations by von
Euler and Liljestrand in 1946,2 that the admin-
istration of 10 per cent oxygen with 90-per
cent nitrogen resulted in a significant rise in
pulmonary arterial pressure in the cat. This
observation was soon confirmed in man by
Motley and associates in 1947.3 In addition,
von Euler and Liljestrand demonstrated that
the administration of 6.5 per cent carbon
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S. GILBERT BLOUNT, JR., M.D.
sponse to altered hydrogen ion concentration
would only be detectable in the presence of
chronic pulmonary disease.
We recently have had the opportunity to
study a woman with hypoventilation and
obesity in whom there was no evidence of
intrinsic lung disease.6'0 The following report
demonstrates that her blood hydrogen ion con-
centration played a dominant role in the regu-
lation of her pulmonary arterial pressure.
Case Report
This 43-year-old white woman was first admit-

dioxide in oxygen increased pulmonary arterial
pressure.2 Liljestrand, in 1958,4 reemphasized
the importance of hydrogen ion concentration
as a chemical stimulus for pulmonary vaso-
constriction.
Recently, Enson and associates5 have shown
the importance of hydrogen ion concentration
in the regulation of pulmonary arterial pres-
sure in patients with chronic lung disease.
They showed that a decrease in blood hydro-
gen ion concentration, induced by the admin-
istration of trihydroxy aminomethane (THAM),
caused pulmonary vasodilatation. Further,
Enson and associates5 suggested that a
change in pulmonary arterial pressure in re-
From the Cardiovascular Laboratory, University of
Colorado Medical Center, Denver, Colorado.
Supported in part by U. S. Public Health Service
(Grants HE 01208 and FR 51), the American Heart
Association (Grant 63 G 158), and the Idaho Heart
Association.
Dr. Vogel is an Advanced Research Fellow, Ameri-
can Heart Association.
788
ted to the University of Colorado Medical Center
on March 19, 1964, with cough and fever, which
cleared in 3 days. Review of her history revealed
that for the past 2 years she had noted a tendency
to fall asleep while sitting in a chair, either read-
ing or watching television. However, her exercise
tolerance had been excellent with no signs or
symptoms of congestive heart failure. There had
been no change in her mental acuity. She had al-
ways been overweight, weighing as much as 160
pounds in high school and over 250 pounds for the
past 5 years.
The physical examination revealed a blood pres-
sure of 140/80 mm. Hg, pulse of 60 beats per
minute and regular, and a respiratory rate of 16.
The patient was 5 feet 6 inches tall, pleasant and
alert, with generalized obesity, weighing 279
pounds. There was some duskiness of her lips and
tongue but no definite cyanosis. Examination was
otherwise normal.
The electrocardiogram and vectorcardiogram
revealed right axis deviation with right ventricular
enlargement and ST-T-wave changes. The chest
x-ray revealed that the pulmonary vascularity was
within normal limits, although the main pulmo-
nary artery was slightly prominent. The over-all
heart size and aorta were within normal limits.
The hematocrit value was 46 per cent, white
blood-cell count 8,200; the differential count was
CiCrcuation, Volume XXXII, November 1965
 HYDROGEN ION CONCENTRATION
normal. The urinalysis was normal. Total pro-
tein was 7.8 Gm. per cent, with a normal al-
bumin-globulin ratio, VDRL nonreactive, 2-hour
postprandial blood sugar 106 mg. per cent, pro-
tein-bound iodine 9.6 micrograms per cent, and
radioactive iodine uptake 14.7 per cent at 24
hours. Vital capacity was 2.92 L. observed, 3.67
predicted; 1-second forced expiratory volume 2.39
L. (82 per cent) observed, over 75 per cent
predicted; maximal midexpiratory flow rate L./
sec. 2.92 observed, 2.97 predicted; and maximal
breathing capacity L./min. 76 observed, 143 pre-
dicted. There was no bronchodilator effect. The
exercise carbon monoxide diffusion capacity was
40.4 (normal 25 to 50).
The clinical impression was pulmonary hyper-
tension with question of atrial septal defect and
alveolar hypoventilation with obesity.
Physiologic Procedures
Right heart catheterization was performed in
the usual manner. A no.-6 electrode catheter was
positioned in the main pulmonary artery. With
the Seldinger technic, a short length of PE-90
tubing was introduced into the right brachial ar-
tery. Hydrogen and ascorbic acid curves ruled out
the presence of a left-to-right shunt" and an in-
tracardiac right-to-left shunt.12' 13 Resting studies
confirmed the presence of pulmonary hypertension
and hypoventilation.
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The effects of hyperventilation, 100 per cent
oxygen, and the combination of hyperventilation
and 100 per cent oxygen were observed. Sub-
sequently, four control observations were made,
following which a 12-per cent solution of THAM*
was infused at a rate of 15 ml. per minute into the
main pulmonary artery. Serial observations were
made at 3-minute intervals during which a total
of 30 Gm. of THAM was administered. Immediate-
ly following completion of the infusion of THAM,
100-per cent oxygen was again administered for
5 minutes, and then combined with hyperventila-
tion for an additional 2 minutes. After a 45-min-
ute rest period, control observations were again
made, following which an intravenous infusion of
ethamivan (Emavin)t was started. The rate of
infusion was initially 5 mg. per minute, but was
raised over a 15-minute period to 25 mg. per
minute, given into the main pulmonary artery.
This infusion was continued for a total of 26 min-
utes. During both control observations and dur-
ing the infusion, the patient was sleeping. After
*Kindly supplied by S. J. Anderson, M.D., Abbott
Laboratories, North Chicago, Illinois.
tKindly supplied by F. F. Teller, M.D., U. S.
Vitamin and Pharmaceutical Corp., New York, New
York.
Circulation, Volume XXXII, November 1965
789
a further 30-minute rest period, observations were
made following the administration of 100 mg. of
ethamivan orally, which was repeated 1 hour later.
The venous catheter was then removed. The
tubing in the brachial artery was left in place
for the following 3 days. Its patency was main-
tained by the use of heparin. This allowed serial
determinations of blood gas tensions, awake and
duiring sleep, both during control periods and
while under the influence of oral ethamivan. In
addition, during the night, sleep patterns were
recorded in conjunction with bloods for gas ten-
sions by means of a small thermistor bead lightly
applied to the face below the nose. The output
of the thermistor bead, which formed part of a
bridge circuit, was amplified and by means of a
differentiating circuit, the first derivative of the
temperature was recorded on a Honeywell oscil-
lographic photographic recorder. The patient tol-
erated the brachial arterial catheter without diffi-
culty. A good radial pulse was present at all times
during the presence of the catheter as well as after
its removal.
Blood samples were analyzed for oxygen con-
tent and capacity and carbon dioxide content by
the method of Van Slyke and Neill, and for
lactic and pyruvic acid by the methods of Scholz
et al.'4 and Gloster and Harris,'5 respectively.
Hemoglobin was determined from the oxygen
capacity. Carbon dioxide tension was calculated
from the whole-blood carbon dioxide content and
blood pH with use of the charts of Van Slyke arid
Sendroy. Blood pH and oxygen tensions were
analyzed with the Radiometer tension equipment.
Expired gas samples were analyzed by the Scho-
lander technic. Blood pH and oxygen tension were
run at 38 C immediately after being withdrawn.
Figure 1
Effects of hyperventilation. Cont, control; Hyper,
hyperventilation; 100 02 100 per cent oxygen;
THAM, trihydroxy aminomethane.
 790 VOGEL, BLOUNT
Table I
Physiologic Data

Pressure,
mm. Hg
Procedure RR PA BA PaO2 PaCO2 pHa SaO2 Cal.
Control (M) 74 94 47.3 60 74.0
Control 48 53.0 54 7.320 81.0
Hyperventilation 26 88 86.9 28 7.502 96.4
Control (M) 38 87 46.8 7.280
100% Oxygen 42 205.0 53 7.313 97.2
100% 02 + hyperventilation 23 100 408.0 29 7.510 100.0
Control (hyperventilating) 29 100 70.1 39 7.414 92.5
Hyperventilation 6 min. 30 25 101.5 19 7.578 97.2
Control #1 THAM 41 48.0 7.371 79.3
Control #2 THAM 19 40 104 42.6 7.351 72.9
Control #3 THAM 40 41.4 7.352 71.4
Control #4 THAM 16 38 51.1 7.372 81.8
After 50 ml. THAM (12%) 27 52.3 7.484 86.3
After 100 ml. THAM 14 30 104 35.8 7.470 71.4
After 150 ml. THAM 15 29 42.6 7.522 81.0
After 200 ml. THAM 30 95 51.0 7.499 86.2
After 250 ml. THAM 20 28 44.9 38 7.560 84.2
Control (imm. after THAM) 14 29 42.1 7.505 80.0
After 5 m n. 100% 02 16 29 240.0 7.481 100.0
100% 02 + hyperventilation (2 min.) 28 388.0 7.550 100.0
Control (45 min. after THAM) 12 35 107 36.8 7.396 67.2
Control #2 (Sleeping) 15 33 39.6 7.406 71.6
After 5 min. IV eth. 5 mg./min. 15 36 40.2 7.399 72.4
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After 10 min. IV eth. 12.5 mg./min. 15 33 52.0 7.372 82.4

After 15 min. IV eth. 25 mg./min. 20 24 62.6 7.433 89.8
After 20 min. IV eth. 25 mg./min. 30 23 65.1 7.500 92.8
After 26 min. IV eth. 25 mg./min. 30 21 92 60.7 33 7.505 91.7
Control (30 min. after eth.) 10 32 94 48.6 44 7.420 81.0
15 min. after 100 mg. eth. oral 10 29 94 58.0 7.443 85.7
30 min. after 100 mg. eth. oral 11 29 100 59.2 7.408 88.0
45 min. after 100 mg. eth. oral 10 29 49.1 7.423 82.7
60 min. after 100 mg. eth. oral 13 34 46.3 52 7.352 76.9
67 min. control 2nd 100 mg. eth. 12 27 104 59.2 7.431 88.1
97 min. (30 min. after 2nd 100 mg.) 17 24 62.3 7.460 90.5
102 min. (35 min. after 2nd 100 mg.) 15 23 98 76.2 42 7.430 94.2
107 min. (40 min. after 2nd 100 mg.) 12 24 95 60.6 7.453 89.5
Abbreviations: M, mask; eth., ethamivan; THAM; trihydroxy aminomethane; RR, respiratory rate; CO, cardiac out-
put; V02' oxygen consumption; MV, minute ventilation L./min.; PO.) and C02, oxygen and carbon dioxide tension in
mm. Hg; PA. mean pulmonary arterial pressure; BA, mean brachial arterial pressure; a, brachial artery blood; Cal.,
calculated saturation from Pa02 and pHa; V.S., Van Slyke saturation; v, mixed venous blood; A diff., arteriovenous oxygen
difference.

The intravenous infusions were given with a Har-
vard dual-syringe variable-speed infusion pump.
Results (Table 1)
Hyperventilation Study
With hyperventilation the mean pulmonary
arterial pressure dropped from a control level
of 48 to 25 mm. Hg (fig. 1). This was associ-
ated with a rise in both arterial oxygen tension
from 53 to 86.9 mm. Hg and in arterial pH
from 7.320 to 7.502.
One Hundred Per Cent Oxygen
The administration of 100 per cent oxygen
resulted in a slight increase in mean puhro-
Circulation, Volume XXXII, November 1965
 HYDROGEN ION CONCENTRATION 791

AV
Diff., CO t02 MV
SaO2 V.S. Pv02 PvC02 pHv SvO2 Cal. SvO2 V.S. Vol. % L./min. ml.lmin. STPD
65.0 34.9 43.0 4.34 5.78 250 3.7
96.1
99.1
100.0
89.4 43.2 41 7.409 76.3 75.2 2.89 10.72 310 8.0
97.1 36.1 22 7.510 73.4 73.9 5.00 7.14 357 32.2

34.0 7.360 59.8

86.8 33.7 42 7.512 70.0 70.3 3.10 7.26 225 5.6

31.2 7.392 56.9

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93.8 34.4 37 7.480 68.1 70.3 4.56 6.03 275 12.0

77.6 35.2 47 7.402 66.0 58.0 3.67 5.32 195 3.1

75.6 33.2 48 7.403 61.2 54.8 3.91 6.01 235 5.4

89.1 35.2 43 7.425 66.4 59.9 5.70 3.86 220 4.3

naryarterial pressure from 38 to 42 mm. Hg Effects of Trihydroxy Aminomethane (THAM)

(fig. 1). This was associated with a rise in
arterial oxygen tension from 46.8 to 205 mm.
Hg, whereas the arterial pH remained low;
changing from 7.280 to 7.313. The addition
of hyperventilation during the administration
of 100 per cent oxygen resulted in a prompt
fall in mean pulmonary arterial pressure from
42 to 23 mm. Hg (fig. 1). This was associ-
ated with a further rise in arterial oxygen
tension from 205 to 408 mm. Hg, and a rise
in arterial pH from 7.313 to 7.510.
Circalation, Volame XXXII, November, 1965
Following four control observations during
which the mean pulmonary arterial pressure
varied from 38 to 41 mm. Hg, THAM was
administered. There was a prompt fall in
mean pulmonary arterial pressure to 27 mm.
Hg within 3 minutes after the beginning of
the infusion (fig. 1), this value remaining
throughout the administration of THAM. Con-
trol arterial oxygen tensions ranged from 41.4
to 51.1 mm. Hg with no change during the
administration of THAM, ranging from 35.8
 792
to 52.3. However, the arterial pH increased
from control values of 7.351 to 7.372 to values
ranging from 7.484 to 7.560 during THAM
infusion. The fall in mean pulmonary arterial
pressure occurred in association with a 25-per
cent increase in cardiac output.
Effect of Intravenous Ethamivan
With the administration of ethamivan the
mean pulmonary arterial pressure fell from
control levels of 33 to 35 mm. Hg to as low
as 21 to 23 (fig. 2). This was associated with
an increase in both arterial oxygen tension
from 39.6 to as high as 65.1 mm. Hg and
arterial pH from 7.396 to as high as 7.505.
These results were similar to those obtained
during voluntary hyperventilation. The pro-
gressive increase in ventilation and respiratory
rate during the infusion of ethamivan, which
occurred while the patient was sleeping, was
readily apparent and not associated with any
obvious muscle twitching.
Effects of Oral Ethamivan
Following the administration of 200 mg. of
ethamivan over a 1-hour period, there was
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a slight increase in arterial oxygen tension
and arterial pH and a decrease in mean pul-
monary arterial blood pressure (fig. 2).
Lactic and Pyruvic Acid Results
The values for lactate and pyruvate were
not elevated at rest or following the above
procedures, ranging from .49 to .77 ym./ml.
56 116 146
I Ethamivon
00 mg-
Figure 2 centration and arterial oxygen tension were
Effects of ethamivan.
VOGEL, BLOUNT
(lactate) and .052 to .068 ,um./ml. (pyruvate).
Sleep Studies
As shown in table 2, the administration of
150 mg. of ethamivan orally every 6 hours
appeared to effect higher arterial oxygen ten-
sions during sleep. Sleep patterns clearly in-
dicated a more effective ventilation. During
control periods a persistent periodic type of
breathing was present with apneic periods as
long as 1 minute (fig. 3). These apneic
periods would be interrupted by the occur-
rence of sudden, rapid, deep breaths, which
after three to four breaths would gradually de-
cline in depth over another three to four
breaths resulting then in apnea. On some occa-
sions the initial breath following an apneic in-
terval would begin slowly. It was noted that
during the apneic periods the patient would
make attempts at breathing but with no effec-
tive ventilation ensuing. Under the influence
of ethamivan occasional periodic breathing
still occurred but the apneic intervals never
exceeded 15 seconds. In addition, it was pos-
sible to record periods as long as 2 hours with-
out any periodic breathing while under the
influence of ethamivan, a finding which was
not apparent during control studies.
Course
The patient weighed 279 pounds when she
was first examined and since has decreased
to a value of 248 pounds. In addition, she
has noted that by taking her ethamivan at
six o'clock in the morning and at noontime,
she has eliminated the somnolence and sleep-
ing which originally occurred at those times.
Thus she remains awake throughout the entire
day and has had no difficulty sleeping at
night, even though taking 180 mg. of ethami-
van four times a day.
Discussion
The preceding results have clearly shown
the importance of hydrogen ion concentration
in the regulation of pulmonary arterial pres-
sure in this patient. With hyperventilation,
during which time both hydrogen ion con-
changed simultaneously, there was a fall in
Circulation, Volume XXXII, November 1965
 HYDROGEN ION CONCENTRlATION 793

'V
40

0
E I1 PA 0
0

mm Hg
30 0 0

0
0@
*
Ifs1\ aS
.
* 0
I

20 -
7.3 7.4 7.5
, ~ ~ ~ ~ ~
pHa

5 sec.
Figure 5
Figure 3 Mean pulmonary artery pressure is plotted against
brachial arterial pH.
Comparison of sleep patterns with and without oral
ethamivan. In the top tracing a 30-second apneic
period is shown. sion and altered ventilation-perfusion rela-
tionships due to hyperventilation, THAM was
pulmonary arterial pressure. However, when administered. This permitted the dissociation
100 per cent oxygen was administered, there of the effects of changing oxygen tension from
was no significant change in mean pulmonary those due to changing hydrogen ion concen-
arterial pressure, in spite of a significant rise tration. With the administration of THAM,16
in arterial oxygen tension. To eliminate the there was a decrease in both hydrogen ion
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influence of a further increase in oxygen ten- concentration and pulmonary arterial pressure,
although the oxygen tension remained essen-
tially unchanged. Thus, these studies have
60
shown that hydrogen ion concentration may
play a significant role in the regulation of
Ao X pulmonary arterial pressure in the patient with
40

MEASURED
PA

mm Hq
P A
2,O~~~oo
zD
o
/

40
20
* resting
ob so reation
P-A
after various mm Hg
procedures 30 * *
0
50. .
20 40 60
PREDICTED PA
mm Hg 5.

Figure 4 1
_L
if
El
o
30 50 *70 90g 00 00 500
Measured mean pulmonary artery pressure is plotted
against predicted mean pulmonary artery pressure Pa2
mm Hg
with Gomez' formulation. For the purposes of cal-
culation normal oxygen saturation was considered to Figure 6
be 94 per cent. The open circles represent values
after hyperventilation, 100 per cent oxygen, THAM, Mean pulmonary artery pressure is plotted against
ethamivan, and combinations thereof. brachial arterial oxygen tension.
Circulation, Volume XXXII, November 1965
 794 VOGEL, BLOUNT
Table 2
Sleep Studies
Cal.
PaO2 PaC02 pHa Sa 02

5/26/64
10:00 PM Night of cath. (sleeping) 74.0 33.3 7.480 93.5
5/27/64
10:00 AM Lying awake 64.0 42.1 7.381 89.2
6:00 PM Lying awake 54.0 7.395 84.6
11:30 PM Sleeping lightly 55.5 42.2 7.395 85.6
5/28/64
2:50 PM 12:30 AM Sleeping 56.0 41.0 7.385 85.6
2:00 AM Sleeping 52.3 43.0 7.390 83.2
10:00 AM Lying awake 63.3 46.0 7.410 89.7
11:00 AM Mask on-sleeping 46.7 45.0 7.410 79.5
2:50 PM Sleeping 47.4 45.3 7.395 80.0
2:55 PM Waking-hypervent. 78.9 38.4 7.415 94.6
2:56 PM Waking-hypervent. 61.3 39.9 7.409 88.8
3:49 PM (150 mg. ethamivan po)
9:00 PM (150 mg. ethamivan po)
10:45 PM Lying awake 68.0 39.9
11:45 PM Sleeping 59.8 44.5
5/29/64
12:50 AM Sleeping 62.8 43.6
1:50 AM Sleeping 53.5 44.2
2:20 AM Sleeping lightly 69.8 41.2
2:45 AM (150 mg. ethamivan po)
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3:30 AM Sound asleep 73.6 40.4

3:50 AM Shallow breaths-sleeping 60.2 39.0
9:00 AM (150 mg. ethamivan po)
10:00 AM Lying awake 62.5 40.7
10:05 AM Mask on-sleeping 54.5 41.9

alveolar hypoventilation, chronic hypoxia, and
normal lungs.
Gomez has analyzed the data of Enson
and associates showing the interplay that
may occur between oxygen tension and
hydrogen ion concentration.5 Pulmonary ar-
terial mean pressure correlated with both ar-
terial oxygen saturation and hydrogen ion con-
centration to a significantly higher degree than
either of the two latter variables considered
alone. Gomez developed a formula for pre-
dicting pulmonary arterial pressure on the
basis of hydrogen ion concentration and oxy-
gen saturation.* With use of the values ob-
tained in our patient (table 1) pulmonary ar-
terial pressures were calculated according to
Gomez' formula. There was a fair correlation
between predicted and measured pressures
(fig 4).
Further, Enson and associates showed that
at low concentrations of hydrogen ion, pul-
monary arterial mean pressure was relatively
insensitive to hypoxia, whereas at high hy-
drogen ion concentrations pulmonary arterial
pressure was extremely sensitive to hypoxia.
In figures 5 and 6, all the pH and arterial
oxygen tensions obtained in our patient are
plotted against the mean pulmonary arterial

*P = K + aH + bS + wHS, where P = pulmonary ion concentration in millimicroequivalents per liter,

arterial mean pressure in mm. Hg, S = arterial oxy- K = 40.363, a = 0.713, b = 3.008 and w =
- -

hemoglobin unsaturation in percentage, H = hydrogen 0.1028.

Circulation, Volume XXXII, November 1965
 HYDROGEN ION CONCENTRATION
pressure at the time the blood samples were
obtained. There appears to be a better cor-
relation between pH and pressure than be-
tween oxygen tension and pressure.
Although it has been suggested that the
pulmonary pressure response to hypoxia is
mediated by the intrapulmonary release of
lactic acid,4 there was no evidence of increased
lactic acid release in our patient, as determined
by measuring circulating levels in both pul-
monary and brachial arteries. These results in
association with previous reports5 17 suggest
that hydrogen ion is of prime importance in
regulating pulmonary arterial tone.
Recent studies have shown that at 5,000
feet, some subjects with cardiopulmonary dis-
ease may have significantly more evidence of
pulmonary arterial vasoconstriction than at sea
level,18 whereas in the normal subject, such
findings are not apparent below 10,000 feet.'9 20
As this study was performed at 5,000 feet,
it is possible that the degree of pulmonary
hypertension and the reactivity of the pul-
monary vascular bed were more pronounced
than they would have been at sea level.
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Summary
The relative importance of arterial oxygen
tension and hydrogen ion concentration in
regulating pulmonary arterial pressure was
evaluated in a 43-year-old woman with hypo-
ventilation and obesity. It was shown that
hydrogen ion concentration played a domi-
nant role in the regulation of her pulmonary
circulation.
Acknowledgment
The authors wish to thank Miss Gail Jamieson for
her valuable technical assistance.
Addendum
After 1 year of treatment with ethamivan (720
mg./day), the patient was recatheterized. At the
time her weight was 260 lb. and the study revealed
a resting mean pulmonary arterial pressure of 27
mm. Hg, brachial arterial saturation of 92 per cent,
pH of 7.499, and a cardiac index of 2.88 L./min.
Persistent sensitivity to pH change was demonstrated
by the administration of 5 per cent carbon dioxide,
which resulted in an increase of mean pulmonary
arterial pressure to 46 and a decrease of pH to
7.400 and cardiac index to 2.64. The ventilatory
Circulation, Volume XXXII, November 1965
795
response was abnormal as minute ventilation in-
creased but 5.39 L. with a rise in PaCo2 from 32.1
to 44.9 mm. Hg.
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3. MOTLEY, H. L., COURNAND, A., WERK6, L.,
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Quantitative Experiment
Stephen Hales-1677-1761
The Royal Society was also the intellectual environment that stimulated, guided,
and encouraged the next contributor of primary importance to the knowledge of the
output of the heart, Stephen Hales (1677-1761).
Hales entered Benet (now Corpus Christi) College, Cambridge, at nineteen, took
his master's degree seven years later, and in 1711 became a bachelor of divinity.
During these years he formed a close friendship with another young man a few years
his junior, William Stukeley (the antiquarian who first explored the Druidical mysteries
of Stonehenge), and the two young enthusiasts worked together on experiments in
anatomy and "chemistry." Hales had the good fortune to receive, as early as 1708, the
perpetual curacy of the vicarage of Teddington, a few miles outside London, and he
continued his experiments there. For an ordained minister of the church to spend his
time in biological experiment was not as strange then as it would be now. This was
the eighteenth century, the "Age of Reason based on Faith," and for Stephen Hales
at the beginning of the century, just as for Joseph Priestley at its close, the study of
Nature was but another way of inquiring into and demonstrating the wisdom of the
Almighty; Hales in his writings constantly reminded his readers of this great truth.
-WILLIAM F. HAMILTON, M.D., and DICKINSON W. RICHARDS, M.D. Circulation of
the Blood. Edited by Alfred P. Fishman, M.D., and Dickinson W. Richards, M.D.
New York, Oxford University Press, 1964, p. 81.

Circulation, Volume XXXII, Novemnber 1965