Jownal of
APPLIED
PHYSIOLOGY
VOLUMB
4
NUMBER z
Relation of Uropepshogen Excretion
to Gastric Pepsin Secretion in Mam
HENRY D. JANOWITZ
the Gastroenterology
New York City
Research
AND
FRANKLIN
Laboratory,
HOLLANDER.
The Mount
Sinai
From
Hospital,
I
T IS WIDELY HELD that there exists a parallelism between the excretion of
urinary pepsinogen and the secretion of pepsin in the stomach. However, the
evidence upon which this generalization
rests is scant and indirect, as assembled in Bucher’s recent review on uropepsin (I). Thus Gottlieb (2), classifying different individuals on the basis of the acid response in a gastric analysis, found that the highest uropepsin output occurred in the hypersecretors of
acid; I. A. Mirsky (3) has demonstrated an increased uropepsinogen output
in peptic ulcer patients and we (4) have recently confirmed this fact. All such
evidence of this parallelism is purely circumstantial,
because none of these
reports contain data on the simultaneous gastric output of the enzyme.
The present study was undertaken in the effort to obtain more direct
evidence of the relation between the output of gastric pepsin and of urinary
pepsinogen by the simultaneous quantitative
measurements of both under
standardized conditions.
METHOD
Sixty-two human subjects with a wide range of gastric secretory activity
were studied. Of these, 2 I had an active duodenal ulcer; 4 had gastric ulcers;
5, pernicious anemia; and 5, gastric carcinoma. The remaining 27 were normal
subjects. All subjects were studied in the fasting, resting state in isolated
rooms. They had subsisted on a liquid diet for 24 hours and then were starved
for 16 hours before each experiment.
The spontaneous non-stimulated
or basal gastric secretion was collected
Received for publication March 26, 1951.
1This study was conducted with the aid of grants from the Altman Foundation and Wyeth, Inc.
53
HENRY
54
D. JANOWITZ
AND FRANKLIN
HOLLANDER
Volume
4
for a period of 3 hours in each subject by gastric intubation;
aspirations were
performed every 5 minutes to insure completeness of collection. Simultaneously, the entire urine output was collected for 3 hours by catheterization
of
all female subjects, and by catheterization
of those male subjects found to
have significant residual urine in a test some days prior to each experiment.
l
g 100
i x
~/agnosis
No.
of Cases
f
9x pxx
(P
2: 5:: 00
4 plus 1
giz 50,Y(8x
x
oxxx
0 plus 5
3
X
, , , , , , , , , , . . . , , ,
0.
norm01
X0 - duodenal
ulcer
0 - gastric
ulcer
I - gastric
cancer
pefnic.
anemia
0
2
4
6
8
GASTRIC
24 plus 3 at 0,O
IO 12 14 16 18 20 22 24 26 28 30 32 34 36 38
PEPSIN
(Units/hour
X 10D3)
Fig. I. SCATTER DIAGRAM SHOWING RELATION OF GASTRIC PEPSIN SECRETION to urinary pepsinogen excretion in 62 human subjects. As indicated in the legend, there are 9 points which fall at
the origin (0, a) and are therefore not shown. [r = +0.84, P < .OOOI].
An attempt was made to evacuate both the stomach and the bladder immediately before the collection period started.
The 3-hour volumes of gastric and urinary collections were measured.
Pepsin activity was determined by the Bucher-Anson-Mirsky
method (I)
using lyophilized bovine hemoglobin powder as the substrate (5). Uropepsin
was determined by Mirsky’s modification
of Bucher’s method (6), using the
same substrate. In our determinations,
one unit of uropepsin is that amount
of enzyme activity which releases I x IO-~ mEq. of tyrosine from the Substrate,
August
1951
UROPEPSINOGEN
AND
GASTRIC
PEPSIN
55
under standardized conditions. Rates of output of pepsin and uropepsin were
calculated in terms of average hourly amounts.
REXJLTS
When the average hourly output of gastric pepsin was compared with
the average hourly excretion of urinary pepsinogen, a moderately high positive correlation (r = +0.84) was obtained. The statistical significance of this
r value at the I per cent level of probability
was established by the t test
=
11.9,
fl
= 60, P < .OOOI]. This relation is demonstrated graphically in
P
the scatter diagram of figure I, where the mean hourly output of pepsin is
plotted against the corresponding value for uropepsin, and the straight line
has been fitted by the method of least squares. The correlation holds not only
for all 62 subjects of this experiment taken together, but for each of two
sub-groups separately. For the duodenal ulcer group, r = +0.79 [t = 5.62,
n i 19, P < .OOOI], and for the nonduodenal ulcer group, r = +0.85 [t=
8.43, n = 39, P < .oooI].
DISCUSSION
These results demonstrate that the urinary excretion of pepsinogen varies
directly with the level of pepsin secretion in the stomach, under the basal
conditions of the present experiment. This observation definitely confirms the
concept that there is a close interdependence
between the hourly rates of
output of gastric and urinary pepsinogen. Our findings are thus in keeping
with the older reports, especially that of Gottlieb. They are also consistent
with the reported failure of histamine to stimulate uropepsin excretion in cats
(7) and in man (3), since histamine is probably not a stimulant for pepsin
secretion in the stomach. The portion of pepsinogen which enters the blood
stream directly has been called an ‘endocrine’ secretion by Mirsky (s), who
has furnished evidence that this fraction is not derived by reabsorption of
pepsin from the gastric lumen. The present study indicates therefore that
under physiological
conditions pepsinogen is partitioned
into an ‘exocrine’
and an ‘endocrine’ portion. The proportion of the total amount of gastric
pepsinogen which travels in each of these directions is moderately constant
under the present ‘basal’ conditions, as revealed by the over-all correlation
coefficient of +0.84. None of the r values exceeds 0.85, probably because of a
multiplicity
of minor physiological factors which also affect the output of the
zymogen in either or both directions. These proportions are best revealed by
the ratio of pepsinogen output per hour for the gastric and renal channels,
i.e. the relative rates of secretion of the zymogen in these two directions. On
the average, this ratio is of the order of 99 : I, which means that, under the basal
conditions of the present investigation,
somewhat less than I per cent of the
56
HENRY
D. JANOWITZ
AND
FRANKLIN
HOLLANDER
total amount of pepsinogen output by the cell moves in the direction
interstitial
spaces, to be excreted in the urine.
Volume
4
of the
Simultaneous measurement of the basal (unstimulated)
gastric secretion
of pepsin and the urinary excretion of pepsinogen was performed in 62 human
subjects, comprising individuals with and without disturbances of the upper
digestive tract (i.e. gastric and duodenal ulcer, pernicious anemia, and gastric
carcinoma). The rate of excretion of uropepsinogen varied directly with the
rate of secretion of pepsin into the stomach, over a wide range of activity.
These results support the concept of an exocrine-endocrine
partition of
gastric pepsinogen, and justify the use of uropepsin determinations
as a measure of gastric enzyme secretory activity, at least under basal conditions.
REFERENCES
I. BUCEER, G. R. Gastroenterology 87: 627, 1947.
2. GOTTLIEB,
E. Skandinav. Arch. j. Physiol. 46: I, 1924.
3. PODORE, C. J., R. H. BROH-KAHN
AND I. A. MIRSKY.
J. C&n. Investigatiorz 27: 834, 1948.
4. JANOWITZ, H. D., M. H. LEVY AND F. HOLLANDER.
Am. J. M. SC. 220: 67g482,Igso.
5. ORRINGER,
D., F. U. LAUBER AND F. HOLLANDER.
ScienceIII : 88, xgso.
6. MIRSKY,I. A., S. BLOCK,S. OSHER ANDR. H. BROHXAHN.J. C&z. Investigation 27:
818,1g48.
7. BUCHER, G. R. ANDA. ANDERSON.
Am. J. Physiol. 153: 454, 1948.