RELATIONSHIP SERUM
BETWEEN
GASTRIN WITH
Isamu
LEVELS
IN
MORPHINE
YAMAGUCHI, and
Research
GASTRIC DOGS
AND
Hiroko
SECRETION ANESTHETIZED
URETHANE
FUKE,
Shigenobu
Michiko
TSUJITA
KUMADA
Laboratories, Fujisawa Pharmaceutical Yodogawa-ku, Osaka 532, Japan Accepted
AND
January
22,
Co., Ltd.,
1978
Abstract-The serum levels of immunoreactive gastrin (IRG) and secretion of gastric juice were simultaneously determined in dogs anesthetized with morphine and urethane. There was a significant positive linear correlation between secretion and serum IRG level in these dogs. Serum IRG level and gastric secretion were reduced by bilateral vagotomy at the neck. The amount of gastric juice was reduced dose-dependently by an intravenous injection of atropine (0.001-0.016 mg/kg), hexamethoniurn (0.0641 mg/kg) and secretin (2-8 U/kg). The reduction of gastric secretion paralleled that of the serum IRG level. However, the reduction of gastric secretion did not parallel that of serum IRG level under the influence of prostaglandin E1 (0.002-0.008 mg/kg i.v.) and duodenal acidification. Prostaglandin E1 and duodenal acidification reduced gastric secretion without the reducing serum IRG level. These findings were discussed in relation to the mechanism of gastric juice stimulation by morphine, and it is suggested that endogenous gastrin release through the vagal and non-vagal pathways participates in morphine-induced gastric secretion. The difference in inhibitory effect between duodenal acidification and secretin suggests the possibility that substances other than secretin may participate in the regulation of gastric secretion in dogs. Yamaguchi
reported
morphine-induced gastric secretion histochemically endocrine-like considered through
gastric
that
the inhibitory
secretion
in Heidenhain cells which seemed
that morphine an activation
dogs (1).
mucosa,
of the cholinergic
secretion
on food-induced
nerve fibers were identified those
with gastrin
on
in close contact
cells (2).
with
Thus it should
by endogenous
gastrin
be
release
nerves.
The present study deals with the relationship
secretory
Cholinergic
gastric
and hexamethonium
the same as that
and particularly
to be identical
may stimulate
(IRG) level and gastric secretion
of atropine
was approximately
pouch
in the antro-pyloric
activity
between
in dogs anesthetized
the serum immunoreactive
with morphine
and urethane
gastrin and given
inhibitors.
MATERIALS AND METHODS Experiments were performed on 19 Beagle dogs of either sex weighing about 10 kg. They were deprived of solid food for 24 hours before experiment, permitted free access to water, and anesthetized with 10 mg/kg of morphine and 1.5 g/kg of urethane given s.c. on the day of the experiment. (1).
The subsequent surgical procedures were as reported previously
The animals with an acute gastric fistula in the body of the stomach and two ligatures
(one at the cervical esophagus and the other at the pylorus) were placed in a prone position. Every 15 min, the volume of the gastric juice was measured in a graduated cylinder. Throughout
the entire period of the experiment, physiological saline was infused intra
venously at a rate of 30 ml/hr to maintain water load. Duodenal acidification A duodenal sac was made by ligating the pylorus and the jejunum at 20 cm proximal to the pylorus.
Two polyethylene tubes were inserted into the duodenal lumen, one from
the pylorus and the other from the jejunum, with their open tips reaching almost completely the opposite ends of the duodenal sac.
The duodenal sac was perfused with physiological
saline or with canine gastric juice which had been collected beforehand from morphine urethane anesthetized dogs.
The H+ concentration
of the gastric juice was 153 mEq/1.
The perfusion fluids were maintained at 37'C and infused at a rate of 1.5 ml/min. Determination of gastrin Blood samples were taken from the leg vein once in the control period and 5, 15, 30, 60 and 90 min after drug administration and bilateral vagotomy. acidification, blood samples were taken every 15 min. were determined by radioimmunoassay
In the case of duodenal
The serum concentrations of IRG
as described by Yalow and Berson (3).
Antisera
to gastrin were produced in rabbits by immunization with synthetic human gastrin I (SHG : 1-17) conjugated to bovine serum albumin.
125I-SHG (specific activity; approx. 600 mCi/
mg) was obtained from Dainabbott Radioisotope Lab., Japan.
Separation of the antibody
bound 125I-SHG was achieved using activated Amberlite IRG-58 (100 to 400 mesh; Organo, Japan).
SHG was used as the standard gastrin.
Procedures of this radioimmunoassay
system were as reported previously (4). Drugs The following drugs were injected intravenously. thonium bromide (Methobromin,
Yamanouchi)
was a gift from Upjohn Research Laboratories,
Atropine sulfate (Merck), hexame
and secretin (Eisai).
Prostaglandin
U.S.A.
E1 was dissolved
Prostaglandin
El
in a minute volume of ethanol and diluted with 0.9 % saline to the appropriate concentration. The other drugs were dissolved in 0.9 % saline. RESULTS Relationship) between serum gastrin The dogs anesthetized
gastric juice, and the secretion samples
were obtained
least 2 hours collected
level and gastric secretion
with morphine
and urethane
rate was rather
constant
from each of the 19 dogs during
after operation)
to determine
serum
secreted a considerable throughout
amount
the experiment.
the control
observation
IRG concentrations.
of
Blood
period
(at
Gastric juice was
for 15 min after blood sampling.
The serum IRG dog (Fig. 1).
There
level was plotted
against
was a significant
linear correlation
serum IRG level (r=0.603).
the corresponding between
gastric secretion the gastric
in each
secretion
and
FIG. 1.
Relationship
between
serum
gastrin
Fic;. 2.
Effect of atropine
and hexamethonium
level and gastric secretion in dogs anesthe tized with morphine and urethane. Values
on serum gastrin level and gastric secre tion in dogs anesthetized with morphine
were obtained
and urethane.
for each of 19 dogs.
Solid and broken
present respectively serum gastrin level. the time of i.v. N=number
lines re
gastric secretion and The arrow indicates administration.
of dogs.
Effect of drugs, vagotomy and duodenal acidification on serum gastrin level and gastric secretion (i) Drugs Atropine in intravenous doses of I to 16 /tg/kg reduced both the serum IRG level and gastric secretion. The serum IRG level decreased to approx. 50% of the control 5 min after injection of 16 ; eg/kg of atropine, and gradually returned to approx. 74% of the control 2 hours after injection (Fig. 2).
The secretion decreased to about 30 % of the control in the
15-30 min period, and returned to about 77 % of control in the subsequent 90 min. Hexamethonium in intravenous doses of 0.064 to 1 mg/kg also reduced the serum IRG level and gastric secretion.
Though the reduction of the serum IRG level slightly preceded
that of gastric secretion, both reductions were quite parallel after the dose of 1 mg/kg of hexamethonium. Secretin (2-8 U/kg i.v.) reduced gastric secretion dose-dependently and was similar to the reduction in serum IRG level. dropped to approximately
20
After an injection of 4 U/kg of secretin, gastric secretion of the control in the 15-30 min period and recovered to
approx. 80;0 of the control 90 min after dosing (Fig. 3). and serum IRG level were roughly in parallel.
The reductions in gastric secretion
The serum IRG level decreased to approx.
40% of the control 15 min after injection of 4 U/kg of secretin, and recovered to approx. 90% of the control in the subsequent 45 min. Prostaglandin El (2-8 /cg/kg i.v.) reduced gastric secretion in a dose-dependent manner
without any reduction in serum IRG level.
After a dose of 8 ,ug/kg of the drug, gastric
secretion fell sharply and recovered gradually, whereas the serum IRG level was little affected in the first 45 min and increased with the recovery of gastric secretion. (ii) Vagotomy The serum IRG level was reduced to approx. 50 % of the control 15 min after bilateral vagotomy at the neck and remained at this level (Fig. 4).
FIG. 4.
Effect of bilateral
anesthetized bilateral
with
vagotomy
vagotomy morphine at the neck.
Gastric secretion was reduced
on serum gastrin level and gastric secretion and
urethane.
The
arrow
indicates
the
in dogs time
of
FIG. 5. Effect of duodenal acidification on serum gastrin level and gastric secretion in dogs anesthetized with morphine and urethane. The duodenum was perfused with saline for the first three 15-min periods, with canine gastric juice for the subsequent four 15-min periods, and with saline for the last four 15-min periods.
to approx. 50" of the control in 30-45 min period, and remained at this level. (iii) Duodenal acidification Gastric secretion was reduced to approx. 30°x; of the control during the perfusion of the duodenum with canine gastric juice, but reverted to the control level when the gastric juice was replaced with saline (Fig. 5). As in the case of prostaglandin El injection, the serum IRG level was minimally changed when gastric secretion was maximally reduced, and increased with the recovery of gastric secretion. DISCUSSION It has been shown that unanesthetized dogs, unlike rats, secrete minimum basal acid, and dogs anesthetized with chloralose and urethane do not secrete measurable amounts of gastric juice (I).
In the present study, dogs anesthetized with morphine and urethane
continuously secreted large amounts of gastric juice. correlated with serum IRG level.
The amount of gastric juice positively
In addition, the almost equal inhibitory effect of vagotomy
on gastric secretion and serum IRG level suggests that vagally released gastrin is important for the secretogogue effect of morphine.
This suggestion is supported by the parallel
reduction of the secretion volume and serum IRG level after dosing with hexamethonium and atropine.
Vagal gastrin release has been well elucidated (5, 6).
The residual secretion and serum IRG level even after vagotomy in the present study suggest a non-vagal gastrin release. demonstrated
Non-vagal gastrin release after peptone meal has been
by Konturek et al. (7).
Furthermore,
Lanciault et al. (8) demonstrated a
clear correlation between serum gastrin levels and gastric secretion in vagotomized dogs under morphine-chloralose
anesthesia. Both the vagal and non-vagal gastrin releases may
participate in the morphine-induced secretion,
Duodenal acidification reduced morphine-induced
secretion without reducing serum
IRG levels. Secretin reduced serum IRG level as well as gastric secretion, and such is in agreement with observations in humans (9) and in Heidenhain pouch dogs (4).
These
results favor the view that substances other than secretin may participate in the feed-back inhibition of gastric secretion by duodenal acidification.
There is in fact evidence which
suggests release of an unidentified substance after duodenal acidification (10). On the other hand, prostaglandin E1 inhibited gastric secretion without reducing serum IRG levels. Prostaglandins are known to be distributed in the gastric mucosa (11). Fur thermore, a supramaximal dose of pentagastrin increased the concentration of prostaglandins in the gastric juice, but reduced gastric secretion (12). These results suggest the possibility that prostaglandins may participate in the inhibition of gastric secretion by acting directly on the parietal cells. REFERENCES 1) YAMAGUCHI,I.: A comparative study on the mechanism of action of morphine on gastric acid secretion in dogs. Japan. J. Pharmacol. 24, 779-786 (1974) 2) YAMAGUCHI,I., MORI, J., ONDA, F., NISHIZAKI, H. AND KUMADA,S.: A histochemical approach to the cholinergic innervation of endocrine-like cells in dog antro-pyloric mucosa. Japan. J. Pharmacol. 24, 721-728 (1974) 3) YALOW, R.S. AND BERSON,S.A.: Radioimmunoassay of gastrin. Gastroenterology 58, 1-14 (1970) 4) FUKE, H., YAMAGUCHI,I., NISHIZAKI,H. ANDHONDA, F.: Effects of drugs on gastrin release and gastric secretion evoked by stimuli in dogs with Heidenhain pouches. Japan. J. Pharmacol. 25, Suppl. 155P (1975) 5) GROSSMAN,M.I.: Physiological role of gastrin. Fedn Proc. 27, 1312-1313 (1968) 6) NILSSON,G., SIMON,J., YALOW, R.S. AND BERSON,S.A.: Plasma gastrin and gastric acid responses to sham feeding in dogs. Gastroenterology 63, 51-59 (1972) 7) KONTUREK,S.J., BIERNAT,J., OLEKSY,J., REHEELD,J.F. AND STADIL,F.: Effect of atropine on gastrin and gastric acid response to peptone meal. J. clin. Invest. 54, 593-597 (1974) 8) LANCIAULT,G., MERRITT, A., ROSATO,E., BONOMA,C. AND BROOKS,F.P.: Comparative relationship between serum gastrin concentration and gastric acid output. Am. J. dig. Dis. 17, 523-526 (1972) 9) HANSKY,J., SOVENY,C. ANDKORMAN,M.G.: Effect of secretin on serum gastrin as measured by immunoassay. Gastroenterology 61, 62-68 (1971) 10) BECKER,H.D., REEDER,D.D. AND THOMPSON,J.C.: Evidence for two duodenal hormones which inhibit both gastrin release and gastric secretion. Gastroenterology 64, 695 (1973) 11) BENNETT,A., FRIEDMANN,C.A. AND VANE,J.R.: Release of prostaglandin E1 from the rat stomach. Nature 216, 873-876 (1967) 12) DOZOIS, R.R. AND THOMPSON,C.J.: Presence of prostaglandins E2 and A2 in canine gastric secretions. Life Sci. 15, 975-986 (1974)
BETWEEN
GASTRIN WITH
Isamu
LEVELS
IN
MORPHINE
YAMAGUCHI, and
Research
GASTRIC DOGS
AND
Hiroko
SECRETION ANESTHETIZED
URETHANE
FUKE,
Shigenobu
Michiko
TSUJITA
KUMADA
Laboratories, Fujisawa Pharmaceutical Yodogawa-ku, Osaka 532, Japan Accepted
AND
January
22,
Co., Ltd.,
1978
Abstract-The serum levels of immunoreactive gastrin (IRG) and secretion of gastric juice were simultaneously determined in dogs anesthetized with morphine and urethane. There was a significant positive linear correlation between secretion and serum IRG level in these dogs. Serum IRG level and gastric secretion were reduced by bilateral vagotomy at the neck. The amount of gastric juice was reduced dose-dependently by an intravenous injection of atropine (0.001-0.016 mg/kg), hexamethoniurn (0.0641 mg/kg) and secretin (2-8 U/kg). The reduction of gastric secretion paralleled that of the serum IRG level. However, the reduction of gastric secretion did not parallel that of serum IRG level under the influence of prostaglandin E1 (0.002-0.008 mg/kg i.v.) and duodenal acidification. Prostaglandin E1 and duodenal acidification reduced gastric secretion without the reducing serum IRG level. These findings were discussed in relation to the mechanism of gastric juice stimulation by morphine, and it is suggested that endogenous gastrin release through the vagal and non-vagal pathways participates in morphine-induced gastric secretion. The difference in inhibitory effect between duodenal acidification and secretin suggests the possibility that substances other than secretin may participate in the regulation of gastric secretion in dogs. Yamaguchi
reported
morphine-induced gastric secretion histochemically endocrine-like considered through
gastric
that
the inhibitory
secretion
in Heidenhain cells which seemed
that morphine an activation
dogs (1).
mucosa,
of the cholinergic
secretion
on food-induced
nerve fibers were identified those
with gastrin
on
in close contact
cells (2).
with
Thus it should
by endogenous
gastrin
be
release
nerves.
The present study deals with the relationship
secretory
Cholinergic
gastric
and hexamethonium
the same as that
and particularly
to be identical
may stimulate
(IRG) level and gastric secretion
of atropine
was approximately
pouch
in the antro-pyloric
activity
between
in dogs anesthetized
the serum immunoreactive
with morphine
and urethane
gastrin and given
inhibitors.
MATERIALS AND METHODS Experiments were performed on 19 Beagle dogs of either sex weighing about 10 kg. They were deprived of solid food for 24 hours before experiment, permitted free access to water, and anesthetized with 10 mg/kg of morphine and 1.5 g/kg of urethane given s.c. on the day of the experiment. (1).
The subsequent surgical procedures were as reported previously
The animals with an acute gastric fistula in the body of the stomach and two ligatures
(one at the cervical esophagus and the other at the pylorus) were placed in a prone position. Every 15 min, the volume of the gastric juice was measured in a graduated cylinder. Throughout
the entire period of the experiment, physiological saline was infused intra
venously at a rate of 30 ml/hr to maintain water load. Duodenal acidification A duodenal sac was made by ligating the pylorus and the jejunum at 20 cm proximal to the pylorus.
Two polyethylene tubes were inserted into the duodenal lumen, one from
the pylorus and the other from the jejunum, with their open tips reaching almost completely the opposite ends of the duodenal sac.
The duodenal sac was perfused with physiological
saline or with canine gastric juice which had been collected beforehand from morphine urethane anesthetized dogs.
The H+ concentration
of the gastric juice was 153 mEq/1.
The perfusion fluids were maintained at 37'C and infused at a rate of 1.5 ml/min. Determination of gastrin Blood samples were taken from the leg vein once in the control period and 5, 15, 30, 60 and 90 min after drug administration and bilateral vagotomy. acidification, blood samples were taken every 15 min. were determined by radioimmunoassay
In the case of duodenal
The serum concentrations of IRG
as described by Yalow and Berson (3).
Antisera
to gastrin were produced in rabbits by immunization with synthetic human gastrin I (SHG : 1-17) conjugated to bovine serum albumin.
125I-SHG (specific activity; approx. 600 mCi/
mg) was obtained from Dainabbott Radioisotope Lab., Japan.
Separation of the antibody
bound 125I-SHG was achieved using activated Amberlite IRG-58 (100 to 400 mesh; Organo, Japan).
SHG was used as the standard gastrin.
Procedures of this radioimmunoassay
system were as reported previously (4). Drugs The following drugs were injected intravenously. thonium bromide (Methobromin,
Yamanouchi)
was a gift from Upjohn Research Laboratories,
Atropine sulfate (Merck), hexame
and secretin (Eisai).
Prostaglandin
U.S.A.
E1 was dissolved
Prostaglandin
El
in a minute volume of ethanol and diluted with 0.9 % saline to the appropriate concentration. The other drugs were dissolved in 0.9 % saline. RESULTS Relationship) between serum gastrin The dogs anesthetized
gastric juice, and the secretion samples
were obtained
least 2 hours collected
level and gastric secretion
with morphine
and urethane
rate was rather
constant
from each of the 19 dogs during
after operation)
to determine
serum
secreted a considerable throughout
amount
the experiment.
the control
observation
IRG concentrations.
of
Blood
period
(at
Gastric juice was
for 15 min after blood sampling.
The serum IRG dog (Fig. 1).
There
level was plotted
against
was a significant
linear correlation
serum IRG level (r=0.603).
the corresponding between
gastric secretion the gastric
in each
secretion
and
FIG. 1.
Relationship
between
serum
gastrin
Fic;. 2.
Effect of atropine
and hexamethonium
level and gastric secretion in dogs anesthe tized with morphine and urethane. Values
on serum gastrin level and gastric secre tion in dogs anesthetized with morphine
were obtained
and urethane.
for each of 19 dogs.
Solid and broken
present respectively serum gastrin level. the time of i.v. N=number
lines re
gastric secretion and The arrow indicates administration.
of dogs.
Effect of drugs, vagotomy and duodenal acidification on serum gastrin level and gastric secretion (i) Drugs Atropine in intravenous doses of I to 16 /tg/kg reduced both the serum IRG level and gastric secretion. The serum IRG level decreased to approx. 50% of the control 5 min after injection of 16 ; eg/kg of atropine, and gradually returned to approx. 74% of the control 2 hours after injection (Fig. 2).
The secretion decreased to about 30 % of the control in the
15-30 min period, and returned to about 77 % of control in the subsequent 90 min. Hexamethonium in intravenous doses of 0.064 to 1 mg/kg also reduced the serum IRG level and gastric secretion.
Though the reduction of the serum IRG level slightly preceded
that of gastric secretion, both reductions were quite parallel after the dose of 1 mg/kg of hexamethonium. Secretin (2-8 U/kg i.v.) reduced gastric secretion dose-dependently and was similar to the reduction in serum IRG level. dropped to approximately
20
After an injection of 4 U/kg of secretin, gastric secretion of the control in the 15-30 min period and recovered to
approx. 80;0 of the control 90 min after dosing (Fig. 3). and serum IRG level were roughly in parallel.
The reductions in gastric secretion
The serum IRG level decreased to approx.
40% of the control 15 min after injection of 4 U/kg of secretin, and recovered to approx. 90% of the control in the subsequent 45 min. Prostaglandin El (2-8 /cg/kg i.v.) reduced gastric secretion in a dose-dependent manner
without any reduction in serum IRG level.
After a dose of 8 ,ug/kg of the drug, gastric
secretion fell sharply and recovered gradually, whereas the serum IRG level was little affected in the first 45 min and increased with the recovery of gastric secretion. (ii) Vagotomy The serum IRG level was reduced to approx. 50 % of the control 15 min after bilateral vagotomy at the neck and remained at this level (Fig. 4).
FIG. 4.
Effect of bilateral
anesthetized bilateral
with
vagotomy
vagotomy morphine at the neck.
Gastric secretion was reduced
on serum gastrin level and gastric secretion and
urethane.
The
arrow
indicates
the
in dogs time
of
FIG. 5. Effect of duodenal acidification on serum gastrin level and gastric secretion in dogs anesthetized with morphine and urethane. The duodenum was perfused with saline for the first three 15-min periods, with canine gastric juice for the subsequent four 15-min periods, and with saline for the last four 15-min periods.
to approx. 50" of the control in 30-45 min period, and remained at this level. (iii) Duodenal acidification Gastric secretion was reduced to approx. 30°x; of the control during the perfusion of the duodenum with canine gastric juice, but reverted to the control level when the gastric juice was replaced with saline (Fig. 5). As in the case of prostaglandin El injection, the serum IRG level was minimally changed when gastric secretion was maximally reduced, and increased with the recovery of gastric secretion. DISCUSSION It has been shown that unanesthetized dogs, unlike rats, secrete minimum basal acid, and dogs anesthetized with chloralose and urethane do not secrete measurable amounts of gastric juice (I).
In the present study, dogs anesthetized with morphine and urethane
continuously secreted large amounts of gastric juice. correlated with serum IRG level.
The amount of gastric juice positively
In addition, the almost equal inhibitory effect of vagotomy
on gastric secretion and serum IRG level suggests that vagally released gastrin is important for the secretogogue effect of morphine.
This suggestion is supported by the parallel
reduction of the secretion volume and serum IRG level after dosing with hexamethonium and atropine.
Vagal gastrin release has been well elucidated (5, 6).
The residual secretion and serum IRG level even after vagotomy in the present study suggest a non-vagal gastrin release. demonstrated
Non-vagal gastrin release after peptone meal has been
by Konturek et al. (7).
Furthermore,
Lanciault et al. (8) demonstrated a
clear correlation between serum gastrin levels and gastric secretion in vagotomized dogs under morphine-chloralose
anesthesia. Both the vagal and non-vagal gastrin releases may
participate in the morphine-induced secretion,
Duodenal acidification reduced morphine-induced
secretion without reducing serum
IRG levels. Secretin reduced serum IRG level as well as gastric secretion, and such is in agreement with observations in humans (9) and in Heidenhain pouch dogs (4).
These
results favor the view that substances other than secretin may participate in the feed-back inhibition of gastric secretion by duodenal acidification.
There is in fact evidence which
suggests release of an unidentified substance after duodenal acidification (10). On the other hand, prostaglandin E1 inhibited gastric secretion without reducing serum IRG levels. Prostaglandins are known to be distributed in the gastric mucosa (11). Fur thermore, a supramaximal dose of pentagastrin increased the concentration of prostaglandins in the gastric juice, but reduced gastric secretion (12). These results suggest the possibility that prostaglandins may participate in the inhibition of gastric secretion by acting directly on the parietal cells. REFERENCES 1) YAMAGUCHI,I.: A comparative study on the mechanism of action of morphine on gastric acid secretion in dogs. Japan. J. Pharmacol. 24, 779-786 (1974) 2) YAMAGUCHI,I., MORI, J., ONDA, F., NISHIZAKI, H. AND KUMADA,S.: A histochemical approach to the cholinergic innervation of endocrine-like cells in dog antro-pyloric mucosa. Japan. J. Pharmacol. 24, 721-728 (1974) 3) YALOW, R.S. AND BERSON,S.A.: Radioimmunoassay of gastrin. Gastroenterology 58, 1-14 (1970) 4) FUKE, H., YAMAGUCHI,I., NISHIZAKI,H. ANDHONDA, F.: Effects of drugs on gastrin release and gastric secretion evoked by stimuli in dogs with Heidenhain pouches. Japan. J. Pharmacol. 25, Suppl. 155P (1975) 5) GROSSMAN,M.I.: Physiological role of gastrin. Fedn Proc. 27, 1312-1313 (1968) 6) NILSSON,G., SIMON,J., YALOW, R.S. AND BERSON,S.A.: Plasma gastrin and gastric acid responses to sham feeding in dogs. Gastroenterology 63, 51-59 (1972) 7) KONTUREK,S.J., BIERNAT,J., OLEKSY,J., REHEELD,J.F. AND STADIL,F.: Effect of atropine on gastrin and gastric acid response to peptone meal. J. clin. Invest. 54, 593-597 (1974) 8) LANCIAULT,G., MERRITT, A., ROSATO,E., BONOMA,C. AND BROOKS,F.P.: Comparative relationship between serum gastrin concentration and gastric acid output. Am. J. dig. Dis. 17, 523-526 (1972) 9) HANSKY,J., SOVENY,C. ANDKORMAN,M.G.: Effect of secretin on serum gastrin as measured by immunoassay. Gastroenterology 61, 62-68 (1971) 10) BECKER,H.D., REEDER,D.D. AND THOMPSON,J.C.: Evidence for two duodenal hormones which inhibit both gastrin release and gastric secretion. Gastroenterology 64, 695 (1973) 11) BENNETT,A., FRIEDMANN,C.A. AND VANE,J.R.: Release of prostaglandin E1 from the rat stomach. Nature 216, 873-876 (1967) 12) DOZOIS, R.R. AND THOMPSON,C.J.: Presence of prostaglandins E2 and A2 in canine gastric secretions. Life Sci. 15, 975-986 (1974)
