Comparison of intravenous amino acids in the stimulation of gastric secretion

0016-5085/78/75050817$02.00/0 G~~NTIWLOCY 75~817-824, 1978 Copyright8 1978by the AmericanGastroenterological Association

Vol. 75, No. 5 Printedin USA.

COMPARISON OF INTRAVENOUS AMINO ACIDS IN THE STIMULATION OF GASTRIC SECRETION STANISLAW J. KONTUREK,

M.D., JANINA TASLER, M.D.,

MAREK CIESZKOWSKI, PH.D., Institute of Physiology,

AND JOLANTA JAWOREK, M.D.

Medical Academy

Krakdw, Poland

This study was undertaken to compare the potency of L- and n-isomers of natural amino acids (AA’s) infused intravenously for stimulation of gastric acid secretion in 3 dogs with Heidenhain pouches (HP) and gastric fistulae. L-Isomers of all natural AA’s were found to stimulate acid secretion from the HP, whereas n-isomers were significantly less effective. The most potent L-isomers of AA’s were histidine, phenylalanine, glycine, tryptophan, and alanine, which caused an increase in acid output reaching, respectively, 63, 45, 42, 39, and 33% of the maximal response to histamine. The stimulation of acid secretion was not accompanied by any significant change in serum gastrin level. Distention of the HP during intravenous infusion of L-histidine or Lphenylalanine solution caused a pressure-related increase in acid output reaching a peak at 30 cm distention pressure. Decreasing the luminal pH of the HP in sequential order from 7.0 to 2.5 resulted in a stepwise reduction of the HP response to intravenous histidine or phenylalanine, falling atpH 2.5 to about 20% of the peak response achieved at pH 7.0. Metiamide caused a profound reduction of histidine but had only a slight effect on acid secretion induced by intravenous infusion of other AA’s, suggesting that histidine excites the oxyntic cells mainly through the transformation to histamine and activation of HP-receptors. Atropine also suppressed gastric acid secretion stimulated by intravenous AA infusion, suggesting a role of a choline@ mechanism in this stimulation. We conclude that L- and, to a lesser degree, n-isomers of natural AA’s infused intravenously cause stimulation of gastric acid secretion by a gastrin-independent mechanism sensitive to distention pressure and pH of gastric content. Previous studieC4 have shown conclusively that the only known chemicals in food that stimulate gastric secretion are products of protein digestion, peptides and amino acids (AA’s). The stimulation of gastric secretion by AA’s was observed after gastri?-” and intestinal administrations7 and attributed to the release of gastrointestinal hormones and to direct action on the oxyntic glands. Unexpectedly, it has been recently reported that an AA mixture may cause gastric secretion also after intravenous administration and without mediation of gastrointestinal hormones.*” In this report, the gastric secretory potencies of L- and n-isomers of individual AA’s infused intravenously have been compared and their lation has been examined.

mechanism

of gastric

stimu-

Methods Three mongrel dogs weighing between 14 and 17 kg were prepared with a Heidenhain type denervated fundic pouch (HP) and gastric fistula (GF). Received November 21, 1977. Accepted May 31, 1978. Address requests for reprints to: Dr. S. J. Konturek, Institute of Physiology, 31-531 Krakow, ul. Grzegorzecka 16, Poland. The authors express their indebtedness to Dr. Morton I. Grossman for his help in designing the in vivo validation system of intrapouch titration as well as for his valuable criticism of the manuscript.

Secretory studies were started about 2 months after surgery. The dogs were deprived of food but not water for at least 18 hr before each test. Throughout each study the GF was left open to prevent acid from entering the duodenum, which might result in gastric acid inhibition. Gastric juice from the GF was collected at 15-min intervals. Titratable acidity was measured by titration of 0.2-ml samples of each 15-min collection topH 7.0 on automatic titrator (Radiometer, Copenhagen, Denmark). In some experiments, a marked reflux of bilestained duodenal content into the stomach occurred and the secretory data from the GF obtained in these tests were not included into results. In all experiments acid secretion from the HP was measured by the method of “intragastric titration” performed in a plastic chamber (20-ml volume) attached to the HP cannula as described previously.4 The HP and the titration chamber were filled with about 120 ml of saline at a constant pressure using the barostat device described previously.” The HP content subjected to intragastric titration was continuously mixed using a peristaltic pump connected to the mixing tubes and set at a delivery rate of about 1800 ml per 15 min. The rate of acid secretion was calculated in terms of milliequivalents of sodium hydroxide infused into the pouch in each 15min period. As suggested by Carter and Grossman,‘” a series of in vivo validation tests was performed to determine whether the amounts of HCl secreted by the HP can be accurately recovered by the intrapouch titration system employed in this study. For this purpose, duplicate tests were done in 2 HP

817

818

ET AL.

KONTUREK

dogs receiving continuously an intravenous infusion of metiamide in a dose of 20 pmoles per kg-hr throughout the study to suppress completely acid secretion. The HP and the titration chamber were filled with saline and the HP distention pressure was set by a barostat at about 20 cm H,O. Under these conditions the HP did not secrete acid in detectable amounts. Then, 0.1 N HCl solution was instilled into the HP in gradually increasing rates ranging from 350 to 5600 PEq per hr via a special catheter inserted into the HP. The titration of HCl delivered into the HP was performed for 1 hr at each HCl infusion rate and made separately (on separate test days) at pH 7.0, 5.0, 3.0, 2.5, 2.0, or 1.0. The results of this validation are presented in table 1. It appears that the intrapouch titration system was capable of recovering quite accurately various amounts of acid added into the HP at all tested pH levels except the lowest one (pH 1.01, when the recovery was only about 10% of the amounts of HCl added. At pH 2.0 the recovery ranged from 80 to 97% of the amounts added. For this reason the study on the pH profile was made atpH levels ranging from 2.5 to 7.0. Several secretory tests with intravenous AA’s were performed. In studies on the comparison of secretory potency of AA’s, L- or n-isomers of each individual AA were used in a 50 mM solution of pH 7.0 (with the exception of tyrosine, which was used at pH 8.0 because of poor solubility at lower pH1 and infused intravenously at a constant rate of 8 mmoles per hr for a 90-min period. For comparison, the HP response to histamine given intravenously in a constant dose (320 pg per kghr) to produce maximal acid secretion was also obtained. The response was taken as the sum of acid outputs in the last two 15-min periods of the AA or histamine infusion. L-Histidine, which was found to be the most potent AA in stimulating acid secretion, and L-phenylalanine were also used in gradually increasing amounts ranging from 2 to 16 mmoles per hr and given in a l-day test. The dose level of these AA’s was changed every 60-min period, whereas the HP acid responses were measured at 0 or 20 cm H,O of the distention pressure. In separate studies on the dependence of acid secretion upon intragastric pressure, L-histidine solution was infused intravenously at a constant rate (8 mmoles per hr), and the pressure in the HP was successively raised by barostat to 10, 20, 30, and 40 cm H20, intragastric titration being made for 45 min at each level of distention pressure.

TABLE 1. Recovery of HCl added enogenously Amounts of HCl added to the HP

to the Heidenhain

The response was taken as the sum of acid outputs in the last two 15-min periods at each pressure level. In the tests with pH profileI the rate of gastric acid secretion was measured during L-histidine infusion at a rate of 8 mmoles per hr while the pH of the HP content was decreased gradually every 45 min in sequential order from 7.0 to 2.5. In control tests, the HP content was adjusted topH 5.0 and maintained at the same level throughout the 225-min tests. In another series of tests, the effects of metiamide (20 @moles per kg-hr) on the HP acid response to L-histidine and other AA’s given intravenously either individually or as a mixture (table 21, simulating the composition of serum albumin,‘j were examined and compared to those obtained by histamine stimulation. In these tests, the AA or histamine infusion was continued for 210 min and after a 90-min period, when gastric acid output reached a well sustained plateau, metiamide was added to the intravenous infusion for a 60-min period. The percentage of gastric acid inhibition during the metiamide infusion was calculated for each test. The mean output of acid during the 30-min period immediately preceding the metiamide infusion was taken as the control, and the mean output during the last 30-min period of metiamide infusion was expressed as a percentage of this control rate. In additional series of experiments, the effects of atropine (0.20 pmole per kg-hr) on acid secretion induced by intravenous infusion of L-histidine or r.-phenylalanine were also examined. The design of these experiments was similar to that in tests with metiamide. Blood samples were obtained from a peripheral vein twice during the basal period and at the end of the period of intravenous infusion of individual AA’s and at each level of pH or distention pressure of the HP. Gastrin concentration in serum was measured by radioimmunoassay, as described by Yalow and Berson.15The routine detection limit of the assay, as used in the present study, was 5 pgEq of synthetic human heptadecapeptide gastrin per ml of serum. Each individual AA was tested twice in each dog and saline control was tested 14 times in each dog. The order of tests was randomized. Mean values for gastric acid were calculated and the significance of the differences between the mean responses to saline and to other test substances as well as between the means for the last two 1Bmin periods at a given distention

pouch (HP) in dogs with complete suppression

of acid secretion by metiamide

Amounts of HCl recovered from the HP during intrapouch titration at various pH values pH 2.0

pH 2.5

pH 3.0

pH 5.0

pH 7.0

CLEolhr 350 700 1400 2800 5600

Vol. 75, No. 5

pH 1.0

CLEqlhr 336 (96) 632 (90) 1314 (93) 2740 (97) 5620 (100)

340 (97) 678 (96) 1516 (108) 2920 (104) 5662 (101)

359 = (102)b 689 (98) 1480 (105) 3087 (110) 5710 (101)

320 623 1280 2690 5456

(91) (89) (91) (96) (97)

292 564 1187 2604 4990

(83) (80) (84) (93) (89)

40 (11) 120 (i7) 135 (10) 220 (8) 680 (12)

u Mean of four tests on 2 HP dogs. b Numbers in parentheses, Per cent of recovery of HCl added to the HP.

TABLE 2.Amino acid mixture corresponding Ala 62

Arg 59

to amino acid composition’4

of bovine serum albumin used for intravenous

infusion”

Asp

CYS

Glu

GUY

Hisb

He

Lou

LYS

Met

Phe

Pro

Ser

Thr

Tyr

Val

109

62

165

18

40

26

123

128

8

66

47

42

58

51

59

D Values are in milligrams per gram. b The amino acid mixture was prepared with or without histidine.

AMINO

November 1978

ACIDS

AND STIMULATION

OF GASTRIC

819

SECRETION

pressure or pH value were compared L-HISTIDINE (8mmol/hr)

2.01

u

‘i

Mann-Whitney P

I/

j6

15 min PERIODS

FIG. 1. Acid secretion from the Heidenhain pouch and gastric fistula in dogs infused intravenously with a constant dose (8 mmoles per hr) of r+-histidine.In this and subsequent figures, each point or column is a mean (2 standard error of the mean) of three tests on each of 3 dogs.

using a nonparametric

U test. I6

Results Typical acid secretory response of the HP and the GF to intravenous infusion of L-histidine is presented in figure 1. Acid secretion from the HP reached a peak within first 30-min period of the AA infusion and then it was well sustained for the rest of experiment. Acid secretion from the GF gradually increased, reaching a peak in the 2nd hr of AA infusion. Figure 2 demonstrates the relative activities of Lisomers of individual AA’s in stimulating acid secretion from the HP. All tested AA’s infused intravenously at a rate of 8 mmoles per hr were effective. Histidine was the most potent stimulant and caused an increase in acid output reaching about 63% of the maximal response to histamine. Phenylalanine, glycine, tryptophan, and alanine were significantly more potent than other AA’s and produced acid secretion reaching, respectively, 45, 42, 39, and 33% of the maximal response to histamine. L-Isomers of all tested AA’s produced significantly greater acid outputs than did their n-isomers (fig. 3). DIsomers of histidine and phenylalanine increased acid output to about half of that obtained with L-isomers of these AA’s, whereas n-isomers of other AA’s produced acid outputs only slightly but significantly greater than in control (saline) tests. Distention of the HP during intravenous infusion of L-histidine at a constant rate (8 mmoles per hr) caused a pressure-related increase in acid output from the HP, reaching a peak at 30 cm H,O distention pressure (fig. 4). In these experiments, acid secretion from the GF

25 1 2.0-

1.5 .t E a +; 1.0. CT Y a5

HI!

a IRP

ALA

? LYSTYR&ASPA;GMETG{U LEU

ILE SFA;,;

lAMlNE

FIG. 2. Acid responses of the Heidenhain pouch to intravenous infusion of L-isomers of individual amino acids (AA’s). Control (saline) infusion was randomized with AA infusion. The maximal response to histamine is presented.

820

Vol. 75,No.5

KONTUREKETAL.

0 L-ISOMERS ? ? D-ISOMERS

FIG. 3.Acid response of the Heidenhain pouch to intravenous infusions of I,- and n-isomers of some amino acids.

30. : 0 +c

2.0.

I lx E 1.0.

SALINE

*

Y

t

1.~ .-

1.5

E

L-HISTIDIM,~ / /’

F------i

/ ?

:: . +x CT F

1.0

0.5

0A3AL Lt.0

Lo

L-HISTIDINE SALINE

60

16.0

(mmol/hr)

FIG. 5. Effect of L-histidine given intravenously (in stepwise fashion) in increasing rates on acid output from the gastric tistula and the Heidenhain pouch maintained at 0 or 20 cm Hz0 distention pressure.

DISTENTION PRESSURE (cm H20) FIG. 4. Effect of distention pressure on the acid output from Heidenhain pouch during intravenous infusion of L-histidine or saline (control).

was relatively well sustained and no significant changes were observed during gradual distention of the HP. In control tests with intravenous infusions of saline, an increase in the intrapouch pressure also resulted in a pressure-related rise in acid output from the HP, but

acid secretion from the GF was not significantly affected. The results of HP and GF responses to L-histidine and L-phenylalanine used at gradually increasing rates from 2 to 16 mmoles per hr are presented in figures 5 and 6. Acid outputs from the HP and the GF increased with increasing rates of the intravenous infusion of these AA’s, reaching a peak at 8 mmoles per hr. When the HP was maintained at 0 cm H,O distention pressure,

November 1978

AMINO ACIDS AND STIMULATION

1.5 .: g +A I

the peak acid outputs were significantly greater at all infusion rates except the lowest one (2 mmoles per hr). Acid response to L-histidine or L-phenylalanine infused intravenously at a constant rate (8 mmoles per hr) waspH dependent. As shown in figures 7 and 8, the highest acid output was reached at pH 5.0 to 7.0. With decreasing pH of the HP content, there was a pHdependent reduction in acid output, falling at pH 2.5 to about 20% of the peak response achieved at pH 7.0. In control tests with the HP content kept at pH 5.0, acid output from the HP was well sustained throughout the experiment. Metiamide given intravenously in a dose of 20 pmoles per kg-hr resulted in a profound inhibition of HP and GF responses to L-histidine (fig. 91, or to an AA mixture simulating the composition of serum albumin and containing L-histidine (table 3). The acid response to other AA’s such as L-phenylalanine (fig. 10) given either individually or as a mixture (without L-histidine) was significantly less suppressed by metiamide (table 3). Gastric secretion induced by histamine, producing the

I

1.0

w” 0.5 E

I

p

2.0

BASAL

821

OF GASTRIC SECRETION

LO

8.0

L-PHENYLALANINE FIG. 6. Effect of L-phenylalanine

16.0

(mmol/hr) given intravenously

(in stepwise

fashion) in increasing rates ranging from 2 to 16 mmoles per hr on acid output from the gastric fistula and the Heidenhain pouch maintained at 0 or 20 cm Hz0 distention pressure.

21)-

-----_

1.5

---

P” S I

l. “._

70

.r

i

L-PHENYLALANINE to-

pH7+2.5

-1

‘\

\

0.5-

I

5.0

70 L-HISTIDINE

(PHI

4.0

30

\

\

L.0

3.0 2.5

(pH)

FIG. 8. Effect of L-phenylalanine given intravenously in a constant rate (8 mmoles per hr) on acid output from the gastric fistula and the Heidenhain pouch maintained at 20 cm H,O distention pressure and gradually decreasingpH values.

\ ‘Y

u= E

5.0

\

25

FIG. 7. Effect of L-histidine given intravenously in a constant rate (8 mmoles per hr) on acid output from the gastric fistula and the Heidenhain pouch maintained at 20 cm H,O distention pressure and gradually decreasingpH values.

822

KONTUREK

L-HISTIDINE

Vol. 75. No. 5

ET AL.

or L-PHENYLALANINE

J-L-PHENYLALANINE

or L-HISTIDINE

1

L-HISTIDINE ??

r

BASAL3

\

q7;

5

7 9 15 min PERIODS

11

13

*

FIG. 9. Effect of metiamide given intravenously in a dose of 20 pmoles per kg-hr on L-histidine (8 mmoles per hr) induced acid secretion from the gastric tistula and the Heidenhain pouch maintained at 20 cm Hz0 distention pressure and atpH 5.0.

I

v_. . BASAL

.

,

,

5

.

,

*

7 9 15 min PERIODS

,

,

.

11

.

1

13

FIG. 10. Effect of atropine given intravenously in a dose of 0.20 pmole per kg-hr on L-phenylalanine (8 mmoles per hr) induced acid secretion from the gastric fistula and the Heidenhain pouch maintained at 20 cm Hz0 distention pressure and atpH 5.0.

TABLE 3. Effect of metiumide (20 pmo1e.s per kg-hr) given intravenously on the Heidenhnin pouch (HP) acid responses to histamine or to various amino acids (AA’s) given intravenously either individually or as an AA mixture simulating the composition of 5% serum albuminI No. of tests

HCl outputs Before metiamide pEqW0

Histamine (60 pg/kg-hr) L-histidine (8 mmoles/hr) L-phenylalanine (8 mmoles/hr) Glycine (8 mmoleslhr) L-tryptophan (8 mmoles/hr) L-alanine (8 mmoles/hr) AA mixture with L-histidine (80 ml/hr) AA mixture without L-histidine (80 ml/hr)

4 8 6 6 6 6 8 6

rate of HP acid output similar to that obtained with intravenous L-histidine, was inhibited by metiamide to a similar degree as in tests with L-histidine. Atropine infused intravenously in a dose of 0.20 pmole per kg-hr resulted in a marked suppression of acid response to L-histidine or L-phenylalanine from both HP and GF (fig. 10). In tests with intravenous infusions of individual AA’s or L-histidine when the HP maintained various distention pressures or luminal pH levels, the serum gastrin levels were not significantly changed and these data are presented in table 4.

1285 * 1324 5 618 + 889 T 914 ” 749 ? 967 2 909 2

89 62 37 10 23 26 16 92

During metiamlde

% of inhibition by metiamide

175 -c 24 260 f 13 461 + 34 592 t 13 724 + 64 512 * 28 182 2 23 798 2 84

86.4 80.4 25.5 33.4 20.8 31.7 81.2 12.3

min

Discussion Previous studies in dogs’-lo showed conclusively that a solution of AA mixture given intravenously evokes a gastric secretory response of similar magnitude to that caused by intrajejunal infusion of the same solution, suggesting that AA’s absorbed into the blood may account for a major portion of the intestinal phase of gastric secretion.g In addition, it was found that the stimulation by intravenous AA’s persists after removal of known sources of gastrointestinal hormones, indicating that AA’s act directly on the parietal cells to stimulate acid production.s

November

AMINO

1978

TABLE 4. Serum gastrin concentrations individual

aminoacids

(AA’s)

ACIDS

AND

(in picograms

STIMULATION

OF GASTRIC

per milliliter) during intravenous

823

SECRETION infusion (8 mmolesihr)

and during intravenous infusion (8 mmoleslhr) of Ghistidine while the intrapouch stepwise or intrapouch pH was gradually decreased

of L- and D-isomers of pressure

was increased

L-histidine L-AA

His Phe Gly Trp Ala Val Leu

78 69 70 62 67 62 72

2 6 k 4 2 8 +- 5 2 12 t 8 + 14

Lys

70 61 63 69 76 58 63 57 69 68

2 -t t ? f 2 t + + t

Tyr Pro Asp Arg Met Ghl Ile Ser Saline (control)

Intrapouch distention 0*40cmHZ0

D-AA

9 10 3 12 8 7 12 8 6 6

IntrnpouchpH I + 2.5

His

73 -t 15

Basal

64 k 8

Basal

58 f 9

!k! Val Leu Tyr

65 70 78 67 60 58

r+ k ” k

812 5 7 9

20 lOcmH,O 0 cm Hz0 H,O 30 cm Hz0 40 cm H,O

72 k 61 68 ?+ 10 12 63 k 14 74 + 10

pH 4.0 5.0 7.0 pH 3.0 pH 2.5

62 60 -t 64 2 5 + 8 13 67 f 10 57 -t 4

Arg Met Glu Ser

65 72 70 73

2 -t ” +

5 13 14 16

Saline (control)

64 + 12

The present study provides evidence that L-isomers and, to a lesser degree, n-isomers of all natural AA’s infused intravenously stimulate gastric secretion, and that the most effective appears to be L-histidine. Acid response to intravenous infusion of AA’s such as Lhistidine or L-phenylalanine is related to the infusion rate of these AA’s, augmented by intraluminal pressure and suppressed pH-dependently by decreasing the pH of gastric content. Actually, similar results were obtained in our previous study on the secretory activity of various AA’s bathing directly the oxyntic gland area.4 In both studies the most potent AA was L-histidine, and the stimulation of gastric secretion by topical AA’s was affected by distention pressure and luminal pH. In both studies n-isomers of AA’s were less effective stimulants of acid secretion and the serum gastrin levels remained unchanged, indicating that the observed gastric stimulation was not mediated by gastrin. The over-all good agreement between the results obtained with intravenous and topical AA’s suggests that the mechanism of AA-induced gastric secretion is basically the same, namely the direct stimulation of the oxyntic glands. It is of interest that the peak acid response of the HP (expressed as the per cent of the maximal response to histamine) obtained by intravenous route in the present study is similar to that achieved by topical administration of L-histidine in the previous study.4 The major difference was the degree of augmentation of gastric secretion by intraluminal distention. At the low distention pressure, L-histidine given intravenously caused much stronger stimulation of the HP secretion than that applied topically, but with further increase in the distention pressure, the increment in the HP response to intravenous L-histidine was smaller than that to topical L-histidine. This could be simply explained by the failure of topical L-histidine applied at low intralu-

minal pressure to saturate sufficiently the oxyntic mucosa and thus to stimulate the oxyntic glands. At higher pressure levels, the effect of L-histidine administered topically or intravenously, was augmented by distention. The HP response to the combination of L-histidine and distention was significantly greater than the sum of the responses to each of these stimulants given alone, suggesting that these stimuli activate different secretory mechanisms of the oxyntic cells. The finding that L-histidine given intravenously is a potent stimulus of gastric acid secretion and the observation that this stimulation can be almost completely suppressed by metiamide, a potent H,-blocker,17 suggests that this AA acts on the oxyntic cells via histamine and Hz-receptors. Because histidine is the only AA that can be transformed to histamine, it was essential to determine the effect of metiamide on gastric response to other AA’s. The finding that metiamide caused only a small suppression of acid secretion induced by other AA’s, or an AA mixture not containing histidine, indicates that histamine and Hz-receptors play a minor role in the stimulation of oxyntic cells by these AA’s. It is of interest that atropine results in a marked inhibition of gastric acid secretion induced by an intravenous infusion of AA’s such as L-histidine or L-phenylalanine. This may suggest that gastric acid stimulation by intravenous AA’s is mediated, at least in part, by a local cholinergic mechanism. The gastric stimulation with intravenous histidine or phenylalanine appears to be pH dependent. The stepwise decrease of the luminal pH results in a reduction of gastric secretion, which at pH 2.5 is only about 20% of the value attained at pH 7.0. This finding is not surprising, as gastric stimulation by topical L-histidine

824

KONTUREK

was also found to be pH dependent.4 It may be important to mention, however, that the intragastric titration at pH below 2.0 is not valid as shown by Carter and Grossman’” and confirmed by our in vivo validation system. For this reason the present study on the pH profile of gastric response to intravenous AA infusion was performed at pH range from 2.5 to 7.0, at which intrapouch titration is valid, and decreases in luminal pH caused decreases in acid secretion in response to parer&r-al AA’s. The results of the earlier and present study suggest that luminal acid acts directly on the parietal cells by decreasing their responsiveness to AA’s applied topically or infused intravenously. The physiological significance of gastric stimulation by intravenous AA’s is not apparent from this study. Although the AA’s given intravenously might produce similar gastric responses to those obtained when an identical AA solution is given intraintestinally, this finding cannot be simply interpreted that AA’s stimulate gastric secretion solely after being absorbed from the gut because intraportal AA’s are much less potent than systemic venous AA’s,83y owing to the liver uptake of AA’s. It is also unlikely that absorbed AA’s are responsible for the major portion of the intestinal phase stimulation of gastric secretion as the AA’s, very effective gastric stimulants after intraduodenal administration7 (e.g., serine, proline) are rather poor stimulants after intravenous infusion. Conversely, L-histidine, which is a very potent stimulus by intravenous route, was found to be almost without effect on gastric secretion when given intraduodenally.7 Further studies are needed to determine the role played by AA’s absorbed from the gut in the total gastric response to a meal. REFERENCES 1. Saint-Hilaire S, Lavers MK, Kennedy J, et al: Gastric acid secretory value of different foods. Gastroenterology 39:1-11,196O

ET AL.

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2. Debas HT, Grossman MI: Chemicals bathing oxyntic gland area stimulate acid secretion. Gastroenterology 69:651-659, 1975 3. Cieszkowski M, Konturek SJ, Obtulowicz W, et al: Chemical stimulatory mechanisms in gastric secretion. J Physiol (Land) 246:143-157. 1975 4. Konturek SJ, Tasler J, Obtulowicz W, et al: Comparison of amino acids bathing the oxyntic gland area in the stimulation of gastric secretion. Gastroenterology 70:66-69, 1976 5. Strunz UT, Walsh JH, Grossman MI: Stimulation of gastrin release in dogs by individual amino acids. Proc Sot Exp Biol Med 157:440-441, 1978 6. Ivy AC, Javois AJ: Contribution of the physiology of gastric secretion. Am J Physiol71:583-620, 1924-1925 7. Konturek SJ, Radecki T, Kwiecien N: Stimuli for the intestinal phase of gastric secretion in dogs. Am J Physiol 234:E64-E69, 1978 8. Landor JH, Elpidio M: Gastric secretory response to intravenous amino acids in eviscerated dogs. Eur Surg Res 9(suppl):140, 1977 9. Landor JH, Beloni A, Mariano EC: Some properties shared by amino acids and entero-oxyntin (abstr). Gastroenterology 72:1085, 1977 10. Landor JH, Ipapo VS: Gastric secretory effect of amino acids given enterally and parenterally in dogs. Gastroenterology 73~781-784,1977 11. Isenberg JI, Maxwell V: Intravenous infusion of amino acids stimulated gastric acid secretion in man. N Engl J Med 298:2729, 1978 12. Carter DC, Grossman MI: Effect of luminal pH on acid secretion from Heidenhain pouches evoked by topical and parenteral stimulants. J Phvsiol (Londl (in mess) 13. Konturek SJ, Obtulowicz W, Taller J: Characteristics of gastric inhibition by acidification of oxyntic gland area. J Physiol (Land) 25:699-709, 1975 14. White A, Handler EL, Smith, et al: Principles of Biochemistry. New York, McGraw-Hill, 1954 15. Yalow RS, Berson SA: Radioimmunoassay of gastrin. Gastroenterology 58:1-14, 1970 16. Siegel S: Nonparametric Statistics for Behavioral Sciences. New York, McGraw-Hill, 1956, p 111-119 17. Konturek SJ, Tasler J, Obtulowicz W, et al: Effect of metiamide, a histamine HZ-receptor antagonist, on mucosal blood flow and serum gastrin level. Gastroenterology 66:982-986, 1974