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The action of somatostatin on intestinal alkaline phosphatase stimulated by secretin and cholecystokinin-pancreozymin
129
Clinica Chimico Acta, 108 (1980) 129-134 0 Elsevier/North-Holland Biomedical Press
CCA 1545
THE ACTION OF SOMATOSTATIN ON INTESTINAL PHOSPHATASE STIMULATED BY SECRETIN AND CHOLECYSTOKININ-PANCREOZYMIN
PETER
M. BAYER. a and HERWIG
POINTNER
ALKALINE
b
a Department of Clinical Chemistry, Wilhelminenspital, Vienna (Austria) and b 1st Department of Medicine, University of Vienna (Austria) (Received
March l&h,
1980)
summary The action of somatostatin on intestinal alkaline phosphatase activity (IAP) in the duodenal juice was examined in 22 subjects undergoing diagnostic secretin-CCK-PZ-tests. Under continuous secretin-CCK-PZ-stimulation there is an increase of IAP which is followed by a period of exhaustion after 1 h of stimulation. The intravenous administration of somatostatin induces a distinct inhibition of IAP which cannot be due to the exhaustion of the enzyme synthesis. As there is a functional relationship between fat absorption and alkaline phosphatase, it is suggested that this inhibition of IAP is one of the mechanisms of the somatostatin-induced inhibition of intestinal fat absorption.
Introduction The hormones secretin and cholecystokinin-pancreozymin (CCK-PZ) have been shown to release brush-border alkaline phosphatase into the small intestinal lumen in man [ 11. Somatostatin, a tetradecapeptide originally extracted from ovine hypothalami [2,3], was later shown to inhibit not only the secretion of growth hormone but also some other hormonally active peptides [ 4,5]. Furthermore an inhibitory effect on exocrine gastrointestinal secretion could be established [ 4,6]. In 1977, Linscheer et al. reported a close relationship between the activity of alkaline phosphatase in the small intestine and fat absorption in man and animals [ 7,8]. In previous studies we demonstrated that intravenously infused somatostatin completely blocks the intestinal absorption of fat in normal and in partially gastrectomized human subjects [9,10]. It was the purpose of this * Address for correspondence: Austria.
Doz. Dr. P.M. Bayer. Wilhelminenspital, Montleartstr. 37. A-1160 Vienna,
130
study to examine whether somatostatin influences the activity of intestinal alkaline phosphatase (IAP) under an exogenous continuous stimulation of secretin and CCK-PZ. By this experimental procedure we expected to obtain further information relating to the mode of action of somatostatin at the intestinal surface and the mechanism of the somatostatin induced inhibition of fat absorption. Material and methods Twenty-two subjects (12 male, 10 female, 19-64 years of age) who underwent a diagnostic secretin-CCK-PZ-test for the assessment of exocrine pancreatic function, were informed about the purpose of the study and agreed to participate. A double lumen Lagerlijf tube was introduced into the duodenum under fluoroscopic control and the duodenal juice was obtained by continuous suction using an automatic pump for 2 h as lo-, 15-, or 20-min samples. Following a baseline period of 15 min, secretin and CCK-PZ was infused intravenously for 2 h in a dose of 1 clinical unit of each peptide per kg bodyweight per hour. Since in the somatostatin trial the state of exocrine pancreatic function was of no importance, no difference was made between pancreatic insufficient and normal subjects. The subjects were distributed at random into three groups for the different experimental procedures. Group A
Ten subjects (5 male, 5 female; 5 pancreatic insufficient, 5 normal). Sixty minutes after the start of the hormonal stimulation by secretin and CCK-PZ, an intravenous bolus injection of 500 ,ug somatostatin was administered which was followed by an intravenous infusion of 250 ,ug somatostatin for 30 min. Duodenal juice was collected at the following intervals: 20, 40, 60, 75, 90, 105, 120 min. Group B
Control group: 5 subjects (3 male, 2 female: 4 normal, 1 pancreatic insufficiency). The same test procedure was used as in Group A with the exception that normal saline solution was infused instead of somatostatin. Group C
Seven subjects (4 male, 3 female: 4 normal, 3 pancreatic insufficient). Twenty minutes after the start of the secretin-CCK-PZ-infusion a bolus injection of 500 fig somatostatin was given intravenously followed by an intravenous infusion of 250 bg somatostatin for 20 min. This modification should exclude any exhaustive effect [8] of the continuously stimulated IAP, which could have been suggested from the test procedure of Group A. Duodenal juice was collected in lo-min samples throughout the total 2-h period of the examination. In all samples the volume and the activity of total alkaline phosphatase and IAP were measured. The output was calculated from volume and activity in each sample. Alkaline phosphatase was determined using a Gemsaec centrifugal analyser following the directions of the German Society of Clinical Chemistry
131
[ll]. The intestinal alkaline phosphatase was measured by the p-bromotetramisole-inhibition method of Van Belle et al. [12]. Secretin and CCK-PZ (80% purity) were products of the Karolinska Institute (G.I.H. Lab., Stockholm, Sweden); somatostatin was used as the synthetic cyclic peptide from Serono, Freiburg, F.R.G. For statistical analysis the Wilcoxon test (for paired data in each single group) and the Student t-test (for unpaired data between the different groups) were used. Results The pattern of total alkaline phosphatase was similar to the activity of the intestinal isoenzyme. For this reason only the results of IAP are demonstrated in the figures and discussed further in this paper (Fig. 1). Group A The stimulation by secretin and CCK-PZ induces a prompt increase of IAP in duodenal juice. The maximum is observed after 40 min and attains a value about 3.3 times that of the baseline. Immediately after the i.v. somatostatin injection a sharp decrease in IAP activity takes place which is statistically significant 0, < 0.01). This inhibition persists even after stopping the infusion of somatostatin and continues to the end of the examination. The nadir of IAP activity after the somatostatin injection is 15% of the maximal stimulated value. Group B (Control) Similarly to Group A, secretin and CCK-PZ increases IAP activity in the duodenal juice. Again the peak is reached 40 min after the start of the stimulation and the peak value of 2.7 times the baseline corresponds well with the respective value measured in Group A. During the .second hour there is a decrease in IAP activity which has a mean about 50% of the maximal stimulated value. This decrease takes place under a continuous secretin-CCK-PZinfusion with a concomitant infusion of saline during the period 60-90 min (p < 0.01 resp. < 0.05 from 90 to 120 min).
Group C There is a double peak demonstrable in this modified experimental procedure. Again, there is an early increase during secretin-CCK-PZ-stimulation, which is clearly blocked by the somatostatin infusion over the period of 20-40 min. Sixty minutes after the start of the experiment, i.e. 20 min after the end of the somatostatin infusion, a second increase in IAP activity can be demonstrated. The mean maximal value of the first peak is 2.7 times greater than the baseline value, and the maximum of the second peak is 3.6 times the basal value. Somatostatin induces a significant Cp< 0.01) fall to 29% of the maximal level. As in Group B, a spontaneous decrease of IAP activity can be observed at the end of the experiment. This decrease reaches a value of 28% of the second maximal value.
132
IAP U/M/N
, ‘, 0.9 0.9 0.2 0.6 es 0.4 43 aa 0.4
IAP U/rllN.
0
(1‘ 0.5 0.4
10
SECRCTIN
IrO
b0
- CCK
I.V. iCU/KG/HOUR
m
1W
QO
wr,*urb?s
1.
B
a3
(COhmOL)
0.1 0.1
0
IAP VlfilN
[
10
SECRETIN-
w CCU
SO’M
400
i20
wuvTes
I v: iCU/KG/HouR
I,2 4.1 4.0
09 0.8 O.? 0.6 OS 0.G 0.3 0.2 01
Fig. 1. Intestinal alkaline phosphatase (mean + S.E.M.) in duodenal juice during stimulation by secretinCCK-PZ and i.v. infusion of somatostatin or saline solution. *, D < 0.01; 9, p < 0.05 (Wilcoxon test; compared with the maximal value of the respective group). 0, p < 0.01 (Student’s t test for unpaired data, Group C vs A).
133
Discussion Our results confirm the observations of Wames et al. [l] that secretin and CCK-PZ enhance the release of IAP into the duodenal juice. An exhaustion of IAP synthesis under hormonal stimulation with secretin and CCK-PZ has been described in rats, but not in humans [8]. In our experimental procedure, which applies submaximal pancreatic stimulation, we were able to establish such an exhaustive effect in human subjects. In all three groups examined, a spontaneous decrease in IAP activity could be demonstrated. This effect is particularly evident in the control trial (Group B). Our results demonstrate further that somatostatin distinctly inhibits IAP activity in duodenal juice. While in Group A an accidental coincidence of the somatostatin effect with the exhaustion of IAP-secretion under the continuous hormonal stimulation cannot be totally ruled out, the test procedure of Group C clearly demonstrated a blocking effect of somatostatin on IAP. In this part of the study the early infusion of somatostatin induces a fall in IAP which is followed by a repeated increase after the end of the somatostatin infusion. However, the exhaustive effect clearly appears at the end of the examination. The inhibition of IAP by intravenously administered somatostatin, despite an exogenous secretin-C!CK-PZ-stimulation, suggests that somatostatin either blocks the receptor for secretin-CCK-PZ at the intestinal cell, or that it affects the membrane of the mucosal cell in such a way that the liberation of IAP can not occur. A blocking effect of somatostatin on IAP synthesis is not very likely because the increase of IAP in the duodenal juice after the end of somatostatin infusion takes place immediately. In the case of a blocked synthesis a gap in time during which the synthesis had to take place should be expected. A functional relationship between fat absorption and intestinal alkaline phosphatase has been suggested from various observations. (1) During fat absorption there is an increase of alkaline phosphatase activity in the thoracic duct lymph, which parallels triglyceride concentration [ 131. (2) Alkaline phosphatase and neutral fat show a histochemically similar pattern in the villi of the intestinal mucosa during fat absorption [ 781. (3) The absorption of oleic acid can be inhibited by 1-phenylalanime, a specific inhibitor of IAP [ 141. (4) Somatostatin is capable of inhibiting fat absorption in normal and partially gastrectomized human subjects [9,10] and - as in this study - inhibits IAP activity in duodenal juice. The inhibitory effect of somatostatin on fat absorption in vivo cannot be explained by a single mode of action, but is certainly due to the synergism of several mechanisms: somatostatin inhibits gastrointestinal motility [ 151, which is important for any normal absorptive procedure [ 161, and it inhibits pancreatic enzyme secretion [6] so that triglycerides cannot be broken down in the intestine. Bile secretion is impaired [6], making fat emulsion difficult and the liberating effect of bile acids on brush border enzymes is not present. As demonstrated for carbohydrates [ 171 and fluorescein-Na [ 181, there is a direct inhibitory effect of somatostatin on the intestinal mucosa. Finally, our present results demonstrate an inhibitory effect on intestinal alkaline phosphatase, an enzyme which plays an important role in fat absorption.
134
Acknowledgement The technical assistance of Eva Knoth and Ilse Lins is gratefully acknowledged. References 1 Wames, T.W.. Hine, P. and Kay, G. (1974) The action of secretin and pancreozymin on small-intestinal alkaline phosphatase. Gut 15,3947 2 Krulich, L. and McCann, S. (1969) Effect of GH-releasing factor and GH-inhibiting factor on the release and concentration of GH in pituitaries incubated in vitro. Endocrinology 85, 319324 3 Brazeau, P.. Vale, W.. Burgus. R.. Ling, N.. Butcher. M., Rivier. J. and Guillemin. R. (1973) HYPOtbalamic polypeptide that inhibits the secretion of immune reactive pituitary growth hormone. Science 179.77-79 4 Bloom, S.R.. Mortimer. C.H., Thomer, M.O.. Besser, G.M.. Hall, R., Gomez-Pan. A., Roy. V.M.. Russ& R.C.G.. Coy, D.H., Kastin. A.J. and SchaIly. A.V. (1974) Inhibition of gastrin and gastric acid secretion by growth hormone release inhibiting hormone. Lancet ii, 1106-1109 5 Koerker, D.J., Ruth. W.. Chideckel, E., Palmer. J., Goodner. Ch.J., Ensinck. J. and Gale, Ch.C. (1974) Somatostatin, hypothalamic inhibitor of the endocrine pancreas. Science 184, 482484 6 Creutzfeldt, W.. Lankisch. P.G. and F8lsch. U.R. (1975) Hemmung der Sekretin- und CholezystokininPankreozymin-induzierten Saft- und Enzymsekretion des Pankreas und der Gallenblasenkontraktion beim Menschen durch Somatostatin. Dtsch. Med. Wschr. 100,1135-1138 7 Linscheer, W.G., Malagelada. J.R., Stolbach, L.L. and Fishman, W.H. (1977) The effect of fatty acid tierfusion on intestinal alkaline phosphatase. I. Studies on man. Am. J. Dig. Dis. 22. 509-515 8 Malagelada. J.R., Linscheer. W.G. and Fishman, W.H. (1977) The effect of fatty acid perfusion on intestinal alkaline phosphatase. II. Studies on the rat. Am. J. Dig. Dis. 22, 516-523 9 Hengl. G., Prager. J. and Pointner, H. (1979) The influence of somatostatin on the absorption of triglycerides in partially gastrectomized subjects. Acta hepatogastroenterol. 26. 392-395 10 Pointer, H.. Hengl, G.. Bayer. P.M. and Flegel. U. (1977) Hemmung des postprandialen Triglyceridanstiegs im Serum durch Somatostatin beim Menschen. Wien, Klin. Wschr. 89.224-227 11 Empfehlungen der Deutschen Gesellschaft fiir Klinische Chemie (1972) J. Clin. Chem. Clin. Biochem. 10.182-192 12 Van Belle, H., De Broe. M.E. and Wieme. R.J. (1977) L-p-bromotetramisole. a new reagent for use in measuring placental or intestinal isoenzymes of alkaline phosphatase in human serum. Clin. Chem. 23. 454459 13 Blomstrand. R. and Werner. B. (1965) Alkaline phosphatase activity in human thoracic duct lymph. Acta Chir. Stand. 129.177-191 14 Linscheer, W.G., Malagelada, J.R. and Fishman, W.H. (1971) Diminished oleic acid absorption in man by I-phenylalanine inhibition of an intestinal phosphohydrolase. Nature, New Biol. 231, 116-117 15 Boden, G., Jacoby. H.J. and Staus. A. (1976) Somatostatin interacts with basal and carbachol stimulated antral and duodenal motility. Gastroenterology 70, 961 (abstract) 16 Matuschansky. C., Rambaud. J.C., Modigliani, R. and Bemier, J.J. (1977) Relations entre mot&it6 et absorption intestinale. Gastroent. Clin. Biol. 1, 225-229 17 Pott. G., Wagner, H.. Zierden, E., HiIke. K.H., Jansen, H., Hengst, K. and Gerlach, U. (1979) Influence of somatostatin on carbohydrate absorption in human small intestine. Klin. Wschr. 57,131-133 18 Laggner, A., Pointner, H. and Deutsch. E. (1980) The influence of somatostatin on intestinal absorption. Studies with fluorescein-Na. Regulatory Peptides 1, 6147
Clinica Chimico Acta, 108 (1980) 129-134 0 Elsevier/North-Holland Biomedical Press
CCA 1545
THE ACTION OF SOMATOSTATIN ON INTESTINAL PHOSPHATASE STIMULATED BY SECRETIN AND CHOLECYSTOKININ-PANCREOZYMIN
PETER
M. BAYER. a and HERWIG
POINTNER
ALKALINE
b
a Department of Clinical Chemistry, Wilhelminenspital, Vienna (Austria) and b 1st Department of Medicine, University of Vienna (Austria) (Received
March l&h,
1980)
summary The action of somatostatin on intestinal alkaline phosphatase activity (IAP) in the duodenal juice was examined in 22 subjects undergoing diagnostic secretin-CCK-PZ-tests. Under continuous secretin-CCK-PZ-stimulation there is an increase of IAP which is followed by a period of exhaustion after 1 h of stimulation. The intravenous administration of somatostatin induces a distinct inhibition of IAP which cannot be due to the exhaustion of the enzyme synthesis. As there is a functional relationship between fat absorption and alkaline phosphatase, it is suggested that this inhibition of IAP is one of the mechanisms of the somatostatin-induced inhibition of intestinal fat absorption.
Introduction The hormones secretin and cholecystokinin-pancreozymin (CCK-PZ) have been shown to release brush-border alkaline phosphatase into the small intestinal lumen in man [ 11. Somatostatin, a tetradecapeptide originally extracted from ovine hypothalami [2,3], was later shown to inhibit not only the secretion of growth hormone but also some other hormonally active peptides [ 4,5]. Furthermore an inhibitory effect on exocrine gastrointestinal secretion could be established [ 4,6]. In 1977, Linscheer et al. reported a close relationship between the activity of alkaline phosphatase in the small intestine and fat absorption in man and animals [ 7,8]. In previous studies we demonstrated that intravenously infused somatostatin completely blocks the intestinal absorption of fat in normal and in partially gastrectomized human subjects [9,10]. It was the purpose of this * Address for correspondence: Austria.
Doz. Dr. P.M. Bayer. Wilhelminenspital, Montleartstr. 37. A-1160 Vienna,
130
study to examine whether somatostatin influences the activity of intestinal alkaline phosphatase (IAP) under an exogenous continuous stimulation of secretin and CCK-PZ. By this experimental procedure we expected to obtain further information relating to the mode of action of somatostatin at the intestinal surface and the mechanism of the somatostatin induced inhibition of fat absorption. Material and methods Twenty-two subjects (12 male, 10 female, 19-64 years of age) who underwent a diagnostic secretin-CCK-PZ-test for the assessment of exocrine pancreatic function, were informed about the purpose of the study and agreed to participate. A double lumen Lagerlijf tube was introduced into the duodenum under fluoroscopic control and the duodenal juice was obtained by continuous suction using an automatic pump for 2 h as lo-, 15-, or 20-min samples. Following a baseline period of 15 min, secretin and CCK-PZ was infused intravenously for 2 h in a dose of 1 clinical unit of each peptide per kg bodyweight per hour. Since in the somatostatin trial the state of exocrine pancreatic function was of no importance, no difference was made between pancreatic insufficient and normal subjects. The subjects were distributed at random into three groups for the different experimental procedures. Group A
Ten subjects (5 male, 5 female; 5 pancreatic insufficient, 5 normal). Sixty minutes after the start of the hormonal stimulation by secretin and CCK-PZ, an intravenous bolus injection of 500 ,ug somatostatin was administered which was followed by an intravenous infusion of 250 ,ug somatostatin for 30 min. Duodenal juice was collected at the following intervals: 20, 40, 60, 75, 90, 105, 120 min. Group B
Control group: 5 subjects (3 male, 2 female: 4 normal, 1 pancreatic insufficiency). The same test procedure was used as in Group A with the exception that normal saline solution was infused instead of somatostatin. Group C
Seven subjects (4 male, 3 female: 4 normal, 3 pancreatic insufficient). Twenty minutes after the start of the secretin-CCK-PZ-infusion a bolus injection of 500 fig somatostatin was given intravenously followed by an intravenous infusion of 250 bg somatostatin for 20 min. This modification should exclude any exhaustive effect [8] of the continuously stimulated IAP, which could have been suggested from the test procedure of Group A. Duodenal juice was collected in lo-min samples throughout the total 2-h period of the examination. In all samples the volume and the activity of total alkaline phosphatase and IAP were measured. The output was calculated from volume and activity in each sample. Alkaline phosphatase was determined using a Gemsaec centrifugal analyser following the directions of the German Society of Clinical Chemistry
131
[ll]. The intestinal alkaline phosphatase was measured by the p-bromotetramisole-inhibition method of Van Belle et al. [12]. Secretin and CCK-PZ (80% purity) were products of the Karolinska Institute (G.I.H. Lab., Stockholm, Sweden); somatostatin was used as the synthetic cyclic peptide from Serono, Freiburg, F.R.G. For statistical analysis the Wilcoxon test (for paired data in each single group) and the Student t-test (for unpaired data between the different groups) were used. Results The pattern of total alkaline phosphatase was similar to the activity of the intestinal isoenzyme. For this reason only the results of IAP are demonstrated in the figures and discussed further in this paper (Fig. 1). Group A The stimulation by secretin and CCK-PZ induces a prompt increase of IAP in duodenal juice. The maximum is observed after 40 min and attains a value about 3.3 times that of the baseline. Immediately after the i.v. somatostatin injection a sharp decrease in IAP activity takes place which is statistically significant 0, < 0.01). This inhibition persists even after stopping the infusion of somatostatin and continues to the end of the examination. The nadir of IAP activity after the somatostatin injection is 15% of the maximal stimulated value. Group B (Control) Similarly to Group A, secretin and CCK-PZ increases IAP activity in the duodenal juice. Again the peak is reached 40 min after the start of the stimulation and the peak value of 2.7 times the baseline corresponds well with the respective value measured in Group A. During the .second hour there is a decrease in IAP activity which has a mean about 50% of the maximal stimulated value. This decrease takes place under a continuous secretin-CCK-PZinfusion with a concomitant infusion of saline during the period 60-90 min (p < 0.01 resp. < 0.05 from 90 to 120 min).
Group C There is a double peak demonstrable in this modified experimental procedure. Again, there is an early increase during secretin-CCK-PZ-stimulation, which is clearly blocked by the somatostatin infusion over the period of 20-40 min. Sixty minutes after the start of the experiment, i.e. 20 min after the end of the somatostatin infusion, a second increase in IAP activity can be demonstrated. The mean maximal value of the first peak is 2.7 times greater than the baseline value, and the maximum of the second peak is 3.6 times the basal value. Somatostatin induces a significant Cp< 0.01) fall to 29% of the maximal level. As in Group B, a spontaneous decrease of IAP activity can be observed at the end of the experiment. This decrease reaches a value of 28% of the second maximal value.
132
IAP U/M/N
, ‘, 0.9 0.9 0.2 0.6 es 0.4 43 aa 0.4
IAP U/rllN.
0
(1‘ 0.5 0.4
10
SECRCTIN
IrO
b0
- CCK
I.V. iCU/KG/HOUR
m
1W
QO
wr,*urb?s
1.
B
a3
(COhmOL)
0.1 0.1
0
IAP VlfilN
[
10
SECRETIN-
w CCU
SO’M
400
i20
wuvTes
I v: iCU/KG/HouR
I,2 4.1 4.0
09 0.8 O.? 0.6 OS 0.G 0.3 0.2 01
Fig. 1. Intestinal alkaline phosphatase (mean + S.E.M.) in duodenal juice during stimulation by secretinCCK-PZ and i.v. infusion of somatostatin or saline solution. *, D < 0.01; 9, p < 0.05 (Wilcoxon test; compared with the maximal value of the respective group). 0, p < 0.01 (Student’s t test for unpaired data, Group C vs A).
133
Discussion Our results confirm the observations of Wames et al. [l] that secretin and CCK-PZ enhance the release of IAP into the duodenal juice. An exhaustion of IAP synthesis under hormonal stimulation with secretin and CCK-PZ has been described in rats, but not in humans [8]. In our experimental procedure, which applies submaximal pancreatic stimulation, we were able to establish such an exhaustive effect in human subjects. In all three groups examined, a spontaneous decrease in IAP activity could be demonstrated. This effect is particularly evident in the control trial (Group B). Our results demonstrate further that somatostatin distinctly inhibits IAP activity in duodenal juice. While in Group A an accidental coincidence of the somatostatin effect with the exhaustion of IAP-secretion under the continuous hormonal stimulation cannot be totally ruled out, the test procedure of Group C clearly demonstrated a blocking effect of somatostatin on IAP. In this part of the study the early infusion of somatostatin induces a fall in IAP which is followed by a repeated increase after the end of the somatostatin infusion. However, the exhaustive effect clearly appears at the end of the examination. The inhibition of IAP by intravenously administered somatostatin, despite an exogenous secretin-C!CK-PZ-stimulation, suggests that somatostatin either blocks the receptor for secretin-CCK-PZ at the intestinal cell, or that it affects the membrane of the mucosal cell in such a way that the liberation of IAP can not occur. A blocking effect of somatostatin on IAP synthesis is not very likely because the increase of IAP in the duodenal juice after the end of somatostatin infusion takes place immediately. In the case of a blocked synthesis a gap in time during which the synthesis had to take place should be expected. A functional relationship between fat absorption and intestinal alkaline phosphatase has been suggested from various observations. (1) During fat absorption there is an increase of alkaline phosphatase activity in the thoracic duct lymph, which parallels triglyceride concentration [ 131. (2) Alkaline phosphatase and neutral fat show a histochemically similar pattern in the villi of the intestinal mucosa during fat absorption [ 781. (3) The absorption of oleic acid can be inhibited by 1-phenylalanime, a specific inhibitor of IAP [ 141. (4) Somatostatin is capable of inhibiting fat absorption in normal and partially gastrectomized human subjects [9,10] and - as in this study - inhibits IAP activity in duodenal juice. The inhibitory effect of somatostatin on fat absorption in vivo cannot be explained by a single mode of action, but is certainly due to the synergism of several mechanisms: somatostatin inhibits gastrointestinal motility [ 151, which is important for any normal absorptive procedure [ 161, and it inhibits pancreatic enzyme secretion [6] so that triglycerides cannot be broken down in the intestine. Bile secretion is impaired [6], making fat emulsion difficult and the liberating effect of bile acids on brush border enzymes is not present. As demonstrated for carbohydrates [ 171 and fluorescein-Na [ 181, there is a direct inhibitory effect of somatostatin on the intestinal mucosa. Finally, our present results demonstrate an inhibitory effect on intestinal alkaline phosphatase, an enzyme which plays an important role in fat absorption.
134
Acknowledgement The technical assistance of Eva Knoth and Ilse Lins is gratefully acknowledged. References 1 Wames, T.W.. Hine, P. and Kay, G. (1974) The action of secretin and pancreozymin on small-intestinal alkaline phosphatase. Gut 15,3947 2 Krulich, L. and McCann, S. (1969) Effect of GH-releasing factor and GH-inhibiting factor on the release and concentration of GH in pituitaries incubated in vitro. Endocrinology 85, 319324 3 Brazeau, P.. Vale, W.. Burgus. R.. Ling, N.. Butcher. M., Rivier. J. and Guillemin. R. (1973) HYPOtbalamic polypeptide that inhibits the secretion of immune reactive pituitary growth hormone. Science 179.77-79 4 Bloom, S.R.. Mortimer. C.H., Thomer, M.O.. Besser, G.M.. Hall, R., Gomez-Pan. A., Roy. V.M.. Russ& R.C.G.. Coy, D.H., Kastin. A.J. and SchaIly. A.V. (1974) Inhibition of gastrin and gastric acid secretion by growth hormone release inhibiting hormone. Lancet ii, 1106-1109 5 Koerker, D.J., Ruth. W.. Chideckel, E., Palmer. J., Goodner. Ch.J., Ensinck. J. and Gale, Ch.C. (1974) Somatostatin, hypothalamic inhibitor of the endocrine pancreas. Science 184, 482484 6 Creutzfeldt, W.. Lankisch. P.G. and F8lsch. U.R. (1975) Hemmung der Sekretin- und CholezystokininPankreozymin-induzierten Saft- und Enzymsekretion des Pankreas und der Gallenblasenkontraktion beim Menschen durch Somatostatin. Dtsch. Med. Wschr. 100,1135-1138 7 Linscheer, W.G., Malagelada. J.R., Stolbach, L.L. and Fishman, W.H. (1977) The effect of fatty acid tierfusion on intestinal alkaline phosphatase. I. Studies on man. Am. J. Dig. Dis. 22. 509-515 8 Malagelada. J.R., Linscheer. W.G. and Fishman, W.H. (1977) The effect of fatty acid perfusion on intestinal alkaline phosphatase. II. Studies on the rat. Am. J. Dig. Dis. 22, 516-523 9 Hengl. G., Prager. J. and Pointner, H. (1979) The influence of somatostatin on the absorption of triglycerides in partially gastrectomized subjects. Acta hepatogastroenterol. 26. 392-395 10 Pointer, H.. Hengl, G.. Bayer. P.M. and Flegel. U. (1977) Hemmung des postprandialen Triglyceridanstiegs im Serum durch Somatostatin beim Menschen. Wien, Klin. Wschr. 89.224-227 11 Empfehlungen der Deutschen Gesellschaft fiir Klinische Chemie (1972) J. Clin. Chem. Clin. Biochem. 10.182-192 12 Van Belle, H., De Broe. M.E. and Wieme. R.J. (1977) L-p-bromotetramisole. a new reagent for use in measuring placental or intestinal isoenzymes of alkaline phosphatase in human serum. Clin. Chem. 23. 454459 13 Blomstrand. R. and Werner. B. (1965) Alkaline phosphatase activity in human thoracic duct lymph. Acta Chir. Stand. 129.177-191 14 Linscheer, W.G., Malagelada, J.R. and Fishman, W.H. (1971) Diminished oleic acid absorption in man by I-phenylalanine inhibition of an intestinal phosphohydrolase. Nature, New Biol. 231, 116-117 15 Boden, G., Jacoby. H.J. and Staus. A. (1976) Somatostatin interacts with basal and carbachol stimulated antral and duodenal motility. Gastroenterology 70, 961 (abstract) 16 Matuschansky. C., Rambaud. J.C., Modigliani, R. and Bemier, J.J. (1977) Relations entre mot&it6 et absorption intestinale. Gastroent. Clin. Biol. 1, 225-229 17 Pott. G., Wagner, H.. Zierden, E., HiIke. K.H., Jansen, H., Hengst, K. and Gerlach, U. (1979) Influence of somatostatin on carbohydrate absorption in human small intestine. Klin. Wschr. 57,131-133 18 Laggner, A., Pointner, H. and Deutsch. E. (1980) The influence of somatostatin on intestinal absorption. Studies with fluorescein-Na. Regulatory Peptides 1, 6147