Bombesin effects on human GI functions

Bombesin effects on human GI functions

I','l>tide~. Vol. ~. Suppl. 3. pp. I 13-116. 1985. A n k h o International Inc. Printed in the U.S.A. 0196-978685 $3.t~,b - .00 B o m b e s i n Ef...

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I','l>tide~.

Vol. ~. Suppl. 3. pp. I 13-116. 1985.

A n k h o International Inc. Printed in the U.S.A.

0196-978685 $3.t~,b - .00

B o m b e s i n Effects on Human GI Functions G. D E L L E F A V E , ' B. A N N I B A L E , L. D E M A G I S T R I S , C. S E V E R I , R. B R U Z Z O N E , M. P U O T I , P. M E L C H I O R R I , * A. T O R S O L I A N D V. E R S P A M E R *

Cattcdra di Gastrocnterologia, e Cattedra di Farmacologia,* Universit6 degli Studi " L a S a p i e n z a " R o m a , Italia

DELLE FAVE. G.. B. ANNIBALE. L. DE MAGISTRIS. C. SEVERI. R, BRUZZONE, M. PUOTI. P. MELCHIORRI, A. TORSOLI AND V. ERSPAMER. B,mbesin ~:l't~'ctson human GI.f, nctions. PEPTIDES 6: Suppl. 3.113-116. 1985.--1n this article some of the actions of amphibian skin peptide Bombesin (BBS) on human gastrointestinal and pancreatic functions are revie~ ed. BBS causes increases of Ioxver esophageal sphincter pressure, delay of gastric emptying, inhibition of mechanical activit.~ of duodenum and jejunum and gallbladder emptying. BBS also releases in man gastrin and stimulates gastric acid secretion. BBS administration induces release of insulin, glucagon and pancreatic polypeptide from human Islet of Langerhans and causes secretion of pancreatic bicarbonates and enzymes in duodenal juice and release of pancreatic enzx rues in blood stream. Bombesin Gut hormones Pancreatic exocrine secretion

Motility Gastric exocrine secretion Pancreatic endocrine secretion

T H E amphibian skin peptide Bombesin (BBS) has largely been studied in man [13]. It is interesting to notice that its effects were described by reports in humans before being investigated and then confirmed by studies "'in vitro." This fact is presumably due to the large number of functions (i.e., gastrointestinal and pancreatic) altered by BBS administration and to the relative Io~v number of side effects recorded during a BBS infusion. Several of the main GI and pancreatic functions, as motility, endocrine and exocrine secretions. are modified by BBS (Table I). One possible explanation of these numerous actions is the wide distribution of nerve fibres containing Bombesin-like peptides in the mammalian [8] and human gastrointestinal tract [19] and pancreas [24], and the presence of Bombesin receptors on intestinal smooth muscle cells [17]. pancreatic acini [16], etc. In this article we review the effects of Bombesin on some GI and pancreatic functions in man.

Gastric endocrine secretion

GASTRIC EXOCRINE AND ENDOCRINE SECRETION BBS causes in man an increase of gastric acid secretion. This increase is 50% lower than that induced by maximal stimulation with pentagastrin, and it is in part inhibited by atropine [10]. Since the effect on gastric secretion follows a prompt increase (5 min after the beginning of BBS infusion) [9] of gastrin release it is generally accepted that the gastric secretion induced by Bombesin is gastrin mediated. Actually, because of the large amount ofgastrin released by BBS, one could expect a " m a x i m a l " stimulation of gastric acid secretion induced by BBS via gastrin. To give an explanation of this phenomenon we studied the effects of BBS on gastrin and gastric acid secretion in subjects with hyper (duodenal ulcer patients) and normal gastric secretion [ l l ] and we found that BBS always causes an increase about 50c~ lower than that induced by pentagastrin. In the subjects with normal secretion the stimulation was lower than in those with hyper secretion, while in both groups the gastrin response to BBS was similar. In other words, the same amount of gastrin caused different rates of acid secretion. Although this represents just an indirect evidence that BBS-induced gastrin release is not the only mediator of acid secretion, other data are suggestive to this hypothesis: (a) the release of other peptide "inhibitors'" [ 14], (b) the tachyphilaxis induced on parietal cells by the large amounts of gastrin released by BBS. Now it is generally accepted that BBS-like peptides are directly involved in the regulation of gastrin release. In man BBS causes increase of circulating levels of gastrin, greater than that induced by meal, and this increase is dose dependent (Fig. I). In addition, we recently found that BBS. in con-

MOTILITY In man. a 30' infusion of 5-10 ng/kg/min of BBS causes: (a) increase of Lower Esophageal Sphincter Pressure by a non-gastrin pancreatic polipeptide mediated mechanism [7]. (b) delay of solid meal gastric emptying [21], (c) inhibition of basal mechanical activity of duodenum and jejunum [6], (d) stimulation of gallbladder contraction and emptying [5]. The demonstration of the presence of nerve fibres containing Bombesin-like immunoreactivity in mammalian and human gut. together with the evidence "'in vitro" of the direct effect of BBS on smooth muscle cell contraction [171, suggest that BBS plays a physiologic role on the control of human gastrointestinal motility.

'Requests for reprints should be addressed to Gianfranco Delle Fave, M.D.. Cattedra di Gastroenterologia. Ist. Clinica Medica 2. Policlinico. 1-00161. Roma, Italia.

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FIG. 1, Mean A serum gastrin (pmol/I) responses to 30 min intravenous discontinue infusions of increasing doses of bombesin (BBS) (0.125, 0.250, 0.500, I, 2, 5, 10 ng.kg-' 'min-') in 10 normal subjects. Each dose is significantly higher than basal (p<0.05).

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TABLE 1 BOMBESIN EFFECTS ON HUMAN GI FUNCTIONS

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Secretion: (exocrine)

Secretion: (endocrine)

Lower Esophageal Sphincter Gastric Emptying Duodenum/Jejunum Mechanical Activity Gallbladder Emptying

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Gastrin

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Insulin Glucagon Pancreatic Polypeptide

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FIG. 2. Pancreatic exocrine secretion. Top panel: flo~: rates (ml/15 min): Middle panel: bicarbonate concentrations (mmol/1): Low panel: chymotripsin concentrations (UI/I): during bombesin (BBS. e ) and secretin plus caerulein (SC, C), Bar between arrows indicates the length of BBS and SC infusions. Values are expressed as increase over basal. Each point is significantly higher than basal (o<0.05). *p<0.05. BBS vs. SC.

BOMBESIN E F F E C T S ON HUMAN GI FUNCTIONS

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TABLE 2 INTEGRATEDPLASMATRIPSIN-LIKEIMMUNOREACTIVITY*DURING BOMBESINt (BBS) AND SECRETiN PLUS CAERULEIN:i:(SC) INFUSIONS§IN 6 NORMAL SUBJECTS Min BBS (mean ± SEM)

0-15

15-30

30-45

45-60

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2837 ± 672¶

2918 ± 693¶

3241 ± 969¶

551 ± 265

658 ± 252

561 ± 217

SC (mean ± SEM)

289 ± 141

*ng/ml/15 min. -t300 ng/kg/hr. :[:Secretin= I U/kg/hr; Caerulein 100 ng/kg/hr. §Both peptides infusions lasted I hr. ~p<0.05 BBS vs. SC.

BBS

trast with other reports, stimulates gastrin release from non-antral tissue (i.e.. in patients with total gastrectomy) [2]. All these data are consistent with the result~ c o n i n g from "'in vitro" experiments indicating the dficct role of BBS-like peptides on the control of gastrin release [17].

mediated (CCK?). BBS causes glucagon release not only from endocrine pancreas but also from the L cells of intestine (secreting glucagon-like peptides). This fact was confirmed by the increase of glucagon-like plasma immunoreactivity induced by BBS in subjects without pancreas [4]. The effect of Bombesin on exocrine pancreas has been investigated through several experimental models in various animal species. In particular on guinea pig pancreatic acini BBS stimulates enzyme release by interacting with specific membrane receptors and by mobilization of intracellular calcium [ 16]. In humans BBS stimulates pancreatic enzymes secretion in duodenal juice (Fig. 2); comparing these data with those obtained by secretin plus caerulein it appears that BBS is more efficacious. BBS also causes increase of bicarbonate concentration in pancreatic juice (Fig. 2), and this effect was similar to that caused by secretin plus caerulein. In addition BBS augments the blood concentration of enzymes of pancreatic origin as amylase, lipase and trypsin. This increase was maximal 30 min after the end of peptide infusion (Fig. 3), and persisted higher than basal until 120 min. By comparing the effects of BBS on blood enzyme concentration with that induced by secretin plus caerulein it appears that BBS has the greater efficacy: 6-fold stimulation vs. 2-fold (Table 2). The question about the mechanism of action of Bombesin in stimulating pancreatic exocrine secretion has been clarified in mammals but not in man. That is. if Bombesin acts directly or by releasing other mediators, as it was proposed, is still an open question, even if it is unlikely that the mechanism in humans was different to all other species.

PANCREATIC ENDOCRINE AND EXOCR.'NE Y~CRETION

CONCLUSIONS

In man BBS stimulates the release of insult:;, glucagon 141 and pancreatic polypeptide (PP) [12]. This effect on Islet of Langerhans has recently been confirmed in i,t~lated islet cell culture and demonstrated to be direct, at Ica~t for insulin [23]. The effect on PP release is poor, not dose dependent [I] and different from other species (i.e.. do~, "nay be

The investigations in humans demonstrated that Bombesin (as well as Bombesin-like peptides: e.g., Gastdn Releasing Peptide) is one of the most important "regulatory peptides" for the physiology of gastrointestinal tract and pancreas. In addition the widespread action of this peptide has been demonstrated to be useful as clinical diagnostic tool [22].

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FIG. 3. Integrated plasma amylase response OAR: U/I/30 min, solid column): integrated plasma lipase response (ILR: U/I/30 min, open columnr and integrated plasma trypsin-like immunoreactivity response (ITR: ng/ml/30 min. stippled column) to bombesin infusion (BBS). Bar between arrows indicates the length of the infusion. Each column is significantly higher than basal (p<0.05).

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DELLE FAVE ET AL. REFERENCES

1. Annibale, B., R. Bruzzone, C. Severi, A. Kohn, L. de Magistris. G. Delle Fave and A. Torsoli, Pancreatic polypeptide (PP) response to graded doses of bombesin (BBS) in man. International symposium on brain-gut axis. Florence, 29 June-I July, 12, 1981. 2. Annibale, B., V. Corleto, C. Severi, L. de Magistris, G. De Toma and G. Delle Fave. Bombesin releases extragastric gastrin in man. Regtd Pept 11: 43-49, 1985. 3. Basso, N., S. Giri, G. lmprota, E. Lezoche, P. Melchiorri, M. Percoco and V. Speranza. External pancreatic secretion after bombesin infusion in man. Gut 16: 994--998, 1975. 4. Bruzzone, R., G. Tamburrano, A. Lala. M. Mauceri, B. Annibale, C. Severi, L. de Magistris. F. Leonetti and G. Delle Fave. Effect of bombesin on plasma insulin, pancreatic glucagon and gut glucagon in man. J Clin Emlocrimd Metabol 56: 643-647, 1983. 5. Corazziari, E.. A. Torsoli, P. Melchiorri and G. Delle Fave. Effect of bombesin on human gallbladder emptying. Rendic Ga,~troenterol 6: 52-55. 1974. 6. Corazziari, E., A. Torsoli, P. Melchiorri, G. Delle Fave and F. I. Habib. Effect of bombesin on the mechanical activity of the human duodenum and jejunum. Rendic Gastroenterol 6: 55-56, 1974. 7. Corazziari, E., G. Delle Fave, C. Pozzessere. A. Kohn, L. de Magistris, F. Anzini and A. Torsoli. Effect of bombesin on lower esophageal sphincter pressure in humans. Gastroenterology 82: 1403-1405, 1982. 8. Costa, M., J. B. Furness, N. Yanaihara. C. Yanaihara and T. W. Moody. Distribution and projections of neurons with immunoreactivity for both gastrin-releasing peptide and bombesin in the guinea-pig small intestine. Cell Tissue Res 235: 285-293, 1984. 9. Delle Fave, G., E. Corazziari, P. Melchiorri and A. Torsoli. Effect of bombesin on plasma gastrin levels and gastric secretion in man. Acta Hepato Gastroenterol 21: 80. 1974. 10. Delle Fare, G., A. Kohn, L. de Magistris. M. Mancuso and C. Sparvoli. Effect of bombesin stimulated gastrin on gastric acid secretion in man. Lift" Sci 27: 993-999, 1980. I1. Delle Fave. G., A. Kohn, L. de Magistris. B. Annibale. R. Bruzzone, C. Sparvoli, C. Severi and A. Torsoli. Effect of bombesin on gastrin and gastric acid secretion in patients with duodenal ulcer. Gut 24: 231-235, 1983. 12. de Magistris. L., G. Delle Fave, A. Kohn and T. W. Schwartz. Differential stimulation of pancreatic-polypeptide and gastrin secretion by bombesin in man. Lift, Sci 28: 2617-2621, 1981.

13. Erspamer, V. Peptides of the amphibian skin active on the gut. !1. Bombesin-like peptides: isolation, structure and basic ft, nctions. In: Gastrointestimd Horm,,nes. edited by G. B. J. Glass. New York: Raven Press, 1980. pp. 343-361. 14. Ghatei. M. A., R. T. Jung, J. C. Stevenson, C. J. Hilliyard, T. E. Adrian, Y. C. Lee, N. D. Christofides, D. L. Sarson. K. Mashiter, J. Mc lntyre and S. R. Bloom. Action of gut hormones and calcium in man. J Clin Emh,crin,I Metab 54: 980985, 1982. 15. Jansen, J. B. M. J. and C. B. H. W. Lamers. Molecular forms of cholecystokinin in human plasma during infusion of bombesin. Life Sci 33: 2197-2205, 1983. 16. Jensen, R. T.. T. Moody, C. Pert. J. E. Rivier and J. D. Gardner. Interaction of Bombesin and litorin with specific receptors on pancreatic acinar cells. Pr, c .Vatl Acad Sci USA 75: 61396143. 1978. 17. Makhlouf. G. M. Hormones and neuropeptides of the gut. In: 771e Gastroetlterology Anmtal. edited by F. Kern and A. L. Blum. Amsterdam: Elsevier Science Publishers. 1983. pp. 181197. 18. Mayer, E. A.. J. Elashoffand J. H. Walsh. Characterization of bombesin effects on canine gastric muscle. Am .I Physiol 243: GI41-GI47, 1982. 19. Polak, J. M., S. R. Bloom, S. Hobbs. E. Solcia. Distribution of a bombesin like peptide in human gastrointestinal tract. Ltmcct I: 1109-1110. 1976. 20. Salera, M., P. Giacomoni, L. E. Hanssen, L. Pironi. M. Capelli. M. Miglioli and L. Barbara. Effect of bombesin on fasting and glucose-stimulated gastric inhibitory polypeptide (GIP) release in man. ltal J Gastroenterol 15: 241-245. 1983. 21. Scarpignato, C.. B. Micali, F. Vitulo, G. Zimbaro and G. Bertaccini. Inhibition of gastric emptying by bombe,,in in man. Dige,stion 23: 128-131, 1982. 22. Severi, C., S. Bellentani, B. Annibale, A, Grisendi, F. Fregni. R. Bruzzone. V. Corleto. L. de Magistris and G. Delle Fave. Effects of bombesin on plasma tripsin-like immunoreactivity in normal subjects and in patients with and without pancreatic steatorrhea. Ital J Gastroenter, I 15: 132-134, 1983. 23. Swope, S. L. and A. Schonbrum. Bombesin stimulates insulin secretion by a pancreatic islet cell line. Proc Natl Acad St'i USA 81: 1822-1826. 1984. 24. Yanaihara, N.. C. Yanaihara. T. Mochizuki. K. lwahaza, T. Fujita and T. lwanga. Immunoreactive GRP. Pcptides 2: 185191. 1981.