I',.ptidc~. Vol. 6. Suppl. 3. pp. 69-73. 1"~-5. Ankho lnternationld Inc. Printed in the U.S.A. 0196-9781,85 $3.00 + .t)0 Intracisternal Bombesin Induced Inhibition of Gastric Secretion Is Not Mediated Through Prostaglandin or Opioid Pathways YVETTE TACHI~ Center fi~r Uh'er am/Edltcation, VA Wadsworth Medical Center Univer.~itv ~[" Califi~rnia. School of Medicine. Los Angeles, CA 90073 TACHI~. Y. Intracisternal hombesin induced inhibition of gasoqc secretion is not mediated through prostaglamlin or opi, id pathway.~. PEP'IIDES 6: Suppl. 3.69-73. 1985.--Neuromedin B, a mammalian decapeptide which shares homol- ogy w,m the carboxyl terminal fragment of ranatensin R and bombesin, injected intracisternally (880 pmol) did not modify gastric acid secretion stimulated either by pylorus ligation in conscious rats or by pentagastrin infusion in urethane- anesthetized rats. lntracisternal bombesin (300 pmol) further enhanced PGE2-induced inhibition of gastric acid secretion and suppressed prostaglandin-induced stimulation of gastric secretory volume. Gastric response to intracisternal bombesin was not modified by indomethacin (10 mg/kg) or naloxone pretreatment (5 mg/kg). These results suggest that prostaglandin and opiate pathways are not mediating the inhibitory effect of intracisternal bombesin on gastric secretion and that neuromedin B does not mimic the central action of bombesin to inhibit gastric acid secretion. Neuromedin B Bombesin Acid secretion Prostaglandin Naloxone Central action of bombesin BOMBESIN is a tetradecapeptide originally isolated from amphibian skin [3]. Mammalian bombesin-like peptides have been characterized from porcine and canine gastrointestinal tracts [l 1,22], porcine spinal cord [15] and recently from a human pulmonary carcinoid tumor [19]. The peptides exist in multiple molecular forms of 27 (gastrin-releasing peptide, GRP) and l0 (GRP-10) amino acids which share carboxyl terminal decapeptide homology with bombesin except for Gin/His interchange in position 7 [11, 15, 19, 22]. The analysis of the gene encoding members of the bombesin-like peptides has allowed the characterization of cDNAs corre- sponding to mRNAs encoding a 148 amino acid precursor of human GRP [25]. Bombesin-like peptides are widely dis- tributed throughout the central nervous sytem and gastroin- testinal tract [5,24]. Recently Minamino et al. characterized from porcine spinal cord a decapeptide named neuromedin B which shares 7 residues homology with the carboxyl terminal decapeptide fragment of bombesin [14]. The content of im- munoreactive neuromedin B in the rat brain was reported to be 2-6 times higher than that of GRP-10 [16]. Bombesin or GRP exert similar wide spectrum of central or peripheral biological effects [7.32]. In particular, bombesin or GRP injected in the cerebrospinal fluid of rats, cats and dogs, or in specific rat hypothalamic nuclei, inhibits gastric secretion through central nervous system mediated action [30]. The neurohumoral pathways subserving the propaga- tion of bombesin inhibitory effect from the brain to the stomach have not been fully elucidated. Evidence has been presented before that, in rats, bombesin action is not mod- ified by pharmacological manipulations designed to interfere with brain catecholaminergic, dopaminergic, or seroto- ninergic system or by hypophysectomy [29], adrenalectomy or vagotomy [20, 26, 31] and is partly reversed by spinal cord transection [31]. The biological activity of neuromedin B has not been studied in vivo [14]. In the present study, we eval- uated in rats whether the recently characterized bombesin- like peptide, neuromedin B, shares the same central action as bombesin to inhibit gastric secretion, and we further in- vestigated mechanisms mediating the antisecretory effect of bombesin by assessing possible interactions with prosta- glandin and opioid pathways. METHOD Animals Male Sprague Dawley rats, weighing 250-300 g were maintained ad lib on Purina Laboratory Chow and tap water. They were housed under conditions of controlled tempera- ture (72_+2°F) and lighting (from 6:00 a.m. to 6:00 p.m.). All the experiments were performed in rats deprived of food for ~Requests for reprints should be addressed to Yvette Tach6, Ph.D., CURE/VA Wadsworth, Building 115, Room 203, Los Angeles, CA 90073. 69
Transcript
I',.ptidc~. Vol. 6. Suppl. 3. pp. 69-73. 1"~-5. Ankho lnternationld Inc. Printed in the U.S.A. 0196-9781,85 $3.00 + .t)0
Intracisternal Bombesin Induced Inhibition of Gastric Secretion
Is Not Mediated Through Prostaglandin or Opioid Pathways
Y V E T T E TACHI~
Center fi~r Uh'er am/Edl tcat ion , VA Wadsworth Medical Center Univer.~itv ~[" Califi~rnia. School o f Medicine. Los Angeles, CA 90073
TACHI~. Y. Intracisternal hombesin induced inhibition of gasoqc secretion is not mediated through prostaglamlin or opi, id pathway.~. PEP'IIDES 6: Suppl. 3.69-73. 1985.--Neuromedin B, a mammalian decapeptide which shares homol- ogy w,m the carboxyl terminal fragment of ranatensin R and bombesin, injected intracisternally (880 pmol) did not modify gastric acid secretion stimulated either by pylorus ligation in conscious rats or by pentagastrin infusion in urethane- anesthetized rats. lntracisternal bombesin (300 pmol) further enhanced PGE2-induced inhibition of gastric acid secretion and suppressed prostaglandin-induced stimulation of gastric secretory volume. Gastric response to intracisternal bombesin was not modified by indomethacin (10 mg/kg) or naloxone pretreatment (5 mg/kg). These results suggest that prostaglandin and opiate pathways are not mediating the inhibitory effect of intracisternal bombesin on gastric secretion and that neuromedin B does not mimic the central action of bombesin to inhibit gastric acid secretion.
Neuromedin B Bombesin Acid secretion Prostaglandin Naloxone Central action of bombesin
BOMBESIN is a te t radecapept ide originally isolated from amphibian skin [3]. Mammalian bombesin-like peptides have been characterized from porcine and canine gastrointestinal tracts [l 1,22], porcine spinal cord [15] and recently from a human pulmonary carcinoid tumor [19]. The peptides exist in multiple molecular forms of 27 (gastrin-releasing peptide, GRP) and l0 (GRP-10) amino acids which share carboxyl terminal decapeptide homology with bombesin except for Gin/His interchange in position 7 [11, 15, 19, 22]. The analysis of the gene encoding members of the bombesin-l ike peptides has allowed the characterizat ion of cDNAs corre- sponding to mRNAs encoding a 148 amino acid precursor of human GRP [25]. Bombesin-like peptides are widely dis- tributed throughout the central nervous sytem and gastroin- testinal tract [5,24]. Recently Minamino et al. character ized from porcine spinal cord a decapept ide named neuromedin B which shares 7 residues homology with the carboxyl terminal decapeptide fragment of bombesin [14]. The content of im- munoreactive neuromedin B in the rat brain was reported to be 2-6 times higher than that of GRP-10 [16].
Bombesin or GRP exert similar wide spectrum of central or peripheral biological effects [7.32]. In particular, bombesin or GRP injected in the cerebrospinal fluid of rats, cats and dogs, or in specific rat hypothalamic nuclei, inhibits gastric secretion through central nervous system mediated action
[30]. The neurohumoral pathways subserving the propaga- tion of bombesin inhibitory effect from the brain to the stomach have not been fully elucidated. Evidence has been presented before that, in rats, bombesin action is not mod- ified by pharmacological manipulations designed to interfere with brain catecholaminergic, dopaminergic, or seroto- ninergic system or by hypophysectomy [29], adrenalectomy or vagotomy [20, 26, 31] and is partly reversed by spinal cord transection [31]. The biological activity of neuromedin B has not been studied in vivo [14]. In the present study, we eval- uated in rats whether the recently characterized bombesin- like peptide, neuromedin B, shares the same central action as bombesin to inhibit gastric secretion, and we further in- vestigated mechanisms mediating the antisecretory effect of bombesin by assessing possible interactions with prosta- glandin and opioid pathways.
METHOD
Animals
Male Sprague Dawley rats, weighing 250-300 g were maintained ad lib on Purina Laboratory Chow and tap water. They were housed under conditions of controlled tempera- ture (72_+2°F) and lighting (from 6:00 a.m. to 6:00 p.m.). All the experiments were performed in rats deprived of food for
~Requests for reprints should be addressed to Yvette Tach6, Ph.D., CURE/VA Wadsworth, Building 115, Room 203, Los Angeles, CA 90073.
69
70 TA C H 1~
TABLE 1 EFFECT OF NEUROMEDIN B ON GASTRIC SECRETION IN
*Twenty-four-hr-fasted rats under light ether anesthesia were in- jected mtracisternally either with saline ( 10 p.I) or neuromedin B (880 pmol/10 tzl). then the pylorus was ligated. Two hours later, the animals were decapitated and gastric secretion collected.
"~Mean +-- SEM (6 rats per group).
24 hr but having free access to water up to the beginning of experiments.
Meast.'e.lents of Gastric Secretion
Pylor.s ligation. Laparotomy and pylorus ligation were performed under light ether anesthesia, with the animals re- gaining the righting reflex 5-10 min after the operation. The rats, who were all conscious, were decapitated 2 hr after pylorus iigation. The stomachs were removed, the gastric contents were collected and centrifuged. The volume and pH of gastric secretion were measured and concentration of acid was determined by titration with 0.1 M NaOH to pH 7.0 on an automatic titrator.
Ac.te gastric fistula. In rats that were under ether anesthesia (1.25 g/kg, IP) for the duration of the experiment, a cannula was inserted in the trachea, and the esophagus was ligated at this level, sparing the vagi. The abdomen was then opened, the pylorus ligated, and a double-lumen cannula was placed through a small incision in the forestomach. The lumen was flushed twice with two 5-ml boluses of 0.15 M NaCI and with one 5-ml bolus of air at the end of each 10-rain period. Acid output was determinated by titration of the flushed perfusate with 0.1 M NaOH to pH 7.0.
Drttg Injections
Bombesin (supplied by Dr. J. Rivier. the Salk Institute. La Jolla. CA) and neuromedin B (Peninsula Lab. Inc.. Bel- mont. CA), in lyophilized form were freshly dissolved in saline before each experiment and injected intracisternally in 10 tzl volume. Pentagastrin solution (Peptavlon Ayerst Lab.. New York, NY) was diluted in saline and infused into the femoral vein at a rate of 1.5 ml/hr through polyethylene tub- ing. Indomethacin (Sigma Chem. Co, St. Louis, MO) was suspended in corn oil and injected subcutaneously in a vol- ume of 0.2 ml, Prostaglandin E2 (Upjohn Co. Kalamazoo, MI) in powder form was dissolved in I% sodium bicarbonate and given by gavage in 1 ml volume. Naloxone hydrochlo- ride solution (Narean, Endo Pharmaceuticals. Inc., Manati, Puerto Rico) was diluted in saline and injected intraperito- neally.
Statistics
T h e s ta t i s t i ca l p r o b a b i l i t i e s w e r e c a l c u l a t e d by o n e - w a y a n a l y s i s o f v a r i a n c e s o r S t u d e n t ' s t - t e s t .
c
O
el
o o
u~ ,¢ (3
20~ 16-"
14-
12-~ i
10- I
8~
6"
Saline or Neuromedin
i.c.
~ -entagatrin 16pg kg-,h-, i.v.J
~--~ Neuromedin B (4)
T[/ Saline (4)
B
/
2-- ~- - . ~ - 41-" 4 " - ' t " ~ T
6 Jo TIME (min)
6'0 9~0
FIG. 1. Effect of intracisternal tiC) injection of neuromedin B (880 pmol) on pentagastrin-stimulated gastric acid output in urethane- anesthetized rats with gastric fistula. Each point represents the mean- -SEM of 4 rats.
iPH
\ \
F'x\ / ," F'x \ / ' / \ \
/ / " , . \
/ / N \ / / x. \
/ / \ . \ f I N \
Volume (ml) 12-
i i s-
4"
O
Acid concentration mmol/I
40
O
FIG. 2. Effect of intracisternal injection of bombesin and per oral administration of prostaglandin E2 given alone or in combination, on gastric acid secretion in conscious pylorus ligated rats. Under light ether anesthesia, rats were injected intracisternally ~i th saline (10 ~1) or bombesin 1300 pmol/10 gl). then the pylorus ~as ligated and vehicle 1 ! ml) or PGE2 (400 gg/I ml) ~as administered per garage. Two hours later the animals were decapitated for collection of gas- tric secretion. Each column represents the m e a n = S E M of 5 rats.
F• Vehicle+Saline
[ ~ PGE2+Saline
[ ~ Vehicle+Bombesin
[ ~ PGE2+Bombesin
RESULTS
P~(/i'ct ,if" Intracistermd Ii!jcction q f Nettromcdhl B on GaMric Acid Secretion
Pyl,,r,s li.vah'd ra t s . In c o n s c i o u s p y l o r u s - l i g a t e d ra ts .
C E N T R A L B O M B E S I N A N D I N H I B I T I O N O F ACID S E C R E T I O N 71
T A B L E 2
EFFECTS OF INDOMETHACIN PRETREATMENT ON BOMBESIN INDUCED INHIBITION OF GASTRIC SECRETION IN PYLORUS-LIGATED RATS
*Twenty-four-hr-fasted rats were pretreated with vehicle 10.2 ml corn oil SC) or in- domethacin ( 10 mg/kg, in suspension in corn oil, SC) I hr prior to intracisternal injection of bombesin (300 pmol), and pylorus ligation performed under light ether anesthesia. Two hours after pylorus ligation, conscious rats were decapitated.
+Mean ± SEM: -p<0.01 as compared to their respective control. - -no t measured.
T A B L E 3
EFFECT OF NALOXONE PRETREATMENT ON BOMBESIN INDUCED INHIBITION OF GASTRIC ACID SECRETION IN PYLORUS-LIGATED RATS
*Tv, enty-four-hr-fasted rats were pretreated with saline (0.5 ml, IP) or naloxone (5 mg/kg. IP) 30 min prior to intracisternal injection of bombesin (300 pmol) and pylorus ligation performed under light ether anesthesia. Two hours later, conscious rats were decapitated.
+Mean ± SEM: -p<0.01 as compared with their respective control.
gas t r ic acid ou tpu t fo l lowing in t rac is te rna l in jec t ion of con- trol sal ine solut ion ~vas 314--101 /zmol/2 hr. In t rac i s te rna l in jec t ion of I /zg (880 pmol) dose of n e u r o m e d i n B did not s ignif icant ly modify gast r ic sec re to ry r e sponse to py lorus l igat ion (Table 1).
A c , t c gastr icf is t tda rats. U r e t h a n e - a n e s t h e t i z e d , gas t r ic f is tula rats have low basal acid secre t ion , bu t fol lowing in- t r a v e n o u s infusion o f pen tagas t r in , acid sec re t ion was in- c r ea sed to reach a p la teau wi th in 60 rain. In t rac i s te rna l in- j e c t i o n of n e u r o m e d i n B (880 pmol) did not s ignif icant ly modify gastr ic r e s p o n s e to pen tagas t r in (Fig. 1).
L{fect~ o f Bombesin a m / P G E 2 Given A/one or in ( 'omhimtt ion on Gastric Ac id Secretion
P G E 2 (400/zg) g iven per gavage in pylorus ligated rats s ignif icant ly inc reased the vo lume of gastr ic secre t ion and r educed by 27% the c o n c e n t r a t i o n of acid: gas t r ic pH values
were not s ignif icant ly modif ied , l n t r ac i s t e rna l in jec t ion of bombes in (300 pmol) g iven a lone or in c o m b i n a t i o n wi th PGE2 signif icant ly e l eva t ed gast r ic pH to 6.31-+0.54 and 5.81 ±0.61 respect ively, suppressed gastr ic vo lume and inhib- ited a lmost complete ly the concen t r a t ion of acid (Fig. 2).
El.feel o f lmlomathacin and Nabs.wine on ln tracis termd Bomhesin Induced Inhibition o.f Gastric Secretion
I n d o m e t h a c i n (10 mg/kg) or n a l o x o n e (5 mg/kg) p re t rea t - ment did not s ignif icant ly modify gas t r ic s ec re t ion in py lorus l igated rats nor the inh ib i to ry effect o f i n t r ac i s t e rna l b o m b e - sin (300 pmol) (Tables 2 and 3).
DISCUSSION
In t rac i s te rna l or i n t r a c e r e b r o v e n t r i c u l a r in jec t ion of b o m b e s i n po ten t ly inh ib i ted gast r ic acid sec re t ion in con-
72
scious or anesthetized rats ([30], present observation). The mammalian bombesin-like peptide, GRP, or the fragment acetyl-GRP-(20-27) injected into the cerebrospinal fluid were also reported to inhibit gastric acid secretion [6,27]. By con- trast intracisternal injection of neuromedin B did not modify gastric acid secretion stimulated either by pylorus ligation in conscious rats or by pentagastrin in urethane-anesthetized rats. Neuromedin B was reported to display only 5% of bombesin potency on isolated rat uterus preparation [15]. These results further emphasize previous structure-activity studies with bombesin/GRP-like peptides demonstrating that the expression of the full biological activity required the in- tact carboxyl terminal nona- or octapeptide fragment [4, 9, 12, 27]. Neuromedin B shares similarity with bombesin/GRP carboxyl-terminal decapeptide except three amino acid sub- stitutions in position 2, 5 and 8 from C-terminal [14] and a complete homology with C-terminal nonapeptide fragment of ranatensin R except substitution in the position 8 [7]. Al- though neuromedin B was described as the major endoge- nous bombesin-like peptide in rat brain [16], this and another study [15] indicate that the peptide displays different spec- trum of biological activity as compared to previously charac- terized mammalian bombesin-like peptides. Since the pep- tide appears more structurally related to ranatensin R, it is probably acting on distinct brain receptors to elicited central biological actions which remain to be elucidated.
The neurohumoral mechanisms through which intracisternal bombesin exerts its potent and long lasting in- hibitory effect on gastric acid secretion is not yet fully un- derstood. We previously reported that changes in the release of gastrin, pituitary- or adrenal-derived substances or vagal activity are not primarily involved in mediating bombesin inhibitor,,' effect in rats and dogs [20, 26-31]. Prostaglandins act centrally and peripherally to inhibit gastric acid secretion [21,23]. Some biological actions of neuropeptides could be exerted through interactions with prostaglandin pathways [8,
TACH 1-.
10, 13], although conflicting data have been reported, par-- ticularly regarding prostaglandin mediation of the inhibition of gastric acid secretion by somatostatin [2, 10, 17]. Our studies demonstrated that prostaglandins are not implicated in bombesin induced inhibition of gastric secretion. First. the gastric inhibitory response to prostaglandin E2 did not mimic the effect of bombesin. Although the concentration of acid was decreased by both bombesin and PGE2, the volume of secretion was increased by PGE2 and inhibited by bombe.,,in given alone or in combination with prostaglandin. Secondl.~. indomethacin pretreatment, administered at dose reported to inhibit prostaglandin synthesis in both the periphery organs and the brain tissues [1], did not modify gastric response to intracisternal bombesin. Another approach was to evaluate ,~ possible interaction with opiates since the opioid peptides are known to act centrally to inhibit gastric acid secretion [18,26]. The lack of modification of bombesin action b~ naloxone pretreatment indicates that opiate and bombesin effects are mediated through different pathways.
In summary, neuromedin B. a peptide which is found in high concentration in rat brain and shares some homol%3 with the carboxyl decapeptide fragment of bombesin and more striking homology with ranatensin R, did not mimic intracisternal bombesin/GRP induced inhibition of gastric secretion. Furthermore, central action of bombesin on gastric secretion appears independent from prostaglandin or opioid pathways.
ACKNOWLEDGEMENTS
The authors thank Mrs. G. Samuel for her excellent techni,:.d assistance as well as Miss S. Heil and A. Starlight for helping in the preparation of the manuscript. This work was supported by the Med- ical Research Council of Canada (Grant MA 6836) and the NationA Institutes of Health NIHDDK (Grant AM 30110). Dr. J. Rivier ~, greatly acknowledged for supplying bombesin.
R E F E R E N C E S
1. Abolel-Halin. M. S.. B. Sjoquist and E. Angord. Inhibition of prostaglandin synthesis in rat brain. Acta Pharmacol Toxic,I (C,,pcnhJ 43: 266--272. 1978.
2. Albinus. M., A. Gomez-Pan, B. Hirst and B. Shaw. Evidence against prostaglandin-mediation of somatostatin-inhibition of gastric secretions. R(,gtd Pept 10: 259-266, 1985.
3. Anastasi. A., V. Erspamer and M. Bucci. Isolation and struc- ture of bombesin and alytensin, two analogous active peptides from the skin of European amphibians. Bombia and Alyts. Ex- percntia 27: 166-167. 1971.
4. Broccardo, M., G. F. Erspamer, P. Melchiorri. L. Negri and R. DeCastiglione. Relative potency of bombesin-like peptides. Br./ Pharmacol 55: 221-227, 1975.
5. Buffa. R.. 1. Solovieva. R. Fiocca. S. Giorgino. G. Rindi, E. Solcia. T. Mochizuchi. C. Yanaihara and N. Yanaihara. Lo- calization of bombesin and GRP (gastrin releasing peptide) se- quences in gut nerves and endocrine cells. Histochemist,3" 77: 457-467. 1982.
6. Dubrasquet, M.. C. Roze, N. Ling and H. Florencio. Inhibition of gastric and pancreatic secretions by cerebroventricular injec- tions of gastrin-releasing peptide and bombesin in rats. Regtd Pcpt 3:105-112, 1982.
7. Erspamer. V. and P. Melchiorri. Actions of amphibian skin peptides on the central nervous system and the anterior pitui- tar). In: N('ttroe/t~b,('rine Perspective.~. vol 2. edited by E. M/.il- ler and R. MacLeod. Amsterdam: Elsevier Science Publishers, 1983. pp. 37-106.
8. Fargeas. M.. J. Fioramonti and L. Bueno. Prostaglandin E: -~ neuromodulator in the central control of gastrointestinal motil- ity and feeding behavior by calcitonin. Scit'm'e 225: 1050-105'.. 1984.
9. Girard. F.. H. Bachelard. S. St. Pierre and F. Rioux. The co=- tractile effect of bombesin, gastrin releasing peptide and varieu, fragments in the rat stomach strip. Eur .I Pharmacol 102: 4~- 497. 1984.
10. Ligumsky. M.. Y. Goto. H. Debas and T. Yamada. Prostagl,:n- dins mediate inhibition of gastric acid secretion by somatosta:?l in the rat. Science 219: 301-303. 1983.
II. McDonald. T. J.. H. Jornvall. G. Nilsson. M. Vagnc. \ I Ghatei. S. R. Bloom and V. Mutt. Characterization of a gastr:n releasing peptide from porcine non-antral gastric tissue Bioclwm Biophy.~ Rc.~ ('omnltm 90: 227-233, 1979.
12. Marki, W.. M. Brown and J. E. Rivier. Bombesin analogs: Ef- fects on thermoregulation and glucose metabolism. Peptidc, 2: Suppl 2. 169-177, 1981.
13. Mason. G.. D. Hernandez. C. Nemeroff. J. Adcock. O. Haflc.~ and A. Prange. Interaction of neurotensin with prostaglandin [: and prostaglandin synthesis inhibitors: effects on colonic tem- perature in mice. Regul Pept 4: 285-29~. 1982.
14. Minamino. N.. K. Kangawa and H. Matsuo. Neuromedin B. ~ nosel bombesin-like peptide identified in porcine spinal curd Bi,~t ht,m Biopltys Rt, s ('omm/ttl I 14: 541-548. 1983.
C E N T R A L B O M B E S I N A N D I N H I B I T I O N O F A C I D S E C R E T I O N 73
15. Minamino, N., K. Kangawa and H. Matsuo. Neuromedin C: a bombesin-like peptide identified in porcine spinal cord. Biochcm Biophy.~ Rc.~ Commtm 119: 14-20, 1984.
16. Minamino, N.. K. Kangawa and H. Matsuo. Neuromedin B is a maior bombesin-like peptide in rat brain: regional distribution of neuromedin B and neuromedin C in rat brain pituitar~ and spi- nal cord. Biochem Biophys Re.~ Contlnlllt 124: 925-932. 1984.
17. Mogard, M., G. Kauffman, M. Pehlevanian. E. Golanska. J. Elashoff and J. Walsh. Prostaglandins may not mediate inhibi- tion of gastric acid secretion by somatostatin in the rat. Regttl Pept 10: 231-236. 1985.
18. Morley, J., A. Levine and S. Silvis. Endogenous opiates inhibit gastric acid secretion induced by central administration of thyrotropin-releasing hormone (TRH). Liih" Sci 29: _93-_97. 1981.
19. Orloff. M., J. Reeve. C. M. Ben-Avram, J. Shivel~ and J. H. Walsh. Isolation and sequence analysis of human bombesin-like peptides. Peptides 5: 865-870. 1984.
20. Pappas, T., D. Hamel. H. Debas. J. Walsh and Y. TachS. Cere- broventricular bombesin inhibits gastric acid secretion in dogs. Ga~'tr,,enter, do.ey 89: 43-48, 1985.
21. Puurunen, J. Inhibition of gastric acid secretion by intracere- broventricularly administered prostaglandin E., in anesthetized rats. Br .I Pharmac, d 78: 131-135, 1983.
22. Reeve. J. R., J. H, Walsh, P. Chew, B. Clark, D. Haw ke and J. E. Shively. Amino acid sequences of three bombesin-like pep- tides from canine intestine extracts . . I Bi, d Chem 258: 5582- 5588. 1983.
23. Robert. A., J. Schultz. J. Nezamis and C. Lancaster. Gastric antisecretory and antiulcer properties of PGE._,, 15-meth.x I PGE.., and 16.16 dimethyl PGE.,. Intravenous. oral and intrajejunal administration. Ga.str, wnterolo,,,y 70: 359-370, 1976.
24. Roth. K.. E. Weber and J. Barchas. Distribution of gastrin re- leasing peptide-bombesin-like immunostaining in rat brain. Braio Res 251: 277-282. 1982.
25. Spindel, E., W. Chin. J. Price. L. Rees, G. Besser and J. Habener. Cloning and characterization of cDNAs, encoding human gastrin-releasing peptide. Pr, J< Nail Acad Sci USA 81: 5699-5703. 1984.
26. Tach& Y., W. Vale. J. Rivier and M. Brown. Brain regulation of gastric secretion: influence of neuropeptides. Proc Natl Acad St'i USA 77: 5515-5519. 1980.
27. Tachr, Y.. W. Marki. J. Rivier, W. Vale and M. Brown. Central nervous system inhibition of gastric secretion in the rat by gastrin releasing-peptide, a mammalian bombesin. Gastroen- terology 81: 298--302. 1981.
28. TachS. Y. Bombesin: Central nervous system action to increase gastric mucus in rats. Gastroenterology 83: 75-80, 1982.
29. TachS, Y. and R. Collu. CNS mediated inhibition of gastric secretion by bombesin: independence from interaction with brain catecholaminergic and serotoninergic pathways and pitui- tary hormones. Regul Pcpt 3:51-59. 1982.
30. Tach,L Y. and M. Gunion. Central nervous system action of bombesin to inhibit gastric acid secretion. Ltlh" Sci 37: 115-123, 1985.
31. Tachr, Y.. D. Lesiege and Y. Goto. Neural pathways involved in intracisternal bombesin induced inhibition of gastric secretion in rats. Dig Dis Sci 30: 402-406° 1985.
32. Walsh, J. Bombesin-like peptides. In: Brain Peptides, edited by D. Krieger. M. Brox~nstein and J. Martin. New York: John Wiley & Sons, Inc.. 1983. pp. 942-960.
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