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Pentadecapeptide BPC 157 Interactions with Adrenergic and Dopaminergic Systems in Mucosal Protection in Stress

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Abstract

Since superior protection against differentgastrointestinal and liver lesions and antiinflammatoryand analgesic activities were noted for pentadecapeptideBPC (an essential fragment of an organoprotective gastric juice protein named BPC), thebeneficial mechanism of BPC 157 and its likelyinteractions with other systems were studied. Hence itsbeneficial effects would be abolished by adrenal glandmedullectomy, the influence of different agents affectingα, β, and dopamine receptors on BPC 157gastroprotection in 48 h restraint stress was furtherinvestigated. Animals were pretreated (1 hr beforestress) with saline (controls) or BPC 157 (dissolved insaline) (10 μg or 10 ng/kg body wt intraperitoneallyor intragastrically) applied either alone to establishbasal conditions or, when manipulating the adrenergic or dopaminergic system, a simultaneousadministration was carried out with various agents withspecific effects on adrenergic or dopaminergic receptors[given in milligrams per kilogram intraperitoneally except for atenolol, which was givensubcutaneously] phentolamine (10.0), prazosin (0.5),yohimbine (5.0), clonidine (0.1) (α-adrenergicdomain), propranolol (1.0), atenolol (20.0)(β-adrenergic domain), domperidone (5.0), and haloperidol(5.0) (peripheral/central dopamine system).Alternatively, agents stimulating adrenergic ordopaminergic systemsadrenaline (5.0) or bromocriptine(10.0)-were applied. A strong protection, noted followingintragastric or intraperitoneal administration of BPC157, was fully abolished by coadministration ofphentolamine, clonidine, and haloperidol, andconsistently not affected by prazosin, yohimbine, ordomperidone. Atenolol abolished only intraperitoneal BPC157 protection, whereas propranolol affectedspecifically intragastric BPC 157 protection.Interestingly, the severe course of lesion developmentobtained in basal conditions, unlike BPC 157gastroprotection, was not influenced by the applicationof these agents. In other experiments, when adrenalineand bromocriptine were given simultaneously, a strong reductionof lesion development was noted. However, when appliedseparately, only adrenaline, not bromocriptine, has aprotective effect. Thus, a complex protectiveinteraction with both α-adrenergic (e.g.,catecholamine release) and dopaminergic (central)systems could be suggested for both intragastric andintraperitoneal BPC 157 administration. The involvementof β-receptor stimulation in BPC 157 gastroprotection appearsto be related to the route of BPC 157 administration.The demonstration that a combined stimulation ofadrenergic and dopaminergic systems by simultaneous prophylactic application of adrenaline(α- and β-receptor stimulant) andbromocriptine (dopamine receptor agonist) maysignificantly reduce restraint stress lesionsdevelopment provides insight for further research on the beneficial mechanism ofBPC 157.

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REFERENCES

  1. Guglietta A: Possible clinical use of peptide growth factors in the GI tract: Perspectives and obstacles. Exp Clin Gastroenterol 3:1–6, 1993

    Google Scholar 

  2. Thompson JC, Greeley GH, Rayford PL, Townsend CM: Gastrointestinal Endocrinology. New York, McGraw-Hill, 1987

    Google Scholar 

  3. Sikiric P, Petek M, Rucman R, Seiwerth S, Grabarevic Z, Rotkvic I, Jagic V, Mildner B, Duvnjak M, Lang N: A new gastric juice peptide, BPC—an overview of stomach/stress/organoprotection hypothesis and BPC beneficial effects. J Physiol (Paris) 87:313–327, 1993

    Google Scholar 

  4. Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Rotkvic I, Turkovic B, Jagic V, Mildner M, Duvnjak M, Danilovic Z: Hepatoprotective effect of BPC 157, a 15-amino acid peptide, on liver lesions induced by either restraint stress or bile duct and hepatic artery ligation or CCl4 administration. A comparative study with dopamine agonists and somatostatin. Life Sci, 53:PL 291–PL 296, 1993

    Google Scholar 

  5. Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Rotkvic I, Turkovic B, Udovicic I, Jagic V, Mildner B, Duvnjak M, Danilovic Z: The effect of pentadecapeptide BPC 157 on inflammatory, non-inflammatory, direct and indirect pain and capsaicin neurotoxicity. Inflammopharmacology 2:121–127, 1993

    Google Scholar 

  6. Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Turkovic B, Rotkvic I, Jagic V, Duvnjak M, Mise S, Djacic S, Separovic J, Veljaca M, Sallmani A, Banic M, Brkic T: The beneficial effect of BPC 157, a 15 amino acid peptide BPC fragment, on gastric and duodenal lesions induced by restraint stress, cysteamine and 96% ethanol in rats. A comparative study with H2 receptor antagonists, dopamine promotors and gut peptides. Life Sci 54:PL63–PL68, 1994

    Google Scholar 

  7. Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V, Turkovic B, Rotkvic I, Mise S, Zoricic I, Gjurasin M, Konjevoda P, Separovic J, Ljubanovic D, Artukovic B, Bratulic M, Tisljar M, Jurina Lj, Buljat G, Miklic P, Marovic A: The beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin and capsaicin neurotoxicity. Dig Dis Sci 41:1604–1614, 1996

    Google Scholar 

  8. Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V, Turkovic B, Rotkvic I, Mise S, Zoricic I, Jurina LJ, Konjevoda P, Hanzevacki M, Ljubanovic D, Separovic J, Gjuasin M, Bratulic M, Artukovic B, Jelovac N, Buljat G: Salutary and prophylactic effect of pentadecapeptide BPC 157 on acute pancreatitis and concomitant gastroduodenal lesions in rats. Dig Dis Sci 41:1518–1526, 1996

    Google Scholar 

  9. Sikiric P, Mikus D, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V, Turkovic B, Rotkvic I, Mise S, Zoricic I, Peric J, Konjevoda P, Perovic D, Jurina LJ, Hanzevacki M, Separovic J, Gjurasin M, Jadrijevic S, Jelovac N, Miklic P, Buljat G, Marovic A: Pentadecapeptide BPC 157, cimetidine, ranitidine, bromocriptine, and atropine effect in cysteamine lesions in totally gastrectomized rats. A model for cytoprotective studies. Dig Dis Sci 1997 (in press)

  10. Sikiric P, Mikus D, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V, Turkovic B, Rotkvic I, Mise S, Zoricic I, Konjevoda P, Perovic D, Simicevic V, Separovic J, Hanzevacki M, Ljubanovic D, Artukovic B, Bratulic M, Tisljar M, Rekic B, Gurasin M, Miklic P, Buljat G: Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agents-induced gastrointestinal lesions and adjuvant arthritis in rats. J Physiol (Paris), 1997 (in press)

  11. Grabarevic Z, Tisljar M, Artukovic B, Bratulic M, Dzaja P, Seiwerth S, Sikiric P, Peric J, Geres D, Kos J: The influence of BPC 157 on nitric-oxyde agonists and antagonist induced lesions in broiler chicks. J Physiol (Paris), 1997 (in press)

  12. Paré W, Klucyznski JM: The effect of new gastric juice peptide BPC on classic stress triad in stress procedure. Exp Clin Gastroenterol 2:234–236, 1992

    Google Scholar 

  13. Veljaca M, Pllana R, Lesch CA, Sanchez B, Chan K, Guglietta A: Protective effect of BPC 157 on a rat model of colitis. Gastroenterology 106:789, 1994

    Google Scholar 

  14. Veljaca M, Lech CA, Pllana R, Sanchez B, Chan K, Guglietta A: BPC-15 reduces trinitrobenzene sulfonic acid-induced colonic damage in rats. J Pharmacol Exp Ther 272:417–422, 1994

    Google Scholar 

  15. Veljaca M, Lesch CA, Sanchez B, Low J, Guglietta A: Protection of BPC-15 on TNBS-induced colitis in rats: Possible mechanisms of action. Gastroenterology 108:936, 1995

    Google Scholar 

  16. Bosnjak ZJ, Graf BM, Sikiric P, Stowe DF: Protective effects of newly isolated gastric peptide following hypoxic and reoxygenation injury in the isolated guinea pig heart. FASEB J 8:A129, 1994

    Google Scholar 

  17. Sandor Z, Vincze A, Szabo S: The protective effect of a recently isolated gastric peptide in acute and chronic gastroduodenal injury. FASEB J 10:A171, 1996

    Google Scholar 

  18. Veljaca M, Chan K, Guglietta A: Digestion of h-EGF, h-TGF alfa, and BPC 15 in human gastric juice. Pharmacol Res 31:70, 1995

    Google Scholar 

  19. Brkic T, Banic M, Anic B, Grabarevic Z, Rotkvic I, Artukovic B, Duvnjak M, Sikiric P, Troskot B, Hernandez DE: A model of inflammatory bowel disease induced by 2,4-dinitrophlourbenzene in previously sensitized BALB-c mice. Scand J Gastroenterol 27:184–188, 1992

    Google Scholar 

  20. Tache Y, Simard P, Collu R: Prevention by bombesin of coloid-restraint stress induced gastric ulcers in rats. Life Sci 24:1719–1726, 1979

    Google Scholar 

  21. Heiling M, Murison R: Intracerebroventricular neuropeptide Y protects against stress-induced gastric lesions in rat. Eur J Pharmacol 137:127–129, 1987

    Google Scholar 

  22. Szabo S, Usadel KH: Cytoprotection-organoprotection by somatostatin: Gastric and hepatic lesions. Experientia 38:254–256, 1982

    Google Scholar 

  23. Senecic I, Sikiric P, Giljanovic S: The effects of somatostatin on stress-induced gastric lesions in mice. Exp Clin Gastroenterol 1:171–173, 1991

    Google Scholar 

  24. Takeuchi K, Johnson LR: Pentagastrin protects against stress ulceration in rats. Gastroenterology 76:788–792, 1979

    Google Scholar 

  25. Evangelista S, Renzi D, Guzzi P, Maggi CA: Decrease of gastric calcitonin gene related peptide-like immunoreactivity is associated with ulcers induced by water immersion stress in rats. Exp Clin Gastroenterol 1:51–53, 1991

    Google Scholar 

  26. Guth PH, Mecriff JC, Paulsen G: Prevention by glucagon of experimental stress induced hemorrhagic gastritis. Gastroenterology 69:1048–1050, 1975

    Google Scholar 

  27. Evangelista S, Maggi CA: Protection induced by cholecystokinin-8 (CCK-8) in ethanol-induced gastric lesions is mediated via vagal capsaicin-sensitive fibers and CCKA receptors. Br J Pharmacol 102:119–122, 1991

    Google Scholar 

  28. Sikiric P, Rotkvic I, Mise S, Seiwerth S, Grabarevic Z, Petek M, Rucman R, Zjacic-Rotkvic V, Duvnjak M, Jagic V, Suchanek E, Marovic A, Banic M, Brkic T, Hanzevacki M, Separovic J, Djacic S, Simicevic V: Dopamine agents efficacy in peptic ulcer healing and relapse prevention—a further indication for importance of stomach dopamine in the stress organoprotection concept. In Neuroendocrinology of Gastrointestinal Ulceration: Hans Selye Symposia on Neuroendocrinology and Stress, Volume 2. S Szabo, Y, Taché, G Glavin (eds). New York, Plenum Publishing, 1995, pp 221–231

    Google Scholar 

  29. Hernandez DE, Adcock JW, Orlando RC, Patrick KS, Nemeroff CB, Prange AJ: Prevention of stress-induced gastric ulcers by dopamine agonists in rat. Life Sci 35:2453–2458, 1983

    Google Scholar 

  30. Szabo S: Dopamine disorder in duodenal ulceration. Lancet 2:880–882, 1979

    Google Scholar 

  31. Sikiric P, Geber J, Suchanek E, Ivanovic D, Gjuris V, Aleksic J, Reic P, Marovic A: The role of dopamine in the formation of gastric ulcer in rats. Eur J Pharmacol 112:127–128, 1985

    Google Scholar 

  32. Sikiric P, Rotkvic I, Mise S, Seiwerth S, Grabarevic Z, Petek M, Rucman R: Dopamine, PGs and somatostatin in gastric protection in rats. Eur J Pharmacol 183:2026–2027, 1990

    Google Scholar 

  33. Sikiric P, Rotkvic I, Mise S, Krizanac S, Gjuris V, Jukic J, Suchanek E, Petek M, Udovicic I, Kalogjera L, Geber J, Tucan-Foretic M, Duvnjak M, Philipp M, Balen I, Anic T: The influence of dopamine agonists and antagonists on indomethacin lesions in stomach and small intestine in rats. Eur J Pharmacol 158:61–67, 1988

    Google Scholar 

  34. Sikiric P, Geber J, Ivanovic D, Suchanek E, Gjuris V, Tucan-Foretic M, Mise S, Cvitanovic B, Rotkvic I: Dopamine antagonists induce gastric lesions in rats. Eur J Pharmacol 131:105–109, 1986

    Google Scholar 

  35. Sikiric P, Rotkvic I, Mise S, Krizanac S, Suchanek E, Petek M, Gjuris V, Tucan-Foretic M, Udovicic I, Anic T, Balen I: The influence of dopamine agonists and antagonists on gastric lesions in mice. Eur J Pharmacol 144:237–239, 1987

    Google Scholar 

  36. Hernandez DE: Neuroendocrine mechanisms of stress ulceration: Focus on thyrotropin releasing hormone (TRH). Life Sci 39:279–296, 1986

    Google Scholar 

  37. Paré W, Glavin G: Restraint stress in biomedical research: A review. Neurosci Biobehav Rev 10:339–370, 1986

    Google Scholar 

  38. Glavin G, Paré W, Sandbak T, Bakke HK, Murison R: Restraint stress in biomedical research: An update. Neurosci Rev 18:223–249, 1994

    Google Scholar 

  39. Glavin GB, Smyth DD: Effect of the selective I1 imidazoline receptor agonist, moxonidine, on gastric secretion and gastric mucosal injury in rats. Br J Pharmacol 114:751–754, 1995

    Google Scholar 

  40. Kent S, Hurd M, Satinoff E: Phentolamine and thermoregulation in rats. Pharmacol Biooch Behav 40:709–716, 1991

    Google Scholar 

  41. Ray A, Sullivan R, Henke P: Adrenergic modulation of gastric stress pathology in rats: A cholinergic link. J Autonom Nerv System 20:265–268, 1987

    Google Scholar 

  42. Lauva IK, Tomanek RJ: The effects of beta adrenoceptor blockade with atenolol on myocardial cellular and subcellular hypertrophy in spontaneously hypertensive rats. Anat Rec 207:615–622, 1983

    Google Scholar 

  43. Tsou MY, Lui PW, Lee TY, Pan JT, Chan SHH: Differential effects of prazosin and yohimbine on fentanyl-induced muscular rigidity in rats. Neuropharmacology 28:1163–1168, 1989

    Google Scholar 

  44. Sikiric P, Rotkvic I, Seiwerth S, Grabarevic Z, Mise S, Duvnjak M, Artukovic B, Dernikovic K, Dodig M, Djermanovic Z, Senecic I, Giljanovic S, Kalogjera L, Rogina Z, Djaja P, Uglesic M: The differences between dopamine gastric and spleen protection in restraint stress. Dig Dis Sci 35:1040, 1990

    Google Scholar 

  45. Sikiric P, Rotkvic I, Seiwerth S, Grabarevic Z, Duvnjak M, Jagic V, Artukovic B, Djermanovic Z, Dodig M, Senecic I, Giljanovic S, Erceg D, Komericki L, Banic M, Brkic T, Anic T: The differences between dopamine gastric and testis protection in restraint stress. Dig Dis Sci 35:1040, 1990

    Google Scholar 

  46. Robert A, Phillips P, Nezamis JE: Production by restraint of gastric ulcers and of hydrothorax in the rat. Gastroenterology 51:75–81, 1966

    Google Scholar 

  47. Robert A, Nezamis JE, Lancaster C, Badalamenti JN: Cysteamine-induced duodenal ulcers: A new model to test antulcer agents. Digestion 11:199–214, 1974

    Google Scholar 

  48. Abdel-Rehim M, Taha S, Abu-Sitta S, Taymour A, El Fiky M, Ibrahim I: A comparative study on the effects of atropine, cimetidine, sulpiride, chlorpromazine and propranolol on gastric stress ulcer. Egypt J Med Sci 7:11–18, 1986

    Google Scholar 

  49. Kuratani K, Yamazaki M, Kodama H, Yamaguchi I: Possible involvement of hyperinsulinemia and adrenergic activation in the pathogenesis of indomethacin-induced antral ulcers in nonfasted hamsters and refed rats. J Pharmacol Exp Ther 263:951–955, 1992

    Google Scholar 

  50. Kiro A, Zahavi I, Marcus H, Dinari G: L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: possible role of an alpha-2-adrenergic mechanism. Life Sci 51:1151–1156, 1992

    Google Scholar 

  51. Tepperman BL, Whittle BJ: Comparison of the effects of neuropeptide Y and noradrenaline on rat gastric mucosal blood flow and integrity. Br J Pharmacol 102:95–100, 1991

    Google Scholar 

  52. Nakane T, Kanie N, Audhya T, Hollander C: The effects of centrally administered neruopeptides on the development of gastric lesions in rats. Life Sci. 36:1197–1203, 1985

    Google Scholar 

  53. Haeusler G: Activation of the central pathway of the baroreceptor reflex, a possible mechanism of the hypotensive action of clonidine. Naunyn Schmiedebergs Arch Pharmacol 278:231–246, 1973

    Google Scholar 

  54. Starke K: Regulation of noradrenaline release by presynaptic receptor system. Rev Physiol Biochem Pharmacol 77:1–124, 1977

    Google Scholar 

  55. Goodman Gilman A, Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Macmillan, 1980

    Google Scholar 

  56. Stanszek WK, Kellerman D, Brodgen RN, Romankiewicz JA: Prazosin update. A review of its pharmacological and therapeutic use in hypertension and congestive heart failure. Drugs 25:339–384, 1983

    Google Scholar 

  57. Davey MJ: Relevant features of the pharmacology of prazosin: J Cardiovasc Pharmacol 2(suppl 3):s287–s302, 1980

    Google Scholar 

  58. Raasch W, Regunathan S, Li G, Reis DJ: Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci 56:2319–2330, 1995

    Google Scholar 

  59. Parini A, Moudanos CG, Pizzinat N, Lanier SM: The elusive family of imidazoline bindings sites. TIPS 17:13–17, 1996

    Google Scholar 

  60. Glavin GB, Hall AM: Brain-gut relationships: Gastricmucosal defense is also important. In Cell Injury and Protection in the Gastrointestinal Tract: From Basic Sciences to Clinical Perspectives. Gy Mózsik, Á Pár, G Csomós, M Kitajima, M Kondo, CJ Pfeiffer, KD Rainsford, P Sikiric, S Szabo (eds). Budapest, Akadémiai Kiadó, 1992, pp 107–115

    Google Scholar 

  61. Henke PG, Ray A: Stress ulcer modulation by limbic system structures. In Cell Injury and Protection in the Gastrointestinal Tract: From Basic Sciences to Clinical Perspectives. Gy Mózsik, Á Pár, G Csomós, M Kitajima, M Kondo, CJ Pfeiffer, KD Rainsford, P Sikiric, S Szabo (eds). Budapest, Akadémiai Kiadó, 1992, pp 117–125

    Google Scholar 

  62. Sikiric P, Rotkvic I, Mise S, Petek M, Rucman R, Seiwerth S, Zjacic Rotkvic V, Duvnjak M, Jagic V, Suchanek E, Grabarevic Z, Anic T, Brkic T, Djermanovic Z, Dodig M, Marovic A, Hernandez DE: Dopamine agonists prevent duodenal ulcer relapse: A comparative study with famotidine and cimetidine. Dig Dis Sci 36:905–910, 1991

    Google Scholar 

  63. Brodie DA, Valitski LS: Production of gastric hemorrhage in rats by multiple stresses. Proc Soc Exp Biol Med 113:998–1001, 1963

    Google Scholar 

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  1. Vjekoslav Jagic
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  2. Branko Turkovic
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  3. Ivo Rotkvic
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Jagic, V., Turkovic, B., Rotkvic, I. et al. Pentadecapeptide BPC 157 Interactions with Adrenergic and Dopaminergic Systems in Mucosal Protection in Stress. Dig Dis Sci 42, 661–671 (1997). https://doi.org/10.1023/A:1018880000644

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