Abstract
Nitric oxide (NO) synthesized froml-arginine interacts with prostaglandins (PG) and sensory neuropeptides in the regulation of mucosal integrity, but the role ofl-arginine, a substrate for NO-synthase, in gastroprotection and healing of chronic gastric ulcers has been little studied. In this study we compared the effects of intragastric (i.g.) and systemic (i.v.) administration ofl-arginine ord-arginine on gastric secretion and acute gastric lesions provoked in rats by i.g. application of 100% ethanol, acidified aspirin (ASA), or the exposure to 3.5h of water immersion and restraint stress (WRS). In addition, the effects ofl-arginine on ulcer healing and the formation of new vessels (angiogenesis) were determined, using monoclonal antibody (MAb E-9).l-arginine (10–200 mg/kg i.g.) failed to significantly affect gastric secretion but dose-dependently reduced the gastric lesions induced by 100% ethanol, ASA, and WRS, the doses inhibiting 50% of these lesions being 65, 94, and 72 mg/kg, respectively. This protection was accompanied by a significant rise in the gastric blood flow (GBF), whereasl-arginine given i.v. failed to affect the ethanol-lesions and the GBF.d-arginine or the NO-related amino acids—l-glutamine,l-citrulline, orl-ornithine—failed to significantly influence these lesions. Suppression of the generation of mucosal PG by indomethacin or capsaicin-denervation attenuated the protection and hyperemia induced byl-arginine. The inhibition of constitutive NO synthase byl-NNA had no significant effect on the protection afforded byl-arginine, but reduced the gastric hyperemia accompanying this protection.l-arginine (150 mg/kg per day, i.g.) accelerated the ulcer healing and increased GBF at the ulcer margin, and angiogenesis, whereas treatment with L-NNA had an opposite effect.l-arginine added to NG-nitro-l-arginine (L-NNA) restored the ulcer healing, hyperemia, and angiogenesis. We conclude that: (1) the protective activity ofl-arginine involves gastric hyperemia mediated by NO and a mild irritant effect due to enhanced generation of endogenous PG, and (2) the ulcer healing properties ofl-arginine depend upon its hyperemic and angiogenic actions, possibly involving NO.
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References
Cynober L. Can arginine and ornithine support gut functions. Gut 1994;35(Suppl 1):S42-S45.
Barbul A, Lazarou SA, Efron BA, et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990;108:331–337.
Ignarro LJ, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265–9269.
Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesise nitric oxide froml-arginine. Nature 1988;333:664–666.
Brown JF, Tepperman BL, Hanson PJ, et al. Differential distribution of nitric oxide synthase between cell fractions isolated from the rat gastric mucosa. Biochem Biophys Res Commun 1992;184:840–868.
Rand MJ. Nitrergic transmission: Nitric oxide as a mediator of non-adrenergic, non-cholinergic, neuro-effector transmission. Clin Exp Pharmacol Physiol 1992;19:147–169.
Palmer RMJ, Rees DD, Ashton DS, et al.l-Arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 1988;153:1251–1256.
Pique JM, Whittle BJR, Esplugues JV. The vasodilator role of endogenous nitric oxide in the rat gastric microciculation. Eur J Pharmacol 1989;174:293–296.
Stark ME, Szurszewski JH. Role of nitric oxide in gastrointestinal function and disease. Gastroenterology 1992;103:1928–1949.
Mac Naughton K, Cirino G, Wallace JL. Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci 1989;45:1869–1876.
Wallace JL, Cirino G, De Nucci G, et al. Endothelin has potent ulcerogenic actions in the stomach. Am J Physiol 1989;256:G661-G666.
Brzozowski T, Drozdowicz D, Szlachcic D, et al. Role of nitric oxide and prostaglandins in gastroprotection induced by capsaicin and papaverine. Digestion 1993;54:24–31.
Whittle BJR, Lopez-Belmonte J, Moncada S. Regulation of gastric mucosal integrity by endogenous nitric oxide: Interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol 1990;99:607–611.
Whittle BJR, Tepperman BL. Role of the endogenous vasoactive mediators, nitric oxide, prostanoids and sensory neuropeptides in the regulation of gastric blood flow and mucosal integrity. In: Garner A, O'Brien PE (eds) Mechanism of injury, protection and repair of the upper gastrointestinal tract. Chichester: John Wiley and Sons, 1991;127–137.
Konturek SJ, Brzozowski T, Majka J, et al. Role of nitric oxide and prostaglandins in sucralfate-induced gastroprotection. Eur J Pharmacol 1992;211:277–279.
Konturek SJ, Brzozowski T, Majka J, et al. Nitric oxide in gastroprotection by aluminium-containing antacids. Eur J Pharmacol 1992;229:155–162.
Lopez-Belmonte J, Whittle BJR, Moncada S. The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol 1993;108:73–78.
Brzozowski T, Konturek SJ, Drozdowicz D, et al. Healing of chronic gastric ulcerations byl-arginine. Role of endogenous prostaglandins, nitric oxide and polyamines. Digestion 1995;56:463–471.
Konturek SJ. Mechanisms of gastroprotection. Scand J Gastroenterol 1990;25(Suppl 174):15–28.
Konturek SJ, Brzozowski T, Majka J, et al. Transforming growth factor alpha and epidermal growth factor in protection and healing of gastric mucosal injury. Scand J Gastroenterol 1992;27:649–655.
Konturek PK, Brzozowski T, Konturek SJ, et al. Role of epidermal growth factor, prostaglandin and sulfhydryls in stress-induced gastric lesions. Gastroenterology 1990;99:1607–1615.
Ishii KB, Chang B, Kerwin JF, et al. N-Nitro-l-arginine: a potent inhibitor of endothelium-derived relaxing factor formation. Eur J Pharmacol 1990;176:219–223.
Konturek SJ, Stachura J, Radecki T, et al. Cytoprotective and ulcer healing properties of prostaglandin E2 in rats. Digestion 1987;38:103–113.
Okabe S, Pfeifer CJ, Roth JLA. A method for experimental penetrating ulcers in rats. Am J Dig Dis 1971;16:277–284.
Brzozowski T, Konturek SJ, Majka J, et al. Involvement of nitric oxide in gastric ulcer healing with antacids. Eur J Gastroenterol Hepatol 1993;5(Suppl 3):S117-S123.
Sternberg LA, Hardy PH, Cuculis JJ, et al. Unlabeled antibody enzyme method for immunohistochemical preparation and properties of soluble antigen-antibody complex (horseradish-anti-horseradish peroxidase) and its use in identification spirochetes. J Histochem Cytochem 1970;18:315–333.
Wang JM, Kumar S, Pye D, et al. Monoclonal antibody detects heterogenity in vascular endothelium of tumors and normal tissue. Int J Cancer 1993;54:363–370.
Barbul A, Lazaron SA, Efron DT, et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990,108:331–336.
Seifter E, Rettura G, Barbul A, et al. Arginine: An essential amino acid for injured rats. Surgery 1978;84:224–230.
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43:109–142.
Brown JF, Hanson PJ, Whittle BJR. Nitric oxide donors increase gel thickness in rat stomach. Eur J Pharmacol 1992;223:103–104.
Wu G, Meininger CJ. Regulation ofl-arginine synthesis froml-citrulline byl-glutamine in endothelial cells. Am J Physiol 1993;265:H1965-H1971.
Takeuchi K, Ohucki T, Kato S, et al. Cytoprotective action ofl-arginine against HCL-induced gastric injury in rats—involvement of nitric oxide. Jpn J Pharmacol 1993;61:13–21.
Konturek SJ, Brzozowski T, Majka J, et al. Nitric oxide in gastroprotection by sucralfate, mild irritant and nocloprost. Role of mucosal blood flow. Dig Dis Sci 1994;39:593–600.
Lambrecht N, Burchert M, Respondek M, et al. Role of calcitonin gene-related peptide and nitric oxide in the gastroprotective effect of capsaicin in the rat. Gastroenterology 1993;104:1371–1380.
Farraz JGP, Tigley A, Wallace JL. Paradoxical effects ofl-arginine on gastric mucosal integrity. Eur J Pharmacol 1994;260:107–111.
Konturek SJ, Brzozowski T, Majka J, et al. Inhibition of nitric oxide synthase delays the healing of chronic gastric ulcers. Eur J Pharmacol 1993;239:215–217.
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Brzozowski, T., Konturek, S.J., Sliwowski, Z. et al. Role ofl-arginine, a substrate for nitric oxide-synthase, in gastroprotection and ulcer healing. J Gastroenterol 32, 442–452 (1997). https://doi.org/10.1007/BF02934081
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DOI: https://doi.org/10.1007/BF02934081