Healing of chronic gastric ulcerations by L-arginine. Role of nitric oxide, prostaglandins, gastrin and polyamines.
This study was designed to determine the efficacy of L-arginine in healing of gastric ulcers induced by acetic acid and to assess the role of nitric oxide (NO), prostaglandins, gastrin and polyamines in the healing process. Intragastric administration of L-arginine (32.5-300 mg/kg/day) enhanced the healing rate of these ulcers in a dose-dependent manner, while D-arginine (300 mg/kg/day) was not effective. The acceleration of healing by L-arginine was accompanied by a marked increase in gastric blood flow (GBF) at the ulcer margin, and an enhancement of serum gastrin level, mucosal DNA synthesis, and DNA and RNA contents and angiogenesis in the granulation tissue in the ulcer bed. A similar increase in ulcer healing associated with hyperemia at the ulcer margin and enhanced angiogenesis but without alteration in serum gastrin were observed after treatment with glyceryl trinitrate, an NO exogenous supplier. Treatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, delayed ulcer healing and this was accompanied by a reduction of GBF at the ulcer margin and in angiogenesis in granulation tissue and by a decrease in serum gastrin level and mucosal growth. Addition of L-arginine to L-NNA restored ulcer healing, hyperemia at the ulcer margin and angiogenesis and prevented the fall in serum gastrin and mucosal growth caused by L-NNA. Pretreatment with indomethacin also delayed ulcer healing and this was reversed by the coadministration of L-arginine. Inhibition of polyamine biosynthesis by difluoro-methyl-ornithine completely abolished the acceleration of the healing and the increase in mucosal growth induced by L-arginine. Our findings indicate that L-arginine accelerates ulcer healing due to its hyperemic, angiogenic and growth-promoting actions, possibly involving NO, gastrin and polyamines.
Institute of Physiology, Jagiellonian University School of Medicine, Krakow, Poland.
T
T
Brzozowski
S J
SJ
Konturek
D
D
Drozdowicz
A
A
Dembiński
J
J
Stachura
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000494:pharmacology; D005755:Gastrins / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D005996:Nitroglycerin / Q000494:pharmacology; D011073:Polyamines / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013270:Stomach / Q000098:blood supply; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D005755:Gastrins; D011073:Polyamines; D011453:Prostaglandins; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin; D007213:Indomethacin; D000518:Eflornithine