Importance of luminal and mucosal zinc in the mechanism of experimental gastric ulcer healing.

Zinc has been reported to exert a gastroprotective action against various experimental gastric lesions suggesting that this trace element is involved in the integrity of the gastric mucosa. Compounds containing zinc, such as polaprezinc, were developed in Japan and used as an antiulcer drugs in the treatment of human peptic ulcer disease. However, the precise mechanism of Zn(2+) containing compounds and their effects on mucosal integrity, gastroprotection and ulcer healing remain unclear. We have determined the efficacy of zinc hydroaspartate, a compound containing Zn(2+), in the mechanism of gastric secretion and ulcer healing in rats with chronic gastric ulcers induced by acetic acid (initial ulcer area = 28 mm(2)). Rats with gastric ulcers were randomized into two groups: A) with gastric fistulas (GF) and B) without gastric fistulas and received a daily treatment with zinc hydroaspartate (32-130 mg/kg-d i.g.) for 3, 7 and 14 days. At the termination of each treatment, the area of gastric ulcers were examined by planimetry, the gastric blood flow (GBF) at ulcer margin was assessed by laser Doppler flowmetry and H(2)-gas clearance methods. The venous blood was withdrawn for a measurement of plasma gastrin levels by radioimmunoassay (RIA). The concentration of Zn(2+) in the gastric juice and mucosa at the ulcer margin were determined by differential pulse anodic stripping voltammetry (DPASV) and flame atomic absorption spectrometry (FAAS) methods and the gastric biopsy samples were taken for histopathological assessment of the quality of ulcer healing. The ulcers healed gradually, with the ulcer area in the vehicle control rats being diminished by 15%, 48% and 78% upon ulcer induction at 3, 7 and 14 days, respectively. Zinc hydroaspartate dose-dependently inhibited the area of gastric ulcer, the dose reducing this area by 50% (ID(50)) being about 60 mg/kg-d. The mucosal concentration of Zn(2+) significantly was unchanged from the baseline immediately after ulcer induction (day 0) and at day 3 but then it rose significantly at day 7 after ulcer induction. Treatment with zinc hydroaspartate (65 mg/kg-d i.g.), which significantly raised the gastric luminal and mucosal levels of Zn(2+), significantly accelerated ulcer healing at day 7 upon ulcer induction. The GBF, which reached a significantly higher value at the ulcer margin than the ulcer bed, was significantly increased in rats treated with zinc hydroaspartate compared with vehicle-controls. The gastric acid output was significantly inhibited in GF rats with gastric ulcer at day 3 then restored at day 14 followed by a significant rise in the plasma gastrin levels. Treatment with zinc hydroaspartate significantly inhibited gastric secretion and also significantly raised the plasma gastrin level when compared to vehicle-control rats. We concluded that 1) trace micronutrients such as Zn(2+) could be successfully measured in the gastric juice and gastric mucosa during ulcer healing; 2) compounds chelating of Zn(2+) can exert a beneficial influence on the ulcer healing via Zn(2+) mediated increase in gastric microcirculation, antisecretory activity and gastrin release, which may enhance the cell proliferation and differentiation during ulcer healing, ultimately exerting a trophic action on the ulcerated gastric mucosa.