Studies of gastrin production after cisplatin treatment in rats.

摘要

Cisplatin administration (9 mg/kg) causes stomach bloating, decreased pH of stomach contents, ulceration, and hypocalcemia in rats. Gastric acid production, which is one of the key factors that regulate the pH in stomach, is mainly stimulated by gastrin in rats. Gastrin both directly stimulates parietal cells to produce gastric acid and indirectly acts on ECL-cells to release histamine, which is a strong acid production stimulant. In rats, somatostatin is the main factor that inhibits the gastrin production, while extracellular calcium concentration is one of the key factors that regulate gastrin production. We tested the hypothesis that the decreased pH of stomach contents and gastric ulceration due to cisplatin treatment is caused by increased gastrin production. Also we checked the changes of the somatostatin levels in order to correlate these to the changes of gastrin after cisplatin administration.; As measured by immunocytochemistry, in situ hybridization, northern blot, and dot blot techniques, gastrin was found to be below detectable limits just 1 day after cisplatin treatment. However, 10--15 days after the last injection of cisplatin, the levels of both gastrin and its mRNA gradually returned to normal. Northern blot studies showed that a decrease in somatostatin mRNA paralleled the changes of gastrin and its mRNA. Immunocytochemistry test showed that inducible nitric oxide synthase levels were also decreased. Supplements of vitamin D to rats, receiving cisplatin treatment, counteracted the inhibition of gastrin production. This effect of vitamin D on gastrin production, through the maintenance of the serum calcium levels, was confirmed by the studies of Rat Insulinoma B6 (RIN B6) cell lines under different concentrations of extracellular calcium with or without cisplatin treatment.; In conclusion, the cisplatin-induced decreased pH of stomach contents is not caused by gastrin. The inhibition of gastrin production is not due to the inhibitory effects of somatostatin; otherwise the somatostatin level should increase after cisplatin treatment. However, supplements of vitamin D can counteract this inhibition of gastrin production due to cisplatin in rats. Recently it is also proven that gastrin, mediated by the nitric oxide pathway, also maintains the gastric blood flow and mucosal integrity, which are keys to protect gastric mucosa from injuries by aggressive factors, such as pepsin and gastric acid. Cisplatin-induced lowered gastrin and nitric oxide production may be part of the reason that leads to gastrin ulceration.