Tissue norepinephrine depletion as a mechanism for calcium chloride inhibition of gastric carcinogenesis in rats after treatment withN-methyl-N<?-nitro-N-nitrosoguanidine and sodium chloride

Abstract

The effects of oral calcium chloride (CaCI2) on sodium chloride (NaCI)-enhanced induction of gastric carcinogenesis by the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine, and the norepinephrine (NE) concentration in the gastric wall, were investigated in Wistar rats. Animals were given the carcinogen for 25 weeks and then chow pellets containing 10% NaCl with or without 8% or 4% CaCI2. In week 52, the incidence of gastric cancers, the N E concentration in the antral portion of gastric wall and the labelling index of antral epithelial cells were significantly greater in rats fed NaCl alone than in untreated control rats. Concomitant oral treatment with CaCI2 at 8%, but not 4%, significantly reduced the incidence of gastric cancers, the N E concentration in the antral portion of gastric wall and the labelling index of the antral epithelial cells in week 52 compared with those in rats fed NaCl alone. Because N E concentration reflects sympathetic nervous system activity, our findings suggest that the sympathetic nervous system could play a role in NaCI-enhanced gastric carcinogenesis. Our findings also suggest that N E depletion by CaCI2 may be related to its inhibition of NaC1-enhanced carcinogenesis.Q 1996 Wilqv-Liss. Inc.Sodium chloride (NaCI) has been proposed as an etiologic factor in gastric carcinogenesis in humans (Hirayama, 1968) and in rats (Ohgaki et al., 1984(Ohgaki et al., , 1989Shirai et al., 1984;Takahashi et aL, 1984 Takahashi et aL, , 1994Tatematsu et al., 1975Tatematsu et al., , 1989. Nishikawa et a/. (1992) examined the effects of calcium chloride (CaCI2) on gastric carcinogenesis induced by N-methyl-N'-nitro-N 4trosoguanidine (MNNG) and NaCl in Wistar rats. They found that both the incidence and number per rat of pre-neoplastic hyperplastic lesions after treatment with MNNG and NaCl followed by 1% or 0.2% CaClz were significantly lower than after MNNG and NaCl alone. However, the exact mechanism of the effects of NaCl and CaC12 remains unclear.A diet high in NaCl induces hypertension in Dahl saltsensitive rats. In these rats, the sympathetic nervous system contributes to elevation of arterial blood pressure (Haywood et al., 1985), and chemical sympathectomy with guanethidine or 6-hydroxydopamine prevents the development of hypertension (Friedman el al., 1979;Takeshita et al., 1979). Moreover, dietary Ca2+ intake influences the activity of the sympathetic nervous system in experimental animals (Hagihara et a/., 1991). These findings suggest that in MNNG-treated rats, a high-NaC1 diet might enhance gastric carcinogenesis, and CaC12 Supplementation might influence NaCl enhancement of carcinogenesis through the sympathetic nervous system. To test this possibility, we investigated the effect of a high-NaC1 diet with and without CaCI2 supplementation on gastric carcinogenesis in Wistar rats. MATERIAL AND METHODS AnimalsOne hundred fifty inbred male Wistar rats that initially weighed approximately 100 g were purchased from Japan SLC (Shizuoka, Japan). The animals were housed in suspended, wire-bo...