Inorganic Alkalizers and Acidifiers under Conditions of High Urinary Na(+) or K(+) on Cell Proliferation and Two‐stage Carcinogenesis in the Rat Bladder

Effects of alkalizers and acidifiers on bladder cell proliferation and two‐stage carcinogenesis were investigated under conditions of high urinary Na(+) or K(+). Animals were given 0.05%N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine in their drinking water for 4 weeks and then received Na(3)PO(4), NaH(2)PO(4), NaCl, NaH(2)PO(4)+NaCl, K(3)PO(4), KH(2)PO(4), KCl, KH(2)PO(4)+KCl or no chemical supplement in the diet from weeks 5 to 8 and from weeks 12 to 20. During weeks 9 to 11, the rats were fed 3% uracil in their diet for acceleration of promotion. Na(3)PO(4) or K(3)PO(4) induced marked natriuresis or kaluresis and alkalinuria associated with strong promoting potential for bladder carcinogenesis. NaH(2)PO(4) induced moderate natriuresis and aciduria and exhibited weak promoting activity. NaH(2)PO(4)+NaCl or KH(2)PO(4)+KCl caused marked increase in the respective cation levels and aciduria with elevation of promotion as compared to NaH(2)PO(4) or KH(2)PO(4) alone. NaCl or KCl induced moderate natriuresis or kaluresis and did not alter urinary pH. NaCl but not KCl also exerted weak promoting activity for bladder carcinogenesis. Increased DNA synthesis after test chemical exposure for 8 weeks and morphological alterations observed by scanning electron microscopy in the bladder epithelium were only quantitatively linked with promoting activity in the Na(3)PO(4) case. With the other treatments no clear correlation between early cell proliferation and promotion potential was apparent. The present results suggest that although elevation in urinary Na(+) or K(+) level may be an essential factor for promotion of rat bladder carcinogenesis, the action of these cations may depend strongly on urinary alkalinity.