EVALUATION OF THE TUMOR-PROMOTING ACTIVITY OF 2 BETA-ADRENOCEPTOR BLOCKING-AGENTS, PROPRANOLOL AND ATENOLOL, IN LIVER OF FISCHER-344 RATS

The tumor-promoting activity of two beta-adrenoreceptor blocking agent s, propranolol and atenolol, was tested in a two-stage protocol of hep atocarcinogenesis in male and female Fischer 344 rats. Propranolol is a lipophilic nonselective beta-blocker mainly eliminated via the liver ; atenolol is a hydrophilic beta(1)-selective blocking agent, mainly e liminated via the kidney. Animals were initiated with a single dose of diethylnitrosamine (DEN, 200 mg/kg, i.p.) and, after 17 days of recov ery, were continuously treated with propranolol (75-100 mg/kg) or aten olol (300 mg/kg) by gavage for up to 21 months. Rats given phenobarbit al (0.05% in the diet) were used as positive controls. After 2, 4 and 8 months of promotion, preneoplastic lesions were quantified by staini ng sections of liver for gamma-glutamyltrans-peptidase (GGT). In non-i nitiated rats, neither propranolol nor atenolol influenced the develop ment of spontaneous preneoplastic or neoplastic liver lesions. The res ults obtained in DEN-initiated rats given propranolol cannot be unequi vocally interpreted. In the male, propranolol seemed to be ineffective , In the female, there was weak enhancement of DEN-induced GGT foci at 4 and 8 months and of neoplastic lesions thereafter. However, there w as great interindividual variability in focus and tumor yields. Unfort unately, due to the high incidence of liver tumors in rats given DEN a lone and the small number of propranolol-treated rats that survived un til the end of the experiment, no definite conclusion can be drawn abo ut the modifying potential of this beta-blocker on liver carcinogenesi s. There was no evidence of liver tumor promotion in DEN-initiated rat s of either sex given atenolol.