Theophylline-induced mesenteric periarteritis in F344/N rats

The toxicity and carcinogenic potential of theophylline (an alkaloid bronch odilator drug) was investigated in male and female F344/N rats in 16-day, 1 4-week, and 2-year gavage and feeding studies. In 16-day studies, rats were fed diets containing 0, 500, 1000, 2000, 4000, and 8000 ppm of theophyllin e or given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twi ce daily), 100 (once daily), 200 (once daily), 200 (twice daily), and 400 ( once daily) mg theophylline/kg body weight in corn oil by gavage. In 14-wee k studies, rats were fed diets containing 0, 1000, 2000, and 4000 ppm theop hylline or given 0, 37.5, 75, and 150 mg/kg body weight theophylline in cor n oil by gavage. In 2-year gavage studies, rats were given 0, 7.5, 25, and 75 mg/kg body weight in corn oil. In 16-day gavage studies, treatment-relat ed periarteritis occurred in arteries of the pancreas and adjacent to the m esenteric lymph nodes of early death male and female rats given 400 mg/kg o nce daily. In the 14-week studies, treatment-related periarteritis occurred at similar sites and in male rats exposed to 75 and 150 mg/kg, and in all exposed female rats (gavage studies), in females exposed to 1000 ppm, and i n both sexes exposed to 2000 and 4000 ppm (feeding studies). In the 2-year study, chronic periarteritis was significantly increased only in the males receiving 75 mg/kg of theophylline. The adventitia, media and intima of med ium- and large-sized mesenteric arteries were involved. Similar to other va sodilator chemicals, the pathogenesis of theophylline-induced vascular lesi ons may be a consequence of hemodynamic changes induced in the vascular wal l.