ABSTRACT. The purpose of this study was to determine the effects of caffeine on growing rats and how protein energy malnutrition can modify these potential effects. Caffeine (1,3,7-trimethylxanthine) is not only the most commonly consumed, neurally active stimulant in our daily lives, but it is widely used in the management of apnea in the premature neonate. One group of dams (20%) (n = 6) was begun on a 20% protein diet ad libitum. The second group (6%) (n = 4) was begun on a 6% protein diet. A third group (20% + C) (n = 4) was pair-fed to group 1 (20%) with the 20% protein diet, but beginning on day 3 the pups received 10 mg/kg body weight of caffeine via intragastric feeding needle every other day. The fourth group (6% + C) (n = 5) was pair-fed with group 2 (6%) with the 6% protein diet and the pups received 10 mg/kg of caffeine in the same manner as the 20% + C group from day 3. Although the 6% protein diet was associated with the expected reduced body and brain growth, there were no additional growth alterations associated with caffeine administration in either the 20% or 6% diet groups. This growth failure was accompanied by the expected reductions in total whole brain DNA, RNA, protein, and cholesterol content regardless of whether caffeine was received or not. Effects of caffeine which were similar in both diet groups included an increase in brain RNA content and concentration and an increase in the RNA/DNA ratio. However, there were differential effects of caffeine seen depending on diet group assignment. These included an increase in brain DNA content and concentration in the 6% protein group only. Furthermore the protein/DNA ratio, an index of mean cell size, was increased in the 20% plus caffeine group and decreased in the 6% plus caffeine group. The present data and our previous work with theophylline on brain development (22) indicate that methylxanthine administration produces differential effects depending on dietary intake. (Pediatr Res 19: 71-74,1985) Caffeine (1,3,7-trimethylxanthine) is not only the most commonly consumed, neurally active stimulant in our daily lives, but also is widely used in the management of apnea in the premature neonate (3). Doses of 10 mg/kg/day produce 15-20 Received March 19, 1984; accepted June 27, 1984. Correspondence may be sent to Griffith E. Quinby, Jr., Department of Physiology, LSU Medical Center, 1100 Florida Ave., New Orleans, LA 701 19.' Present address: Hacettepe University Medical Center Ankara, Turkey. S u p ported by a fellowship grant from the World Health Organization. mg/liter serum concentrations (3). Cerebrospinal fluid levels of caffeine have been shown to be essentially equivalent to serum levels (25). Presumably, caffeine exerts its antiapneic effect by direct stimulation of central respiratory activity (26). In addition, caffeine stimulates smooth muscle, dilates systemic blood vessels, constricts cerebral blood vessels, alters glucose homeostasis and produces diuresis (1 1). Recently, we found (22) that a related xanthine derivative, th...
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