Degree Name

Master of Science (MS)

Semester of Degree Completion

1987

Thesis Director

Kip L. McGilliard

Abstract

Apnea, a prolonged cessation of breathing, is commonly seen in premature infants. This condition, in its severest form, can be lethal and is a suspected cause of sudden infant death syndrome (SIDS). Sometimes referred to as apnea of prematurity, recurrent apnea is presently being treated with respiratory stimulants known as methylxanthines (MX) such as theophylline and caffeine. The benefits of MXs are accompanied by central nervous system stimulation and cardiostimulation which may be detrimental to a premature infant. Theophylline (1,3-diMX) has been shown to produce some of its effects by antagonizing endogenous adenosine. Another xanthine, enprofylline (3-propylxanthine), is presently being investigated as an antiasthmatic drug due to its bronchodilating effects. Unlike theophylline it has no CNS toxicity nor does it antagonize adenosine, except in high concentrations. Due to its lack of antagonism one would deduce that enprofylline would not stimulate respiration. The present study focused on the effects of these two xanthines on the respiration of adult mice and newborn rats. Respiratory studies were conducted on newborn rats (4- to 7-days old) and adult mice (20-30 g), using the volume displacement body plethysmograph. Subcutaneous injections of aminophylline (the ethylenediamine salt of theophylline) or enprofylline were administered and the effects compared to baseline respiration. Aminophylline (20 mg/kg) significantly increased VE by 30% in adult mice with a peak effect at 20 min. This increase was due to significant increases in both VT (13%) and f (18%). Aminophylline significantly increased VE by 44% in neonatal rats with a peak effect at 20 min. The increase was due to increases in both VT (30%) and f (9%). Only f was significantly greater than saline controls. Enprofylline (20 mg/kg) showed no consistent pattern of effects nor nor were its effects significantly different from saline for adult mice or neonatal rats. There were no significant differences in VE between doses (10, 20 and 40 mg/kg) of aminophylline in mice. Enprofylline (20, 40 and 80 mg/kg) also showed no significant differences in VE between doses for mice. However, doses of enprofylline were significantly different from one another in neonatal rats. The trend shown by enprofylline (40 mg/kg) was a consistent respiratory depression whereas the 80 mg/kg dose showed a latent stimulation in respiration. During these experiments 7 of 8 pups died after injection of 80 mg/kg enprofylline. In summary aminophylline stimulated respiration in both adult mice and neonatal rat pups, while enprofylline did not stimulate respiration at any dose tested, except at a dose which was lethal to neonatal rats. These data support the hypothesis that theophylline stimulates respiration by adenosine antagonism.

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