The Effects of Theophylline and 8-Cyclopentyltheophylline on the Respiratory Response to Carbon Dioxide in Neonatal Rats
Master of Science (MS)
Semester of Degree Completion
Kip L. McGilliard
Premature infants are often plagued with respiration problems ranging from periodic breathing to apnea. These respiratory complications can be a result of underdeveloped respiratory organs, immaturity of the brainstem respiratory control center, genetic irregularities, or a combination of all three. This study sought to increase respiration with the administration of methylxanthines, which are respiratory stimulants, coupled with carbon dioxide (CO2), also a respiratory stimulant. Neonatal rats aged 4 to 7 days old were used to mimic premature infants' response to the interaction of methylxanthines and CO2. Before beginning the respiratory studies, sections of a 4- and 7-day-old rat brainstem were examined to compare the differences in development. The 4-day-old rat brain had large folds (folia), while the 7-day-old rat brain lost those folds and was much denser in neuroglial and nerve cells. These differences show that as the rat matures, the brain also matures because the folds disappear, meaning that the brain is growing and new cells are synthesized as a part of this growth. After establishing this difference in brain development between the youngest and oldest rats, various doses of two different methylxanthines, theophylline (THEO) and 8-cyclopentyltheophylline (CPT), were injected into neonatal rats and paired with CO2 percentages ranging from 1 to 6%. The interaction of the drug and CO2 was observed over a 45-minute period. Each rat was placed into a body plethysmograph that was connected by plastic tubing to a pneumotachograph to measure the rat's respiration. A control period of normal breathing for 5 minutes followed in order to establish a baseline respiration, which was followed by a CO2 -response test involving exposure to increasing percentages of CO2 from 1 to 6%, delivered at 2-minute intervals. This same procedure was repeated in 15-minute intervals until the 45-minute period concluded. CO2 exposure produced a consistent increase in minute ventilation, tidal volume, and mean inspiratory flow, but not in respiratory rate, all of which were independent of the drug response. Although there was not an overall significant difference between doses of THEO, the highest dose, 40mg/kg, showed significant increases in minute ventilation, tidal volume, and mean inspiratory flow when paired with 5-6% CO2. The dose of 10 mg/kg of THEO also showed increases in minute ventilation and tidal volume at higher CO2 percentages. In contrast, CPT showed no significant increases in respiration at any dose. Interestingly, THEO doses were significant though CPT is the more potent form of the drug and has a higher affinity for adenosine A1 receptors. In summary, CO2 alone produced increases in minute ventilation, tidal volume, and mean inspiratory flow, and when paired with a dose of 40 mg/kg of THEO, these parameters increased further, showing that the highest doses of THEO paired with the highest doses of CO2 produce a significant increase in respiration.
Albers, Christine E., "The Effects of Theophylline and 8-Cyclopentyltheophylline on the Respiratory Response to Carbon Dioxide in Neonatal Rats" (2014). Masters Theses. 1279.