Date of Award

1989

Degree Type

Thesis

Degree Name

Master of Science (MS)

Author's Department

Zoology

First Advisor

Kip L. McGilliard

Abstract

Methylxanthines (MX), such as theophylline, are commonly used in the treatment of recurrent apnea due to their stimulant effects on the respiratory center. Structure-activity studies have demonstrated that substitution of alkyl groups on the 3-position of the xanthine nucleus results in increased bronchodilator potency, while substitution on the 1-position is important for adenosine antagonism and CNS stimulation. Three different alkylxanthines were studied to determine the structural requirements for respiratory stimulation. Respiratory rates and volumes were determined in 4- to 7-day-old rats using a volume displacement body plethysmograph. Measurements were made before and at 5 minute intervals after subcutaneous (s.c.) injection of drug. Theophylline (1,3-diMX, 10-40 mg/kg) increased minute ventilation (VE) in a dose-related mannor by as much as 45% over baseline. Increases were observed in both tidal volume (VT) and respiratory rate (f). 1-MX (20-40 mg/kg) increased VE by almost 20%, primarily by increasing f. 3-MX (10-20 mg/kg) failed to produce a significant change in VE. These data suggest that substitution at the 1-position of the xanthine nucleus is essential for respiratory stimulation. The effect may be further enhanced by substitution at the 3-position. The data further suggest that antagonism of adenosine receptors is necessary for alkylxanthine-induced respiratory stimulation.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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