Degree Name

Master of Science (MS)

Semester of Degree Completion

1987

Thesis Director

Kip L. McGilliard

Abstract

Methylxanthines are commonly used in the treatment of respiratory disorders such as asthma, apnea of prematurity and Cheyne-Stokes respiration. Recently, certain methylxanthines have been found to potentiate the contraction of the diaphragm and increase contraction strength of the fatigued diaphragm. The mechanism of action of the methylxanthines is unknown. Three theories have been proposed but each has its supportive and negative points. One theory is that methylxanthines inhibit cyclic AMP phosphodiesterase (PDE) which facilitates contraction by increasing cyclic AMP levels in the cell. Another theory is that methylxanthines antagonize adenosine, thus blocking the adenosine-induced inhibition of contraction. The third theory involves changes in calcium permeability of the cell membrane or sarcoplasmic reticulum, resulting in increased calcium influx into the cytoplasm. The effects of xanthine and adenosine analogs were tested on isolated, electrically stimulated diaphragms from four- to seven-day-old rat pups. The effects of direct vs. indirect (phrenic nerve) stimulation were studied in the presence of varying concentrations of caffeine. The directly stimulated diaphragms had significantly larger increases in twitch tension in response to caffeine than the indirectly stimulated diaphragms. Caffeine (0.05 to 5 mM) and theophylline (0.05 to 5 mM), methylxanthines which are known to antagonize adenosine and inhibit PDE, increased twitch tension in a dose-dependent manner. Enprofylline (3-propylxanthine), which inhibits PDE, but does not antagonize adenosine, increased twitch tension at 1 mM. Adenosine (10 mM) stimulated contraction but only at high doses. Adenosine (1 mM) and the stable adenosine analog N6-cyclohexyladenosine (CHA) (1 mM) significantly inhibited contraction of the diaphragm, although the effects of adenosine were transient. The interaction of adenosine and caffeine was not significant due to adenosine's instability, but caffeine (1 to 10 mM) antagonized the effect of 1mM CHA. These data support the hypothesis that the methylxanthines stimulate contractility of the newborn rat diaphragm by antagonism of adenosine receptors. The observation that high doses of enprofylline also stimulated contractility suggests that PDE is another important mechanism.

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