Degree Name

Master of Science (MS)

Semester of Degree Completion

2014

Thesis Director

Kip L. McGilliard

Abstract

Methylxanthines have been shown to be promising respiratory stimulants in newborns suffering from recurrent apnea. The respiratory stimulant effects of methylxanthines are most likely due to their antagonism of adenosine receptors. These drugs have been shown to stimulate respiration in newborn rats in doses in excess of 10 mg/kg body weight. Structure-activity studies have shown that methylxanthines not only differ in the antagonism of A1 and A2 adenosine receptors but also, as a consequence of their different chemical structures, differ in potency as respiratory stimulants. To assess this, two potent A1 adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-cyclopentyltheophylline (CPT) were compared in relation to respiratory response in 4 -to 7-day-old rats using a body plethysmograph. DPCPX and CPT were administered in dosages of 10, 20, 40, 80, 160, 320, and 640 μg/kg body weight. Respiratory recordings were analyzed every 5 minutes for 60 minutes for minute ventilation (VE), respiratory rate (f), tidal volume (VT), and mean inspiratory flow (MIF). Our hypotheses were that 1) both DPCPX and CPT will stimulate respiration compared to saline treated rats, 2) there will be a dose-response relationship between DPCPX/CPT treatment and respiratory stimulation and 3) that DPCPX will be more potent than CPT as a respiratory stimulant based on its higher affinity for A1 adenosine receptors. As predicted, DPCPX and CPT stimulated respiration compared to saline treated rats. Overall, DPCPX exhibited greater respiratory stimulation than CPT in terms of VE, f, and MIF mean percent change, in the dosage range of 80-320 μg/kg. This along with the fact that unlike DPCPX, CPT shows no significant dosage-response relationship, suggests that DPCPX is a more potent respiratory stimulant.

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