Effect of aminophylline on high-energy phosphate metabolism and fatigue in the diaphragm

Background: Diaphragmatic fatigue causes respiratory failure, for which aminophylline has been used as therapy. Because the mechanism of action of aminophylline in reversing diaphragmatic fatigue is unclear, we used in vive ³¹P magnetic resonance spectroscopy (MRS) to determine the relation between diaphragmatic activation, force output, and aerobic metabolism. Methods: Bilateral phrenic stimulation was used to pace the diaphragm in pentobarbital-anesthetized piglets (6-10 weeks old; n = 44). Esophageal and abdominal pressures were measured to calculate transdiaphragmatic pressure (Pdi) (Pdi = abdominal pressure - esophageal pressure) as an index of force output. Activation was determined by the amplitude of the compound action potential of the diaphragmatic electromyogram. Aerobic metabolism was assessed with a ³¹P MRS surface coil on the right hemidiaphragm with the animal in a 4.7-T magnet. The animals were divided into four groups based on aminophylline loading dose: saline, aminophylline 10 mg/kg (A10), aminophylline 20 mg/kg (A20), and aminophylline 40 mg/kg (A40). After aminophylline loading the diaphragm was paced for 25 min followed by a 10- min recovery. Results: Aminophylline concentrations were 12.2 ± 0.7, 21.9 ± 2.4, and 44.9 ± 3.6 mg/l in the A10, A20, and A40 groups, respectively. Compound action potential amplitude decreased in all groups by 30% after 25 min of pacing. Conversely, Pdi remained at 100 ± 3% of the initial value after 5 min of pacing in the A40 group but decreased to 75 ± 3% in the saline group. Pdi recovered completely (103 ± 17%) in the A40 group but remained depressed (72 ± 6%) in the saline group. Pdi values were intermediate in the A10 and A20 groups. MRS data revealed inadequate energy supply/demand ratio in the saline group such that the ratio of inorganic phosphate to phosphocreatine (Pi/PCr) increased to 1.01 ± 0.09 after 5 min of pacing. Pi/PCr remained unchanged in the A40 group and was intermediate in the A10 and A20 groups. β-Adenosine triphosphate and intracellular pH did not differ among groups or as a function of pacing. Diaphragmatic blood flow increased from a resting value of 35-60 to 300-410 ml · min^-1 · 100 g^{- 1} during pacing in all groups and was not affected by aminophylline dose. Conclusions: Aminophylline, in a dose-dependent fashion, delays the onset of fatigue and improves recovery from fatigue. Delayed fatigue is associated with improved aerobic metabolism as reflected in a low Pi/PCr ratio.