Effects of theophylline on isolated diaphragmatic fibers. A model for pharmacologic studies on diaphragmatic contractility.

An in vitro model of isolated diaphragmatic muscle fibers was developed to study the effects of theophylline on diaphragmatic contractility. The effects of theophylline on this model were compared for each dose with the effects of the drugs on a "classic" hemidiaphragmatic muscle preparation. Diaphragmatic strips obtained from 20 rats were placed into an open topped channel of a plexiglass tissue chamber and perfused with continuously flowing Krebs solution heated to 37 degrees and bubbled with a 95% O2 and 5% CO2 gas mixture so as to maintain pH, PO2, PCO2 constant (7.4, 100, and 35 mmHg, respectively). Isometric force generated in response to 1 Hz supramaximal electrical stimulation was measured with a highly sensitive photoelectric transducer. Graded doses of aminophylline (15 to 75 mg/L) were administered and their effect assessed on diaphragmatic peak twitch tension. On the single diaphragmatic muscle fibers preparation, theophylline produced a dose dependent increase in peak twitch tension, which, at a concentration of theophylline of 15 mg/L, a therapeutic dose, amounted to 111 +/- 1.5% of control (p less than 0.05). At a concentration of 60 mg/L the increase in peak twitch tension averaged 35 +/- 2.5% of control, (p less than 0.001). On the other hand, theophylline had no effect on the hemidiaphragm preparation until a dose of 250 mg/L. These findings suggest that the effects of theophylline on diaphragmatic contractility are due to a direct action of the drug on the contractile properties of the diaphragmatic fibers and also validate the presented in vitro model as a promising one for future pharmacologic studies on diaphragmatic contractility.