This study compared the effects of theophylline and adenosine on the contractile activity of respiratory smooth and skeletal muscles in vitro. Studies were performed on isolated strips of tracheal smooth and diaphragmatic skeletal muscle from 22 Hartley strain guinea pigs. The changes in diaphragm and tracheal smooth muscle tension in response to electrical stimulation and histamine-induced contraction, respectively, were assessed over a range of theophylline and adenosine concentrations (10-7 to 10-3 M for each). Theophylline increased diaphragmatic tension and reversed histamine-induced smooth muscle contractions in a dose-dependent fashion. Theophylline, however, decreased tracheal tension at concentrations an order of magnitude lower than those that increased diaphragmatic tension. Adenosine mimicked the effect of theophylline on tracheal muscle but had no effect on the force of diaphragm contraction. Moreover, adenosine failed to alter the theophylline dose-response curve for diaphragmatic tension. This study demonstrates that airway smooth muscle is more sensitive than is respiratory skeletal muscle to the effects of theophylline. Furthermore, these data suggest that the effects of theophylline on diaphragm skeletal muscle are not mediated by adenosine receptor blockade.