Phosphodiesterase 4 Inhibitor Roflumilast Improves the Bronchodilative Effect of Sevoflurane in Sensitized Airways

Background: Although phosphodiesterase 4 inhibitors and the volatile anesthetic sevoflurane are known to have independent bronchodilator properties, the combined administration of these two agents may have the potential to exert an additive or synergistic bronchodilator effect. The authors tested this hypothesis and investigated the common site of this combined relaxation effect in a model of airway hyperresponsiveness with ovalbumin-sensitized guinea pigs. Methods: Ovalbumin-sensitized animals (n = 138) were randomized into six groups: sensitized, sevoflurane, rolipram1.0, roflumilast1.0, sevoflurane/rolipram1.0, and sevoflurane/roflumilast1.0. Total lung resistance in vivo, airway smooth muscle tension in vitro, and intracellular cyclic adenosine monophosphate levels were measured to evaluate the relaxation effect. Results: Among the six sensitized groups, total lung resistance was higher in the order of sensitized > sevoflurane > rolipram 1.0 > roflumilast1.0 > sevoflurane/rolipram1.0 > sevoflurane/roflumilast1.0, with an increase in acetylcholine concentration. Compared with the other five groups, the muscle tensions in the sevoflurane/roflumilast1.0 group were significantly lower at carbacholine doses of 10(-7), 10(-6), and 10(-5) M; the cyclic adenosine monophosphate concentrations (means SD) in the sevoflurane/rolipram1.0 (1.61 +/- 0.34) and sevoflurane/roflumilast1.0 (1.50 +/- 0.20) groups were higher than that in the sensitized (0.52 +/- 0.15) and sevoflurane (1.12 +/- 0.32) groups. Conclusions: The combined use of phosphodiesterase 4 inhibitors with the volatile anesthetic sevoflurane had an additive bronchodilator effect in ovalbumin-sensitized guinea pigs. The concurrent increase in cyclic adenosine monophosphate levels in sensitized airway smooth muscle might be a mechanism of this combined relaxation effect.