Phosphodiesterase v inhibition reduces airway responsiveness, but does not improve the beneficial effect of deep inspiration

摘要

Background: Deep inspirations (DIs) can prevent (bronchoprotection; BP) and reverse (bronchodilation; BD) methacholine (Mch)-induced bronchoconstriction, but this effect is reduced or absent in people with asthma or airways hyperresponsiveness (AHR). The mechanisms of this defect are unknown. Objective: To indirectly examine the role of guanosine 3′,5′-cyclic monophosphate (cGMP) by testing the hypothesis that the phosphodiesterase (PDE) V inhibitor, sildenafil, would improve DI-induced BP in individuals with AHR. Methods: Thirty-two individuals were screened and 15 met all the inclusion/exclusion criteria (7 subjects with AHR and 8 healthy subjects). A single-dose Mch challenge inducing a 20% reduction in FEV1 in the absence of DIs was first identified. Thereafter, every study participant had 4 pairs of visits, each pair testing DI-induced BP and BD against the single-dose Mch, with no drug, or pretreatment with 25, 50 and 100 mg of sildenafil, respectively, in consecutive order. Results: Sildenafil did not influence baseline lung function. However, in the absence of DIs, the drug caused a dose-dependent attenuation of the Mch-induced decrease in FEV1 by 17% (median value; 25th percentile: 1, 75th percentile: 16), 35% (-3, 61) and 37% (13, 79) for the 25-, 50- and 100-mg doses, respectively (p = 0.0004). No differences between the two participant groups were found. There were no effects of sildenafil on DI-induced BP or BD. Conclusion: We infer from these results that the mechanism responsible for the defective ability of DIs to protect the airways from bronchoconstriction is unlikely to be due to dysregulation of cGMP. Of importance, a potential role for PDE V inhibition as a bronchoprotector treatment needs to be explored.