title: Phosphodiesterase V inhibition reduces airway responsiveness, but does not improve the beneficial effect of deep inspiration.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Division of Allergy and Clinical Immunology, Baltimore, Md., USA.
authors.forename: George
authors.initials: G
authors.lastname: Pyrgos
authors.forename: Alkis
authors.initials: A
authors.lastname: Togias
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D064368:Healthy Volunteers; D006801:Humans; D001239:Inhalation / Q000187:drug effects*; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D012130:Respiratory Hypersensitivity / Q000188:drug therapy*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate