title: Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension.
abstract: OBJECTIVE
  To determine whether inhalation of aerosolized sildenafil with and without inhaled nitric oxide (NO) causes selective pulmonary vasodilation in a sheep model of pulmonary hypertension.
  
  
  METHODS
  A controlled laboratory study in instrumented, awake, spontaneously breathing lambs.
  
  
  METHODS
  Animal research laboratory affiliated with a university hospital.
  
  
  METHODS
  Twenty Suffolk lambs.
  
  
  METHODS
  Lambs were instrumented with a carotid artery catheter, a pulmonary artery catheter, and a tracheostomy tube and studied awake. After baseline measurements, pulmonary hypertension was induced by the continuous infusion of U46619, a thromboxane A2 analog. After breathing three concentrations of inhaled NO (2, 5, and 20 ppm), lambs were divided into two groups. Group 1 (n = 7) breathed aerosols containing 1, 10, and 30 mg of sildenafil alone, and group 2 (n = 4) simultaneously breathed NO (2 and 5 ppm) and aerosols containing 10 mg of sildenafil. Hemodynamic measurements were obtained before and at the end of each drug administration. Venous admixture was calculated, and plasma cyclic guanosine monophosphate and sildenafil concentrations were measured.
  
  
  RESULTS
  Aerosols containing 10 mg and 30 mg of sildenafil selectively decreased the pulmonary artery pressure by 21% +/- 3% and 26% +/- 3%, respectively (p < .05 vs. baseline pulmonary hypertension). When 10 mg of sildenafil was inhaled while simultaneously breathing 2 ppm and 5 ppm NO, the pulmonary artery pressure decreased by 35% +/- 3% and 43% +/- 2% (p < .05 vs. baseline pulmonary hypertension). Inhaled sildenafil did not impair systemic oxygenation, increase right-to-left intrapulmonary shunting, or impair the ability of inhaled NO to reduce right-to-left shunting.
  
  
  CONCLUSIONS
  Nebulized sildenafil is a selective pulmonary vasodilator that can potentiate the pulmonary vasodilating effects of inhaled NO.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ichinose@etherdome.mgh.harvard.edu
authors.forename: F
authors.initials: F
authors.lastname: Ichinose
authors.forename: J
authors.initials: J
authors.lastname: Erana-Garcia
authors.forename: J
authors.initials: J
authors.lastname: Hromi
authors.forename: Y
authors.initials: Y
authors.lastname: Raveh
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: Krim
authors.forename: M W
authors.initials: MW
authors.lastname: Clark
authors.forename: J D
authors.initials: JD
authors.lastname: Winkler
authors.forename: K D
authors.initials: KD
authors.lastname: Bloch
authors.forename: W M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000208:Acute Disease; D000280:Administration, Inhalation; D000336:Aerosols; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D009569:Nitric Oxide / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000627:therapeutic use*; D010879:Piperazines / Q000097:blood / Q000627:therapeutic use*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011687:Purines; D012756:Sheep; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000336:Aerosols; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate