title: Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.
abstract: Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, but demands continuous supply of the gaseous agent. We investigated the suitability of aerosolization of NO-donor drugs for achieving sustained reduction of pulmonary vascular tone. In buffer-perfused rabbit lungs, stable pulmonary hypertension was achieved by continuous infusion of the thromboxane-analogue U46619. The NO-donor drugs molsidomine, 3-morpholinosydnone-imine (SIN-1), sodium nitroprusside (SNP) and glyceryl-trinitrate reduced the pulmonary hypertension in a dose-dependent fashion, whether admixed to the perfusate or inhaled as alveolar-accessible aerosol particles (aerosolization time 3-6 min), with an efficiency ranking of SNP > SIN-1 >> molsidomine and glyceryl-trinitrate. Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation. Appearance of sydnonimines in the perfusate after aerosolization and reduction of SIN-1 efficacy when nebulized in nonrecirculatingly perfused lungs demonstrated substantial entry of this prodrug into the vascular space after alveolar deposition. In contrast, undiminished vasodilatory efficacy of aerosolized SNP under conditions of non-recirculating perfusion suggested predominant efficacy via local NO release for this agent. We conclude that short aerosolization maneuvers of NO-donor drugs are suitable to achieve dose-dependent, extensive and sustained vasodilation in the pulmonary circulation, thus offering a new therapeutic approach in pulmonary hypertension.
authors.affiliation: Department of Internal Medicine, Justus-Liebig University, Giessen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schütte
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
authors.forename: J
authors.initials: J
authors.lastname: Otterbein
authors.forename: R
authors.initials: R
authors.lastname: Spriestersbach
authors.forename: K
authors.initials: K
authors.lastname: Mayer
authors.forename: D
authors.initials: D
authors.lastname: Walmrath
authors.forename: W
authors.initials: W
authors.lastname: Seeger
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D005260:Female; D008168:Lung / Q000098:blood supply* / Q000502:physiology; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000493:pharmacokinetics; D009569:Nitric Oxide / Q000008:administration & dosage*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000493:pharmacokinetics; D009599:Nitroprusside / Q000008:administration & dosage / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000008:administration & dosage / Q000493:pharmacokinetics; D011817:Rabbits; D013558:Sydnones / Q000008:administration & dosage / Q000493:pharmacokinetics; D013928:Thromboxane A2 / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000336:Aerosols; D011355:Prodrugs; D011450:Prostaglandin Endoperoxides, Synthetic; D013558:Sydnones; D009599:Nitroprusside; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D008981:Molsidomine; D005996:Nitroglycerin