title: Zardaverine and aerosolised iloprost in a model of acute respiratory failure.
abstract: In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane-A2-mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from approximately 2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 microg x kg(-1) for 15 min caused a decrease in pulmonary artery pressure (Ppa) and a limitation of maximum shunt flow to approximately 37%. When nebulised PGI2 was combined with subthreshold intravascular zardaverine, which did not affect pulmonary haemodynamics per se, the duration of the PGI2 effect was increased. Aerosolisation of 3 microg x kg(-1) PGI2 resulted in a transient decrease in Ppa and a reduction in shunt flow. In the presence of subthreshold zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 microg x kg(-1)) for 15 min caused a more sustained decrease in Ppa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to approximately 32%. Most impressively, when combined with subthreshold zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to approximately 8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.
authors.affiliation: Dept of Internal Medicine, Justus-Liebig-University, Giessen, Germany. ralph.schermuly@innere.med.uni-giessen.de
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: H
authors.initials: H
authors.lastname: Leuchte
authors.forename: H A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: F
authors.initials: F
authors.lastname: Rose
authors.forename: M
authors.initials: M
authors.lastname: Kohstall
authors.forename: H
authors.initials: H
authors.lastname: Olschewski
authors.forename: C
authors.initials: C
authors.lastname: Schudt
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: D
authors.initials: D
authors.lastname: Walmrath
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000280:Administration, Inhalation; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000008:administration & dosage; D005260:Female; D016285:Iloprost / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011724:Pyridazines / Q000008:administration & dosage*; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D014665:Vasodilator Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D016285:Iloprost; C066436:zardaverine