title: Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors.
abstract: Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 microg/kg x min 8-Methoxymethyl-IBMX, 1 microg/kg x min sildenafil, 5 microg/kg x min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of PPA reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor.
authors: Medical Clinic II/V, Justus-Liebig-University Giessen, 35392 Giessen, Germany. ralph.schermuly@innere.med.uni-giessen.de
authors: Ralph Theo
authors: RT
authors: Schermuly
authors: Christiane
authors: C
authors: Inholte
authors: Hossein Ardeschir
authors: HA
authors: Ghofrani
authors: Henning
authors: H
authors: Gall
authors: Norbert
authors: N
authors: Weissmann
authors: Andreas
authors: A
authors: Weidenbach
authors: Werner
authors: W
authors: Seeger
authors: Friedrich
authors: F
authors: Grimminger
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology*; D016285:Iloprost / Q000008:administration & dosage*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011817:Rabbits; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D004338:Drug Combinations; D010726:Phosphodiesterase Inhibitors; D016285:Iloprost