title: Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.
abstract: Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany; and Byk Gulden, Konstanz, Germany.
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: H A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: B
authors.initials: B
authors.lastname: Enke
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: C
authors.initials: C
authors.lastname: Schudt
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; D000336:Aerosols; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000008:administration & dosage* / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D011688:Purinones / Q000008:administration & dosage / Q000494:pharmacology; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology; D014662:Vasoconstrictor Agents; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000336:Aerosols; D000959:Antihypertensive Agents; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011724:Pyridazines; D014662:Vasoconstrictor Agents; C094030:tolafentrine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C051270:motapizone; D011464:Epoprostenol; C011145:zaprinast; D020889:Rolipram; C066436:zardaverine