title: Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange.
abstract: Aerosolized prostacyclin (PGI(2)) has been suggested for selective pulmonary vasodilation, but its effect rapidly levels off after termination of nebulization. Stabilization of the second-messenger cAMP by phosphodiesterase (PDE) inhibition may offer a new strategy for amplification of the vasodilative response to nebulized PGI(2). In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was used to establish stable pulmonary hypertension [increase in pulmonary arterial pressure (pPA) from approximately 7 to approximately 32 mm Hg], which is accompanied by progressive edema formation and severe disturbances in gas exchange with a predominance of shunt flow (increase from <2 to approximately 58%, as assessed by the multiple inert gas elimination technique). In the absence of PGI(2), dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibitor motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 inhibitor tolafentrine on pulmonary hemodynamics were established (potency rank order: rolipram > tolafentrine approximately motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI(2) was chosen to effect a moderate pPA decrease (approximately 4 mm Hg; rapidly returning to prenebulization values within 10-15 min) with only a slight reduction in shunt flow (approximately 49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmonary hemodynamics, caused prolongation of the post-PGI(2) decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI(2) to approximately 9 to 10 mm Hg, prolonged the post-PGI(2) vasorelaxation to >60 min, reduced the extent of lung edema formation by 50%, and decreased the shunt flow to approximately 19% (i.v. rolipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude that lung PDE3/4 inhibition, achieved by intravascular or transbronchial administration of subthreshold doses of specific PDE inhibitors, synergistically amplifies the pulmonary vasodilatory response to inhaled PGI(2), concomitant with an improvement in ventilation-perfusion matching and a reduction in lung edema formation. The combination of nebulized PGI(2) and PDE3/4 inhibition may thus offer a new concept for selective pulmonary vasodilation, with maintenance of gas exchange in respiratory failure and pulmonary hypertension.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: A
authors.initials: A
authors.lastname: Roehl
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: H A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: C
authors.initials: C
authors.lastname: Schudt
authors.forename: H
authors.initials: H
authors.lastname: Tenor
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 / Q000494:pharmacology; D000336:Aerosols; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D011464:Epoprostenol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology*; D008168:Lung; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011817:Rabbits; D020889:Rolipram / Q000494:pharmacology; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000336:Aerosols; D000959:Antihypertensive Agents; D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D014662:Vasoconstrictor Agents; C094030:tolafentrine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C051270:motapizone; D011464:Epoprostenol; D000242:Cyclic AMP; D020889:Rolipram