Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension.
Inhalation of aerosolized prostacyclin (PGI(2)) exerts selective pulmonary vasodilation, but its effect is rapidly lost after termination of nebulization. Amplification of the vasodilatory response to inhaled PGI(2) might be achieved by phosphodiesterase (PDE) inhibitors to stabilize its second messenger, cAMP. We established stable pulmonary hypertension in perfused rabbit lungs by continuous infusion of U-46619. Short-term (10-min) aerosolization maneuvers of PGI(2) effected a rapid, moderate decrease in pulmonary arterial pressure, with post-PGI(2) vasorelaxation being lost within 10-15 min, accompanied by a marginal reduction in shunt flow. Preceding administration of subthreshold doses of the PDE inhibitors theophylline, dipyridamole, and pentoxifylline via the intravascular or inhalational route, which per se did not influence pulmonary hemodynamics, caused more than doubling of the immediate pulmonary arterial pressure drop in response to PGI(2) and marked prolongation of the post-PGI(2) vasorelaxation to >60 min (all PDE inhibitors via both routes of application). This was accompanied by a reduction in shunt flow in the case of aerosolized theophylline (27.5%), pentoxifylline (30.5%), and dipyridamole (33.4%). Coaerosolization of PGI(2) and PDE inhibitors may be considered as a therapeutic strategy in pulmonary hypertension.
Schermuly
R T
RT
Department of Internal Medicine, Justus-Liebig-University Giessen, D-35392 Giessen, Germany. ralph.schermuly@innere.med.uni-giessen.de
Roehl
A
A
Weissmann
N
N
Ghofrani
H A
HA
Leuchte
H
H
Grimminger
F
F
Seeger
W
W
Walmrath
D
D
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D009330:Nebulizers and Vaporizers; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011312:Pressure; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011817:Rabbits; D013806:Theophylline / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014692:Ventilation-Perfusion Ratio / Q000187:drug effects
D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D014662:Vasoconstrictor Agents; D004176:Dipyridamole; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013806:Theophylline; D011464:Epoprostenol; D000242:Cyclic AMP; D010431:Pentoxifylline