RT Journal Article
SR Electronic
T1 Subthreshold Doses of Specific Phosphodiesterase Type 3 and 4 Inhibitors Enhance the Pulmonary Vasodilatory Response to Nebulized Prostacyclin with Improvement in Gas Exchange
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 512
OP 520
VO 292
IS 2
A1 Ralph Theo Schermuly
A1 Axel Roehl
A1 Norbert Weissmann
A1 Hossein Ardeschir Ghofrani
A1 Christian Schudt
A1 Herrmann Tenor
A1 Friedrich Grimminger
A1 Werner Seeger
A1 Dieter Walmrath
YR 2000
UL http://jpet.aspetjournals.org/content/292/2/512.abstract
AB Aerosolized prostacyclin (PGI2) 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 PGI2. 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 ∼7 to ∼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 ∼58%, as assessed by the multiple inert gas elimination technique). In the absence of PGI2, 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 ∼ motapizone; highest efficacy on coapplication of rolipram and motapizone). Ten-minute aerosolization of PGI2 was chosen to effect a moderate pPA decrease (∼4 mm Hg; rapidly returning to prenebulization values within 10–15 min) with only a slight reduction in shunt flow (∼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-PGI2 decrease in pPA. The most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI2 to ∼9 to 10 mm Hg, prolonged the post-PGI2 vasorelaxation to >60 min, reduced the extent of lung edema formation by 50%, and decreased the shunt flow to ∼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 PGI2, concomitant with an improvement in ventilation-perfusion matching and a reduction in lung edema formation. The combination of nebulized PGI2 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. The American Society for Pharmacology and Experimental Therapeutics