Subthreshold Doses of Specific Phosphodiesterase Type 3 and 4 Inhibitors Enhance the Pulmonary Vasodilatory Response to Nebulized Prostacyclin with Improvement in Gas Exchange1

Abstract

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.