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.