Subthreshold doses of specific phosphodiesterase type 3 and 4 inhibitors enhance the pulmonary vasodilatory response to nebulized prostacyclin with improvement in gas exchange

Aerosolized prostacyclin (PGI(2)) has been suggested for selective pulmonar y vasodilation, but its effect rapidly levels off after termination of nebu lization. Stabilization of the second-messenger cAMP by phosphodiesterase ( PDE) inhibition may offer a new strategy for amplification of the vasodilat ive response to nebulized PGI(2). In perfused rabbit lungs, continuous infu sion of the thromboxane mimetic U46619 was used to establish stable pulmona ry hypertension [increase in pulmonary arterial pressure (pPA) from similar to 7 to similar to 32 mm Hg], which is accompanied by progressive edema fo rmation and severe disturbances in gas exchange with a predominance of shun t flow (increase from <2 to similar to 58%, as assessed by the multiple ine rt gas elimination technique). In the absence of PGI(2), dose-effect curves for intravascular and aerosol administration of the specific PDE3 inhibito r motapizone, the PDE4 inhibitor rolipram, and the dual-selective PDE3/4 in hibitor tolafentrine on pulmonary hemodynamics were established (potency ra nk order: rolipram. tolafentrine; motapizone; highest efficacy on coapplica tion of rolipram and motapizone). Ten-minute aerosolization of PGI2 was cho sen to effect a moderate pPA decrease (similar to 4 mm Hg; rapidly returnin g to prenebulization values within 10-15 min) with only a slight reduction in shunt flow (similar to 49%). Prior application of subthreshold doses of i.v. or inhaled PDE3 or PDE4 inhibitors, which per se did not affect pulmon ary hemodynamics, caused prolongation of the post-PGI(2) decrease in pPA. T he most effective approach, rolipram plus motapizone, amplified the maximum pPA decrease in response to PGI(2) to similar to 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 similar to 19% (i.v. rol ipram/motapizone) and 28% (aerosolized rolipram/motapizone). We conclude th at lung PDE3/4 inhibition, achieved by intravascular or transbronchial admi nistration of subthreshold doses of specific PDE inhibitors, synergisticall y amplifies the pulmonary vasodilatory response to inhaled PGI(2), concomit ant with an improvement in ventilation-perfusion matching and a reduction i n lung edema formation. The combination of nebulized PGI(2) and PDE3/4 inhi bition may thus offer a new concept for selective pulmonary vasodilation, w ith maintenance of gas exchange in respiratory failure and pulmonary hypert ension.