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 nebulizat ion. Amplification of the vasodilatory response to inhaled PGI(2) might be achieved by phosphodiesterase (PDE) inhibitors to stabilize its second mess enger, cAMP. We established stable pulmonary hypertension in perfused rabbi t lungs by continuous infusion of U-46619. Short-term (10-min) aerosolizati on maneuvers of PGI(2) effected a rapid, moderate decrease in pulmonary art erial pressure, with post-PGI(2) vasorelaxation being lost within 10-15 min , accompanied by a marginal reduction in shunt flow. Preceding administrati on of subthreshold doses of the PDE inhibitors theophylline, dipyridamole, and pentoxifylline via the intravascular or inhalational route, which per s e did not influence pulmonary hemodynamics, caused more than doubling of th e immediate pulmonary arterial pressure drop in response to PGI(2) and mark ed prolongation of the post-PGI(2) vasorelaxation to >60 min (all PDE inhib itors via both routes of application). This was accompanied by a reduction in shunt flow in the case of aerosolized theophylline (27.5%), pentoxifylli ne (30.5%), and dipyridamole (33.4%). Coaerosolization of PGI(2) and PDE in hibitors may be considered as a therapeutic strategy in pulmonary hypertens ion.