Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension

Inhalation of aerosolized prostaglandin I-2 (PGI(2)) causes selective pulmo nary vasodilation, but the effected rapidly levels off after termination of nebulization. in experimental pulmonary hypertension in intact rabbits, pr ovoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of a erosolized PGI(2.) We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors d ose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an similar to 20% decrease in pulmonary vascular resistance being 5 mu g/k g for motapizone, 25 mu g/kg for rolipram, 500 mu g/kg for zardaverine, 1 m g/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was not ed when combining the monoselective 3 plus 4 3 plus 5, and 4 plus 5 inhibit ors. in parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg min) reduced the U46619-evoked increase in Ppa by similar to 30%. This vasorelaxant effect was fully lost within 1 0 min after termination of PGI(2) nebulization. Coapplication of subthresho ld doses of intravenous PDE inhibitors, which per se did not affect pulmona ry and systemic hemodynamics, resulted in a marked prolongation of the post -PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 mu g/kg, rolipr am at 5.5 mu g/kg, zaprinast at 100 mu g/kg). The most effective agents, za rdaverine (50 mu g/kg) and tolafentrine (100 mu g/kg), augmented the maximu m Ppa drop during nebulization by similar to 30-50% and prolonged the post- PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arter ial pressure and arterial oxygenation. We conclude that subthreshold system ic doses of monoselective PDE 3, 4 and 5 inhibitors and in particular dual- selective PDE 3/4 inhibitors cause significant amplification of the pulmona ry vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-do se systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertensi on.