Am. J. Respir. Crit. Care Med., Volume 160, Number 5, November 1999, 1500-1506

Low-dose Systemic Phosphodiesterase Inhibitors Amplify the Pulmonary Vasodilatory Response to Inhaled Prostacyclin in Experimental Pulmonary Hypertension

RALPH THEO SCHERMULY, HOSSEIN ARDESCHIR GHOFRANI, BEATE ENKE, NORBERT WEISSMANN, FRIEDRICH GRIMMINGER, WERNER SEEGER, CHRISTIAN SCHUDT, and DIETER WALMRATH

Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany; and Byk Gulden, Konstanz, Germany

Inhalation of aerosolized prostaglandin I₂ (PGI₂) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked 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 aerosolized PGI₂. 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 dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an ~ 20% decrease in pulmonary vascular resistance being 5 µg/kg for motapizone, 25 µg/kg for rolipram, 500 µg/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI₂ (56 ng/kg · min) reduced the U46619-evoked increase in Ppa by ~ 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI₂ nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI₂ decrease in Ppa for all blockers (motapizone at 2.2 µg/kg, rolipram at 5.5 µg/kg, zaprinast at 100 µg/kg). The most effective agents, zardaverine (50 µg/kg) and tolafentrine (100 µg/kg), augmented the maximum Ppa drop during nebulization by ~ 30-50% and prolonged the post-PGI₂ pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI₂, while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI₂ with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension. Schermuly RT, Ghofrani HA, Enke B, Weissmann N, Grimminger F, Seeger W, Schudt C, Walmrath D. Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.

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