15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and zardaverine

In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane-A2-mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from approximately 2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 microg x kg(-1) for 15 min caused a decrease in pulmonary artery pressure (Ppa) and a limitation of maximum shunt flow to approximately 37%. When nebulised PGI2 was combined with subthreshold intravascular zardaverine, which did not affect pulmonary haemodynamics per se, the duration of the PGI2 effect was increased. Aerosolisation of 3 microg x kg(-1) PGI2 resulted in a transient decrease in Ppa and a reduction in shunt flow. In the presence of subthreshold zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 microg x kg(-1)) for 15 min caused a more sustained decrease in Ppa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to approximately 32%. Most impressively, when combined with subthreshold zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to approximately 8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Antihypertensive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Female; Iloprost; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Pyridazines; Rabbits; Respiratory Distress Syndrome; Vasodilator Agents

Inhalation of aerosolized prostaglandin I(2) (PGI(2)) 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 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 dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/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 PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) 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-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) 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 PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and c

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Aerosols; Animals; Antihypertensive Agents; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Naphthyridines; Phosphodiesterase Inhibitors; Pulmonary Circulation; Purinones; Pyridazines; Rabbits; Rolipram; Vasoconstrictor Agents; Vasodilation