Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension - Maintenance of lung selectivity

Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, bu t demands multiple daily inhalation maneuvers because of the short-term eff ect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafte r, the influence of aerosolized iloprost on pulmonary and systemic hemodyna mics and gas exchange was investigated in the presence and absence of phosp hodiesterase (PDE) inhibitors for stabilization of the second-messenger cAM P. First, dose-effect curves for pulmonary artery pressure (Ppa) decline we re established for the nonspecific PDE inhibitors pentoxifylline and dipyri damole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were the n combined with a standardized iloprost aerosolization maneuver, which resu lted in a substantial prolongation, but not augmentation, of the lung vasod ilatory response for the prostanoid. Next, higher doses of each PDE inhibit or were employed for nebulization, causing per se some pulmonary vasodilati ve effect, in the absence of arterial pressure decrease or impairment of ga s exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilato r response, marked prolongation of the pressure relief overtime, and a 2- t o 4-fold increase in the area under the curve of pulmonary vasodilation (ef ficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arter ial pressure was not suppressed and gas exchange was fully maintained. We c onclude that coadministration of PDE inhibitors with inhaled iloprost marke dly enhances the prostanoid-induced pulmonary artery pressure decrease whil e maintaining the lung selectivity of the vasodilatory response, and that c oaerosolization is a particularly suitable route of administration. Even no nselective clinically approved PDE inhibitors may be employed for this purp ose.