Inhalation of aerosolized
iloprost, a stable
prostacyclin analog, has been suggested for treatment of primary and secondary
pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits,
pulmonary hypertension was induced by continuous infusion of the stable
thromboxane mimetic
U46619. Thereafter, the influence of aerosolized
iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of
phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose-effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors
pentoxifylline and
dipyridamole 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 then combined with a standardized
iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the
prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized
iloprost caused approximate doubling of the immediate pulmonary
vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy
tolafentrine >
dipyridamole >
pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled
iloprost markedly enhances the
prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.