Combined inhaled nitric oxide and inhaled prostacyclin during experimental chronic pulmonary hypertension

Inhaled nitric oxide (NO) and inhaled prostacyclin (PGI(2)) produce selective reductions in pulmonary vascular resistance (PVR) through differing mechanisms. NO decreases PVR via cGMP, and PGI(2) produces pulmonary vasodilation via cAMP. As a general pharmacological principle, two drugs that produce similar effects via different mechanisms should have additive or synergistic effects when combined. We designed this study to investigate whether combined inhaled NO and PGI(2) therapy results in additive effects during chronic pulmonary hypertension in the rat. Monocrotaline injected 4 wk before study produced pulmonary hypertension in all animals. Inhaled NO (20 parts/million) reversibly and selectively decreased pulmonary artery pressure (Ppa) with a mean reduction of 18%. Four concentrations of PGI(2) were administered via inhalation (5, 10, 20, and 80 mu g/ml), both alone and combined with inhaled NO. Inhaled PGI(2) alone decreased Ppa in a dose-dependent manner with no change in mean systemic arterial pressure. Combined inhaled NO and PGI(2) selectively and significantly decreased Ppa more did than either drug alone. The effects were additive at the lower concentrations of PGI(2) (5, 10, and 20 mu g/ml). The combination of inhaled NO and inhaled PGI(2) may be useful in the management of pulmonary hypertension.