OBJECTIVE To compare the direct pulmonary vasodilating activity and specificity of phosphodiesterase-5 (zaprinast) and phosphodiesterase-3 (milrinone) inhibitors on the pulmonary vascular (PV) bed of the spontaneously breathing cat with an intact chest. METHODS Prospective, randomized animal study. METHODS Laboratory of university hospital. METHODS Experiments were performed in vivo in intact-chest, spontaneously breathing cats with controlled pulmonary blood flow and constant left atrial pressure. METHODS The responses to intralobar injections of zaprinast and milrinone were investigated at low PV tone. PV tone was then increased by intralobar arterial infusion of a thromboxane A(2) mimic, U46619. Animals received intralobar bolus injections of zaprinast or milrinone, followed by continuous IV infusion of the drug, which was administered in incremental doses titrated to produce a 20% reduction in mean systemic arterial pressure. RESULTS At low PV tone, zaprinast, but not milrinone, decreased lobar arterial pressure (LoAP). At elevated PV tone, both drugs caused dose-dependent decreases in LoAP; however, milrinone caused significantly less pulmonary vasodilation. Dose-related decreases in mean systemic arterial pressure were observed with milrinone, but not with zaprinast. When the continuous IV infusion was titrated to produce a 20% reduction in mean systemic arterial pressure, the decreases in lobar arterial pressure with zaprinast infusion were significantly greater than those produced by milrinone. CONCLUSIONS These data show that zaprinast and milrinone exert a direct in vivo vasodilator effect on the PV bed at low (zaprinast) and elevated (zaprinast and milrinone) PV tone; however, at elevated PV tone, the pulmonary vasodilator effect was greater with zaprinast then with milrinone. This suggests that phosphodiesterase-5 inhibitors may potentially offer a therapeutic alternative in the management of acute pulmonary hypertension.