Effects of a new phosphodiesterase enzyme type V inhibitor (UK 343-664) versus milrinone in a porcine model of acute pulmonary hypertension

Background: Perioperative pulmonary hypertension remains a clinical challenge. The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available. This study evaluated the effects of a new intravenous sildenafil analogue--UK 343-664--compared with milrinone during acute pulmonary hypertension in a porcine model of thromboxane-induced pulmonary hypertension.

Methods: After acute pulmonary hypertension, 24 adult swine were randomized to 3 groups. Group 1 (n = 9) received an intravenous dose of 500 microg of UK 343-664, group 2 (n = 8) received milrinone 50 mg/kg, and group 3 (n = 7) received 10 mL of normal saline solution. All agents were administered for more than 5 minutes. Data were recorded continuously for 30 minutes.

Results: Both milrinone and UK 343-664 partially reversed thromboxane-induced pulmonary hypertension, with a notable decrease in mean pulmonary artery pressure and pulmonary vascular resistance and a concomitant increase in cardiac output. In addition, milrinone improved right ventricular contractility but produced marked systemic vasodilatation. In contrast, the administration of UK 343-664 was associated with pulmonary vasodilatation, without appreciable changes in systemic arterial pressure or vascular resistance.

Conclusions: Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity. Potential uses for this new phosphodiesterase enzyme type V inhibitor warrant further study.