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Pulmonary Responses to Selective Phosphodiesterase-5 and Phosphodiesterase-3 Inhibitors^*

^* From the Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Correspondence to: Idit Matot, MD, Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, PO Box 12000, Jerusalem 91120, Israel; e-mail: matoth{at}cc.huji.ac.il

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.

Design: Prospective, randomized animal study.

Setting: Laboratory of university hospital.

Subjects: Experiments were performed in vivo in intact-chest, spontaneously breathing cats with controlled pulmonary blood flow and constant left atrial pressure.

Interventions: 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 A₂ 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.

Measurements and main 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.

Key Words: milrinone • phosphodiesterase inhibitor • pulmonary hypertension • thromboxane A₂ • vasodilation • zaprinast

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