Inhaled
nitric oxide (NO) has been shown to selectively dilate the pulmonary vasculature.
Zaprinast, an inhibitor of
guanosine 3',5'-cyclic monophosphate-specific
phosphodiesterase, augments smooth muscle relaxation induced by
endothelium-dependent vasodilators. The present study was designed to determine whether
intravenous administration of
Zaprinast potentiates the vasodilating effects or prolongs the duration of action of intermittent NO inhalation. Eight awake lambs with U-46619-induced
pulmonary hypertension breathed three concentrations of NO (5, 10, and 20 ppm) in a random order before and during an intravenous
Zaprinast infusion (0.1 mg.kg-1.min-1). Inhaled NO decreased pulmonary arterial pressure (PAP) in a dose-dependent fashion, with mean PAP reduction at 5, 10, and 20 ppm NO inhalation of 6 +/- 1, 7 +/- 1, and 9 +/- 1 (SE) mmHg, respectively. Although the
Zaprinast infusion did not change the magnitude of mean PAP reduction, it caused a statistically significant reduction of pulmonary vascular resistance and prolonged the duration of action of inhaled NO (half-times of
vasodilator response to 5, 10, and 20 ppm NO inhalation: 1.9 +/- 0.1, 2.1 +/- 0.2, and 2.1 +/- 0.2 min, respectively; half-times of NO inhalation with
Zaprinast: 9.7 +/- 1.7, 11.5 +/- 2.2, and 12.3 +/- 2.0, respectively). Plasma concentrations as well as the transpulmonary differences of
guanosine 3',5'-cyclic monophosphate were increased by the
Zaprinast infusion during NO inhalation. A stable level of pulmonary vasodilation was demonstrated in four additional lambs by combining intermittent NO breathing with an
intravenous infusion of
Zaprinast.