title: Prolonged pulmonary vasodilator action of inhaled nitric oxide by Zaprinast in awake lambs.
abstract: 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.
authors.affiliation: Department of Anesthesia, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: F
authors.initials: F
authors.lastname: Ichinose
authors.forename: C
authors.initials: C
authors.lastname: Adrie
authors.forename: W E
authors.initials: WE
authors.lastname: Hurford
authors.forename: W M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000280:Administration, Inhalation; D000818:Animals; D006152:Cyclic GMP / Q000097:blood*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D007262:Infusions, Intravenous; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011450:Prostaglandin Endoperoxides, Synthetic; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011688:Purinones / Q000494:pharmacology*; D012756:Sheep; D013928:Thromboxane A2 / Q000031:analogs & derivatives; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D011450:Prostaglandin Endoperoxides, Synthetic; D011688:Purinones; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C011145:zaprinast; D006152:Cyclic GMP