title: Intratracheal instillation of a novel NO/nucleophile adduct selectively reduces pulmonary hypertension.
abstract: We examined the pulmonary and systemic hemodynamic effects of administering soluble nitric oxide (NO) donor compounds (NO/nucleophile adducts, i.e., NONOates) directly into the trachea of animals with experimentally induced pulmonary hypertension. Steady-state pulmonary hypertension was created by using the thromboxane agonist U-46619. Yorkshire pigs were randomly assigned to one of four groups: group 1, intratracheal saline (control; n = 8); group 2, intratracheal sodium nitroprusside (n = 6); group 3, intratracheal ethylputreanine NONOate (n = 6); and group 4, intratracheal 2-(dimethylamino)-ethylputreanine NONOate (DMAEP/NO; n = 6). Pulmonary and systemic hemodynamics were monitored after drug instillation. Group 4 had significant reductions in pulmonary vascular resistance index (PVRI) at all time points compared with steady state and compared with group 1 (P < 0.05), whereas systemic vascular resistance index did not change. The mean change in mean pulmonary arterial pressure in group 4 was -33.1 +/- 1.2% compared with +6.4 +/- 1.3% in group 1 (P < 0.001), and the mean change in mean arterial pressure was -9.3 +/- 0.7% compared with a control value of -0.9 +/- 0.5% (P < 0.05). Groups 2 and 3 had significant decreases in both PVRI and systemic vascular resistance index compared with steady state and with group 1. In conclusion, intratracheal instillation of a polar-charged tertiary amine NONOate DMAEP/NO results in the selective reduction of PVRI. Intermittent intratracheal instillation of selective NONOates may be an alternative to continuously inhaled NO in the treatment of pulmonary hypertension.
authors.affiliation: Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati 45229, Ohio 45229, USA. brilr0@chmcc.org
authors.forename: R J
authors.initials: RJ
authors.lastname: Brilli
authors.forename: B
authors.initials: B
authors.lastname: Krafte-Jacobs
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Roselle
authors.forename: D
authors.initials: D
authors.lastname: Passerini
authors.forename: A
authors.initials: A
authors.lastname: Vromen
authors.forename: L
authors.initials: L
authors.lastname: Moore
authors.forename: C
authors.initials: C
authors.lastname: Szabó
authors.forename: A L
authors.initials: AL
authors.lastname: Salzman
mesh_terms: D000599:Amino Acids, Diamino / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001784:Blood Gas Analysis; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D007442:Intubation, Intratracheal; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D013552:Swine; D013931:Thromboxanes / Q000819:agonists; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C110153:2-(dimethylamino)ethylputreanine-nitric oxide adduct; D000599:Amino Acids, Diamino; D000959:Antihypertensive Agents; D013931:Thromboxanes; D014665:Vasodilator Agents; C110152:ethylputreanine-nitric oxide adduct; D009599:Nitroprusside; D009569:Nitric Oxide