Effects of intravenous Zaprinast and inhaled nitric oxide on pulmonary hemodynamics and gas exchange in an ovine model of acute respiratory distress syndrome.
BACKGROUND
Inhaled nitric oxide (No) selectively dilates the pulmonary vasculature and improves gas exchange in acute respiratory distress syndrome. Because of the very short half-life of NO, inhaled NO is administered continuously. Intravenous Zaprinast (2-o-propoxyphenyl-8-azapurin-6-one), a cyclic guanosine monophosphate phosphodiesterase inhibitor, increases the efficacy and prolongs the duration of action of inhaled NO in models of acute pulmonary hypertension. Its efficacy in lung injury models is uncertain. The authors hypothesized that the use of intravenous Zaprinast would have similar beneficial effects when used in combination with inhaled NO to improve oxygenation and dilate the pulmonary vasculature in a diffuse model of acute lung injury.


METHODS
The authors studied two groups of sheep with lung injury produced by saline lavage. In the first group, 0, 5, 10, and 20 ppm of inhaled NO were administered in a random order before and after an intravenous Zaprinast infusion (2 mg/kg bolus followed by 0.1 mg. kg-1. min-1). In the second group, inhaled NO was administered at the same concentrations before and after an intravenous infusion of Zaprinast solvent (0.05 m NaOH).


RESULTS
After lavage, inhaled NO decreased pulmonary arterial pressure and resistance with no systemic hemodynamic effects, increased arterial oxygen partial pressure, and decreased venous admixture (all P < 0.05). The intravenous administration of Zaprinast alone decreased pulmonary artery pressure but worsened gas exchange (P < 0.05). Zaprinast infusion abolished the beneficial ability of inhaled NO to improve pulmonary gas exchange and reduce pulmonary artery pressure (P < 0. 05 vs. control).


CONCLUSIONS
This study suggests that nonselective vasodilation induced by intravenously administered Zaprinast at the dose used in our study not only worsens gas exchange, but also abolishes the beneficial effects of inhaled NO.
Adrie
C
C
Department of Anesthesia and Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston 02114, USA.
Holzmann
A
A
Hirani
W M
WM
Zapol
W M
WM
Hurford
W E
WE
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008954:Models, Biological; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D011688:Purinones / Q000008:administration & dosage / Q000627:therapeutic use*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D012756:Sheep
D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009569:Nitric Oxide; C011145:zaprinast