title: Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs.
abstract: OBJECTIVE
  To determine the effects of inhaled nitric oxide on endogenous cyclic adenosine monophosphate in the intact lamb, and to determine the potential role of cyclic adenosine monophosphate in the rebound pulmonary hypertension associated with nitric oxide withdrawal.
  
  
  METHODS
  Prospective, placebo-controlled experimental study.
  
  
  METHODS
  University-based basic science research laboratory.
  
  
  METHODS
  One-month-old lambs.
  
  
  METHODS
  Six 1-month-old control lambs, and 6 milrinone- (phosphodiesterase-3 inhibitor) treated lambs, were mechanically ventilated. Inhaled nitric oxide (40 ppm) was administered for 24 hrs and then acutely withdrawn. Sequential peripheral lung biopsies were obtained before, during, and 2 hrs after withdrawing inhaled nitric oxide therapy.
  
  
  RESULTS
  In control lambs, initiation of nitric oxide decreased left pulmonary vascular resistance by 29.6%, and withdrawal rapidly increased pulmonary vascular resistance by 77.1% (p <.05). Lung tissue cyclic adenosine monophosphate concentrations decreased by 25.3% during nitric oxide therapy (p <.05). In milrinone-treated lambs, nitric oxide decreased pulmonary vascular resistance by 26.6% (p <.05), but pulmonary vascular resistance was unchanged after acute withdrawal. Lung tissue cyclic adenosine monophosphate concentrations were preserved during nitric oxide therapy.
  
  
  CONCLUSIONS
  Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of guanosine-3',5'-cyclic monophosphate. However, alterations in endogenous nitric oxide/guanosine-3',5'-cyclic monophosphate during inhaled nitric oxide have been implicated in the clinically significant increases in pulmonary vascular resistance noted upon its acute withdrawal. Previous in vitro data suggest that exogenous nitric oxide/guanosine-3',5'-cyclic monophosphate can also alter cyclic adenosine monophosphate concentrations via their effect on cyclic adenosine monophosphate production and metabolism. The current in vivo study demonstrates that lung tissue cyclic adenosine monophosphate concentrations are decreased during inhaled nitric oxide and suggests a role for decreased cyclic adenosine monophosphate in the rebound pulmonary hypertension noted upon inhaled nitric oxide withdrawal. Milrinone may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic adenosine monophosphate concentrations and prevent rebound pulmonary hypertension.
authors.affiliation: Department of Cardiothoracic Surgery, University of California, San Francisco, CA, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Thelitz
authors.forename: Peter
authors.initials: P
authors.lastname: Oishi
authors.forename: Lucienne S
authors.initials: LS
authors.lastname: Sanchez
authors.forename: Janine M
authors.initials: JM
authors.lastname: Bekker
authors.forename: Boaz
authors.initials: B
authors.lastname: Ovadia
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johengen
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D045462:Endothelium-Dependent Relaxing Factors / Q000008:administration & dosage*; D006976:Hypertension, Pulmonary / Q000209:etiology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D020105:Milrinone / Q000494:pharmacology; D009569:Nitric Oxide / Q000008:administration & dosage*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects*; D028761:Withholding Treatment
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D000242:Cyclic AMP; D020105:Milrinone