title: Endogenous nitric oxide and pulmonary vascular tone in the neonate.
abstract: OBJECTIVE
  In newborns, inhaled nitric oxide (NO) has been shown to ameliorate increased pulmonary vascular resistance (PVR) precipitated by hypoxia. The role of endogenous NO production in this response is not clear. The contribution of endogenous NO to resting PVR in normoxic newborns also has not been well studied. The authors used an isolated, in situ, neonatal piglet lung-perfusion model, devoid of systemic detractors in which endogenous NO could be selectively inhibited, to determine whether (1) endogenous NO plays a role in the maintenance of PVR with normoxia, (2) endogenous NO plays a role in the response to hypoxia, and (c) inhaled NO can reverse changes induced by inhibition of endogenous NO.
  
  
  METHODS
  Sixteen neonatal piglets underwent occlusive tracheostomy and pressure-cycled ventilation. After heparinization and ligation of the ductus arteriosus, left atrial and pulmonary arterial cannulation were performed, without ischemia, via a median sternotomy. The aorta was ligated, and lung perfusion was set at 80 mL/kg/min via an extracorporeal membrane oxygenation circuit. Hematocrit (40% to 45%), pH (7.37 to 7.44), Pco2 (35 to 40 mm Hg), and peak inspiratory pressures (20 mm Hg) were constant. Pulmonary artery pressure (PPA), left atrial pressure (PLA), and circuit flow (QPA) were recorded continuously. PVR calculated as follows: PVR[(dynes x seconds x cm(-5)) x 1,000] = [(PPA-PLA/(QPA x 1,000/60)] x 1,332. The experimental animals were ventilated with normoxic gas (FIO2, 0.21), followed by hypoxic gas (FIO2, 0.07), returned to normoxia, and then divided into two groups of eight animals each. One group remained normoxemic (FIO2, 0.21; SPA02, 100%) while the other group was made hypoxemic by ventilation with hypoxic gas (FIO2, 0.07; SPA02, 50%). Endogenous NO was suppressed with L-arginine-N-omega methyl ester (L-NAME) at 40 mg/kg in both groups. Inhaled NO was given at 40 ppm in both groups. Analysis of variance for repeated measures was used to test for statistical significance.
  
  
  RESULTS
  Baseline normoxic PVR (3,403 +/- 1,169) was increased significantly by hypoxia (6,524 +/- 1,018, P < .01) and was fully resorted to baseline by normoxia (3,497 +/- 1,079; P = NS). In normoxic animals, inhibition of endogenous NO production by L-NAME increased PVR to levels similar to those seen during hypoxic stress (6,345 +/- 1,441, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to normoxic baseline values (3,986 +/- 1,363, P = NS). In hypoxic animals, inhibition of endogenous NO production by L-NAME also increased PVR from hypoxic baseline (9,655 +/- 1,642, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to hypoxic baseline (6,450 +/- 1,796, P = NS).
  
  
  CONCLUSIONS
  In this piglet model, endogenous NO is important in the regulation of pulmonary vascular tone during both normoxia and hypoxia. Inhaled NO completely reversed the elevations in PVR caused by inhibition of endogenous NO and may normalize PVR in diseases in which the production of endogenous NO is compromised.
authors.affiliation: Division of Pediatric Surgery, Columbia University, New York, NY, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Lipsitz
authors.forename: S
authors.initials: S
authors.lastname: Weinstein
authors.forename: A J
authors.initials: AJ
authors.lastname: Smerling
authors.forename: C J
authors.initials: CJ
authors.lastname: Stolar
mesh_terms: D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D007231:Infant, Newborn; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology* / Q000627:therapeutic use; D011652:Pulmonary Circulation / Q000502:physiology*; D015656:Respiratory Mechanics; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester