No redistribution of lung blood flow by inhaled nitric oxide in endotoxemic piglets pretreated with an endothelin receptor antagonist

J Appl Physiol (1985). 2015 Mar 15;118(6):768-75. doi: 10.1152/japplphysiol.00591.2014. Epub 2014 Dec 30.


Inhaled nitric oxide (INO) improves ventilation-perfusion matching and alleviates pulmonary hypertension in patients with acute respiratory distress syndrome. However, outcome has not yet been shown to improve, and nonresponse is common. A better understanding of the mechanisms by which INO acts may guide in improving treatment with INO in patients with severe respiratory failure. We hypothesized that INO may act not only by vasodilation in ventilated lung regions, but also by causing vasoconstriction via endothelin (ET-1) in atelectatic, nonventilated lung regions. This was studied in 30 anesthetized, mechanically ventilated piglets. The fall in oxygenation and rise in pulmonary artery pressure during a sepsislike condition (infusion of endotoxin) were blunted by INO 40 ppm. Endotoxin infusion increased serum ET-1, and INO almost doubled the ratio between mRNA expression of endothelin receptor A (mediating vasoconstriction) and B (mediating vasodilation and clearance of ET-1) (ET-A/ET-B) in atelectatic lung regions. INO caused a shift in blood flow away from atelectatic lung regions in the endotoxemic piglets, but not during ET receptor antagonism. We conclude that INO in short-term experiments, in addition to causing selective pulmonary vasodilation in ventilated lung regions, increases the ET-A/ET-B mRNA expression ratio in lung tissue. This might augment the vasoconstriction in atelectatic lung regions, enhancing the redistribution of pulmonary blood flow to ventilated lung regions which are reached by INO. Such vasoconstriction may be an important additional factor explaining the effect of INO.

Keywords: endothelin receptor; endothelin-1; hypoxemia; inhaled nitric oxide; lung perfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Endothelin Receptor Antagonists / pharmacology*
  • Endothelin-1 / metabolism
  • Endotoxins / pharmacology
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / physiopathology
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / physiopathology
  • Lung Injury / metabolism
  • Lung Injury / physiopathology*
  • Nitric Oxide / pharmacology*
  • Pulmonary Circulation / drug effects*
  • Pulmonary Circulation / physiology
  • RNA, Messenger / metabolism
  • Receptors, Endothelin / metabolism
  • Respiration / drug effects
  • Respiration, Artificial / methods
  • Respiratory Distress Syndrome / drug therapy
  • Respiratory Distress Syndrome / metabolism
  • Respiratory Distress Syndrome / physiopathology
  • Swine
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology


  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Endotoxins
  • RNA, Messenger
  • Receptors, Endothelin
  • Nitric Oxide