title: No redistribution of lung blood flow by inhaled nitric oxide in endotoxemic piglets pretreated with an endothelin receptor antagonist.
abstract: 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.
authors.affiliation: Department of Medical Sciences, Hedenstierna Laboratory, Uppsala University, Uppsala, Sweden; University Department of Anesthesiology and Pain Medicine, University Hospital, Inselspital, Bern, Switzerland;
authors.forename: Sebastien
authors.initials: S
authors.lastname: Trachsel
authors.affiliation: Department of Anesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Kristina
authors.initials: K
authors.lastname: Hambraeus-Jonzon
authors.affiliation: Department of Medical Sciences, Hedenstierna Laboratory, Uppsala University, Uppsala, Sweden;
authors.forename: Maria
authors.initials: M
authors.lastname: Bergquist
authors.affiliation: Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden;
authors.forename: Cecile
authors.initials: C
authors.lastname: Martijn
authors.affiliation: Department of Medical Sciences, Hedenstierna Laboratory, Uppsala University, Uppsala, Sweden; Karolinska Institutet, Solna, Sweden.
authors.forename: Luni
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medical Sciences, Hedenstierna Laboratory, Uppsala University, Uppsala, Sweden; goran.hedenstierna@medsci.uu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Hedenstierna
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D055370:Lung Injury / Q000378:metabolism / Q000503:physiopathology*; D009569:Nitric Oxide / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012121:Respiration, Artificial / Q000379:methods; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004731:Endotoxins; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D009569:Nitric Oxide
keywords: endothelin receptor; endothelin-1; hypoxemia; inhaled nitric oxide; lung perfusion