title: Cardiopulmonary bypass is associated with altered vascular reactivity of isolated pulmonary artery in a porcine model: therapeutic potential of inhaled tezosentan.
abstract: OBJECTIVE
  Whereas it is established that endothelin-1 elicits sustained deleterious effects on the cardiovascular system during cardiopulmonary bypass (CPB), presently it remains unknown whether the inhaled administration of the dual ETA and ETB antagonist tezosentan prevents the development of pulmonary endothelial dysfunction.
  
  
  METHODS
  A prospective, randomized laboratory investigation.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Landrace swine.
  
  
  METHODS
  Three groups of animals underwent a 90-minute period of full bypass followed by a 60-minute period of reperfusion. Among treated groups, one received tezosentan through inhalation prior to CPB, whereas the other one received it intravenously at weaning from CPB; the third group remained untreated. Pulmonary vascular reactivity studies, realized on a total of 285 rings, were performed in all groups, including 1 sham.
  
  
  RESULTS
  The contractility of pulmonary arteries to prostaglandin F2α and to the thromboxane A2 mimetic U46619 was preserved in animals submitted to CPB. By contrast, there were significant increases both in the maximal contraction to endothelin-1 and in the plasma levels of the peptide 60 minutes after reperfusion. Tezosentan administered by inhalation or intravenously did not prevent the development of pulmonary CPB-associated endothelial dysfunction. However, while hemodynamic disturbances were improved with both routes, the inhaled administration had a beneficial effect on oxygen parameters over intravenous administration.
  
  
  CONCLUSIONS
  Despite the blockade of the endothelin-1 pathway with tezosentan, the development of the pulmonary endothelial dysfunction associated with CPB still occurred. However, only the inhalation route had a significant impact on gas exchange during CPB.
authors.affiliation: Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiovascular Surgery, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiac Surgery, University Hospital of Strasbourg, Strasbourg, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mommerot
authors.affiliation: Department of Anesthesiology, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: André Y
authors.initials: AY
authors.lastname: Denault
authors.affiliation: Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiovascular Surgery, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Carrier
authors.affiliation: Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiovascular Surgery, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. Electronic address: Louis.perrault@icm-mhi.org.
authors.forename: Louis P
authors.initials: LP
authors.lastname: Perrault
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D011446:Prospective Studies; D011651:Pulmonary Artery / Q000503:physiopathology*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D044022:Receptor, Endothelin A / Q000187:drug effects; D044023:Receptor, Endothelin B / Q000187:drug effects; D013552:Swine; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan
keywords: CPB; endothelium; physiology/pathophysiology; pulmonary vascular resistance/hypertension; vascular tone and reactivity