title: Dual endothelin receptor blockade with tezosentan markedly attenuates hypoxia-induced pulmonary vasoconstriction in a porcine model.
abstract: OBJECTIVE
  Our aim was to test the hypothesis that dual endothelin receptor blockade with tezosentan attenuates hypoxia-induced pulmonary vasoconstriction.
  
  
  METHODS
  Fourteen anaesthetized, ventilated pigs, with a mean ± SEM weight of 30.5 ± 0.6 kg, were studied, in normoxia (FiO(2) 0.21) and with tezosentan (5 mg kg(-1)) infusion during (n = 7) or before (n = 7) hypoxia (FiO(2) 0.10).
  
  
  RESULTS
  Compared to normoxia, hypoxia increased (P < 0.05) pulmonary vascular resistance (PVR) by 3.4 ± 0.7 WU, mean pulmonary artery pressure by 13.7 ± 1.3 mmHg, mean right atrial pressure by 1.9 ± 0.4 mmHg and decreased (P < 0.02) systemic vascular resistance (SVR) by 5.2 ± 2.1 WU. Pulmonary capillary wedge pressure (PCWP), mean aortic blood pressure, heart rate, cardiac output, stroke volume and blood-O(2)-consumption were unaltered (P = ns). Tezosentan infused during hypoxia, normalized PVR, decreased (P < 0.05) maximally mean pulmonary artery pressure by 7.5 ± 0.8 mmHg, SVR by 5.8 ± 0.7 WU, mean aortic blood pressure by 10.8 ± 3.0 mmHg and increased (P < 0.04) stroke volume by 8.5 ± 1.8 mL. Mean right atrial pressure, PCWP, heart rate, cardiac output and blood-O(2) -consumption were unaltered (P = ns). Tezosentan infused before hypoxia additionally attenuated approx. 70% of the initial mean pulmonary artery pressure increase and abolished the PVR increase, without additionally affecting the other parameters.
  
  
  CONCLUSIONS
  Dual endothelin receptor blockade during hypoxia attenuates the 'sustained' acute pulmonary vasoconstrictor response by reducing the mean pulmonary artery pressure increase by approx. 62% and by normalizing PVR. Pre-treatment with tezosentan before hypoxia, additionally attenuates the initial hypoxia-induced mean pulmonary artery pressure rise by approx. 70% and abolishes the PVR increase, during stable circulatory conditions, without affecting oxygenation.
authors: The Öresund Cardiovascular Research Collaboration, The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden.
authors: P
authors: P
authors: Hedelin
authors: D
authors: D
authors: Kylhammar
authors: G
authors: G
authors: Rådegran
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007262:Infusions, Intravenous; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013552:Swine; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan