title: Haemodynamic and neuroendocrine effects of tezosentan in chronic experimental pulmonary hypertension.
abstract: OBJECTIVE
  Chronic pulmonary hypertension (PH) therapy is poorly investigated in intensive care. Our aim was to evaluate haemodynamic and neuroendocrine effects of the dual endothelin-1 (ET-1) blocker tezosentan in monocrotaline (MCT)-induced PH.
  
  
  METHODS
  Male Wistar rats (180-200 g, n = 194) randomly received 60 mg kg(-1) MCT or vehicle, subcutaneously, and 2 days later, a subgroup of MCT-injected rats was gavaged with 300 mg kg(-1) day(-1) bosentan (MCT BOS, n = 46), while another (MCT, n = 125) and control rats (Ctrl, n = 23) received vehicle. At 25-30 days, 48 h after interrupting bosentan, rats randomly underwent either a dose-response evaluation (0.5-20 mg kg(-1), n = 7 each group) or a 4 h perfusion of tezosentan (20 mg kg(-1) in 10 min + 10 mg g(-1) h(-1)) or vehicle (n = 8 per group, each). Haemodynamics, including blood gas analysis, were evaluated after thoracotomy under anaesthesia. After plasma, right ventricle (RV) and lung collection, plasma ET-1, cytokines, nitrate and 6-keto-PGF1α, and lung and right ventricular gene expression and cyclooxygenase (COX) and nitric oxide synthase (NOS) activities were quantified.
  
  
  RESULTS
  Monocrotaline resulted in PH, RV dilation and decreased cardiac output (CO) that were attenuated in MCT BOS. Pulmonary hypertension was attenuated by tezosentan without systemic hypotension. Tezosentan increased CO without changing ventilation-perfusion matching. Both bosentan and tezosentan reduced ET-1 and cytokine plasma levels and tissue expression, and inducible NOS and COX-2 RV activities. Bosentan increased nitrate plasma levels and non inducible NOS activities whereas tezosentan decreased circulating 6-keto-PGF1α but increased lung COX-1 activity.
  
  
  CONCLUSIONS
  Tezosentan may be useful for haemodynamic handling and bosentan replacement in critically ill PH patients exerting important beneficial neuroendocrine and anti-inflammatory actions.
authors.affiliation: Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: André P
authors.initials: AP
authors.lastname: Lourenço
authors.forename: Francisco
authors.initials: F
authors.lastname: Vasques-Nóvoa
authors.forename: José
authors.initials: J
authors.lastname: Oliveira-Pinto
authors.forename: Dulce
authors.initials: D
authors.lastname: Fontoura
authors.forename: Roberto
authors.initials: R
authors.lastname: Roncon-Albuquerque
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
mesh_terms: D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009489:Neurosecretion / Q000187:drug effects*; D009569:Nitric Oxide; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016278:Ventricular Function, Right / Q000187:drug effects
chemical_list: D016207:Cytokines; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; D009569:Nitric Oxide; C120582:tezosentan; D011451:Prostaglandin-Endoperoxide Synthases