title: Cyclooxygenase-2 inhibition and thromboxane A(2)  receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model.
abstract: OBJECTIVE
  Hypoxic pulmonary vasoconstriction (HPV) causes pulmonary hypertension that may lead to right heart failure. We hypothesized that the COX-2 inhibitor nimesulide and the thromboxane A(2) receptor antagonist daltroban would attenuate HPV.
  
  
  METHODS
  Haemodynamic measurements and blood sampling were performed in 18 anaesthetized, mechanically ventilated pigs, with mean ± SEM weights of 31.3 ± 0.6 kg, in normoxia (F(i)O(2)~0.21) and hypoxia (F(i)O(2)~0.10), before and 5, 15 and 45 min after initiation of right atrial infusion of nimesulide (n = 6) or daltroban (n = 6), respectively, and in six control pigs.
  
  
  RESULTS
  Compared with normoxia, hypoxia (n = 18) increased mean pulmonary artery pressure by 15.8 ± 0.8 mmHg (P < 0.001), pulmonary vascular resistance (PVR) by 2.7 ± 0.3 WU (P < 0.05) and mean right atrial pressure by 2.3 ± 0.3 mmHg (P < 0.001). In the control pigs, mean pulmonary artery pressure, PVR and mean right atrial pressure remained stable (P = ns) throughout 45 min hypoxia, compared with hypoxia baseline. Nimesulide decreased mean pulmonary artery pressure by 3.7 ± 1.3 mmHg after 45 min (P < 0.013), as well as PVR by 0.8 ± 0.2 WU (P < 0.05), levelling off after 15 min. Daltroban transiently increased (P < 0.001) mean pulmonary artery pressure and mean right atrial pressure by 7.2 ± 1.2 and 2.7 ± 0.4 mmHg, respectively, but they returned to hypoxia baseline (P = ns) within 5 min. Daltroban then decreased mean pulmonary artery pressure to after 45 min be 4.2 ± 1.6 mmHg lower (P < 0.005) than at hypoxia baseline.
  
  
  CONCLUSIONS
  COX-2 inhibition and thromboxane A(2) receptor antagonism attenuate HPV by decreasing mean pulmonary artery pressure by approximately 10-11%, as measured 45 min after initiation of nimesulide or daltroban infusion respectively.
authors.affiliation: The Öresund Cardiovascular Research Collaboration, The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden. david.kylhammar@med.lu.se
authors.forename: D
authors.initials: D
authors.lastname: Kylhammar
authors.forename: G
authors.initials: G
authors.lastname: Rådegran
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D000860:Hypoxia; D008168:Lung / Q000098:blood supply*; D010648:Phenylacetates / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C051762:daltroban; C012655:nimesulide