title: Antagonism of thromboxane receptors by diclofenac and lumiracoxib.
abstract: OBJECTIVE
  Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesic and anti-inflammatory by virtue of inhibition of the cyclooxygenase (COX) reaction that initiates biosynthesis of prostaglandins. Findings in a pulmonary pharmacology project gave rise to the hypothesis that certain members of the NSAID class might also be antagonists of the thromboxane (TP) receptor.
  
  
  METHODS
  Functional responses due to activation of the TP receptor were studied in isolated airway and vascular smooth muscle preparations from guinea pigs and rats as well as in human platelets. Receptor binding and activation of the TP receptor was studied in HEK293 cells.
  
  
  RESULTS
  Diclofenac concentration-dependently and selectively inhibited the contraction responses to TP receptor agonists such as prostaglandin D2 and U-46619 in the tested smooth muscle preparations and the aggregation of human platelets. The competitive antagonism of the TP receptor was confirmed by binding studies and at the level of signal transduction. The selective COX-2 inhibitor lumiracoxib shared this activity profile, whereas a number of standard NSAIDs and other selective COX-2 inhibitors did not.
  
  
  CONCLUSIONS
  Diclofenac and lumiracoxib, in addition to being COX unselective and highly COX-2 selective inhibitors, respectively, displayed a previously unknown pharmacological activity, namely TP receptor antagonism. Development of COX-2 selective inhibitors with dual activity as potent TP antagonists may lead to coxibs with improved cardiovascular safety, as the TP receptor mediates cardiovascular effects of thromboxane A2 and isoprostanes.
authors.affiliation: Division of Physiology, Centre for Allergy Research, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Selg
authors.forename: C
authors.initials: C
authors.lastname: Buccellati
authors.forename: M
authors.initials: M
authors.lastname: Andersson
authors.forename: G E
authors.initials: GE
authors.lastname: Rovati
authors.forename: M
authors.initials: M
authors.lastname: Ezinga
authors.forename: A
authors.initials: A
authors.lastname: Sala
authors.forename: A-K
authors.initials: AK
authors.lastname: Larsson
authors.forename: M
authors.initials: M
authors.lastname: Ambrosio
authors.forename: E
authors.initials: E
authors.lastname: Ambrosio
authors.forename: L
authors.initials: L
authors.lastname: Låstbom
authors.forename: V
authors.initials: V
authors.lastname: Capra
authors.forename: B
authors.initials: B
authors.lastname: Dahlén
authors.forename: A
authors.initials: A
authors.lastname: Ryrfeldt
authors.forename: G C
authors.initials: GC
authors.lastname: Folco
authors.forename: S-E
authors.initials: SE
authors.lastname: Dahlén
mesh_terms: D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004008:Diclofenac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017482:Receptors, Thromboxane; D004008:Diclofenac; C473384:lumiracoxib