title: Anti-thrombotic effects of nebivolol and carvedilol: Involvement of β2 receptors and COX-2/PGI2 pathways.
abstract: BACKGROUND
  Third generation β-adrenolytics, such as selective β1 adrenoceptor antagonist nebivolol and non-selective β1/β2 and α1 adrenoceptor antagonist carvedilol, display beneficial nitric oxide (NO)-dependent vasodilator activities that contribute to their therapeutic efficacy. In the present work, we analyzed whether nebivolol and carvedilol, as well as other β-adrenolytics with similar pharmacological profiles (selective β1 adrenoceptor antagonist - atenolol and non-selective α/β adrenoceptor antagonist - labetalol), possess the ability to induce PGI2-dependent anti-thrombotic activity in vivo in normotensive rats.
  
  
  METHODS
  Anti-thrombotic effects of nebivolol and carvedilol were studied in vivo in anaesthetized rats with extracorporeal circulation superfusing collagen strips. We also assessed vasodilation induced by these drugs in isolated perfused guinea pig hearts according to Langendorff's procedures.
  
  
  RESULTS
  Nebivolol (both d- and l-isomers) (0.1-1mgkg(-1)) and carvedilol (1-3mgkg(-1)), but not atenolol (1mgkg(-1)) or labetalol (3mgkg(-1)), induced a dose-dependent and sustained anti-thrombotic response in rat model of thrombosis with extracorporeal circulation. The cyclooxygenase (COX)-2 inhibitors, rofecoxib (1mgkg(-1)) and indomethacin (5mgkg(-1)) abrogated this response, while l-NAME (5mgkg(-1)) had no significant effect. In the presence of β1/β2 adrenoceptor antagonist nadolol (1mgkg(-1)), but not in the presence of selective β1 adrenoceptor antagonist atenolol (4mgkg(-1)), anti-thrombotic responses to nebivolol, as well as carvedilol, were lost. Neither nebivolol nor carvedilol affected platelet aggregation in vitro, however both nebivolol and carvedilol induced NO-dependent vasodilation in guinea pig coronary circulation that was not dependent on β2 adrenoceptors.
  
  
  CONCLUSIONS
  We demonstrated for the first time that nebivolol and carvedilol, independently of their adrenergic receptor blocking activities, induced anti-thrombotic effects in vivo that involved β2 adrenoceptors and the activation of the COX-2/PGI2 pathway.
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland; Chair of Pharmacology, Grodno Medical University, Grodno, Belarus.
authors.forename: Valery I
authors.initials: VI
authors.lastname: Kozlovski
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lomnicka
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bartus
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sternak
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Kraków, Poland; Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D000068577:Nebivolol / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D005343:Fibrinolytic Agents; D011412:Propanolamines; D000068577:Nebivolol; D000077261:Carvedilol; D011464:Epoprostenol; D051546:Cyclooxygenase 2
keywords: Carvedilol; Nebivolol; Prostacyclin; Thrombosis; β-Adrenoceptors