Anti-thrombotic effects of nebivolol and carvedilol: Involvement of beta 2 receptors and COX-2/PGI(2) pathways

作者：Kozlovski Valery I; Lomnicka Magdalena; Bartus Magdalena; Sternak Magdalena; Chlopicki Stefan^*

来源：Pharmacological Reports, 2015, 67(5): 1041-1047.

DOI：10.1016/j.pharep.2015.03.008

• Nebivolol
• Carvedilol
• Prostacyclin
• beta-Adrenoceptors
• Thrombosis

Background: Third generation beta-adrenolytics, such as selective beta 1 adrenoceptor antagonist nebivolol and non-selective beta 1/beta 2 and alpha 1 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 beta-adrenolytics with similar pharmacological profiles (selective beta 1 adrenoceptor antagonist - atenolol and non-selective alpha,beta-adrenoceptor antagonist - labetalol), possess the ability to induce PGI(2)-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 Langendorffs procedures.
Results: Nebivolol (both D- and L-isomers) (0.1-1 mg kg(-1)) and carvedilol (1-3 mg kg(-1)), but not atenolol (1 mg kg(-1)) or labetalol (3 mg kg(-1)), induced a dose-dependent and sustained anti-thrombotic response in rat model of thrombosis with extracorporeal circulation. The cyclooxygenase (COX)-2 inhibitors, rofecoxib (1 mg kg(-1)) and indomethacin (5 mg kg(-1)) abrogated this response, while L-NAME (5 mg kg(-1)) had no significant effect. In the presence of beta 1/beta 2 adrenoceptor antagonist nadolol (1 mg kg(-1)), but not in the presence of selective beta 1 adrenoceptor antagonist atenolol (4 mg kg(-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 beta 2 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 beta 2 adrenoceptors and the activation of the COX-2/PGI(2) pathway.

• 出版日期2015