Protective effects of triflusal on secondary thrombus growth and vascular cyclooxygenase-2.
BACKGROUND
Carotid residual mural thrombus predisposes to recurrent thrombosis and/or distal embolization (i.e. cerebrovascular ischemia).


OBJECTIVE
Our aims were (i) to analyze and compare the efficacy of aspirin, triflusal, and its main metabolite 2-hydroxy-4-trifluorometylbenzoic acid (HTB) on secondary thrombus growth; and (ii) evaluate to what extent the three Cox-1 inhibitors influenced vascular Cox-1/Cox-2 expression and endothelial prostacyclin synthesis.


METHODS
In a rabbit model of ex vivo thrombosis, a fresh mural thrombus was formed on damaged vessels at flow conditions typical of mild and severe carotid stenoses. The effects of Cox-1 inhibitors administered both intravenously (i.v.) (aspirin 5 mg kg(-1), triflusal 10 mg kg(-1), and HTB 10 mg kg(-1)) and orally (p.o.) (8 days; aspirin 30 mg kg(-1) day(-1), and triflusal 40 mg kg(-1) day(-1)) on secondary thrombus growth were assessed by In-(111)deposited platelets and compared with a placebo control. Arterial Cox-1/Cox-2 expression after 8-day treatment was evaluated at mRNA and protein levels. Additionally, a drug-related dose-dependent in vitro assay was performed for endothelial PGI(2) release measurement (Cox-2 activity).


RESULTS
All Cox inhibitors similarly and significantly (P < 0.05) reduced secondary thrombus formation after i.v. and p.o. administration versus placebo control. Treatments exerted no effect on vascular Cox-1 mRNA whereas Cox-2 mRNA was moderately reduced by aspirin and triflusal (placebo 100% +/- 9%, aspirin 70% +/- 2% and triflusal 70% +/- 2%; P < 0.05). Cox-2 protein levels were slightly higher in the triflusal versus aspirin group (placebo 100% +/- 6%, aspirin 35% +/- 10% and triflusal 61% +/- 9%; P < 0.005 versus placebo). Interestingly, in vitro, HTB solely maintained endothelial PGI(2) synthesis levels similar to the control.


CONCLUSIONS
At a similar level of efficacy in inhibiting secondary thrombosis, triflusal seems to better preserve Cox-2 expression than aspirin and its metabolite HTB was able to protect endothelial prostacyclin production.
Duran
X
X
Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Sánchez
S
S
Vilahur
G
G
Badimon
L
L
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001483:Base Sequence; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D012008:Recurrence; D012459:Salicylates / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*
D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D005343:Fibrinolytic Agents; D012333:RNA, Messenger; D012459:Salicylates; C016167:triflusal; C033502:4-trifluoromethylsalicylic acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin