An investigation of the antiplatelet effects of succinobucol (AGI-1067).
Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10-5-10-4M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.
a Institute of Cardiovascular and Medical Sciences , University of Glasgow , Glasgow , UK.|b Manchester Immunology Group , Manchester , UK.
Stephanie A
SA
Houston
a Institute of Cardiovascular and Medical Sciences , University of Glasgow , Glasgow , UK.|c Department of Physiology, Faculty of Medicine , National University of Malaysia Medical Centre , Kuala Lumpur , Malaysia.
Azizah
A
Ugusman
a Institute of Cardiovascular and Medical Sciences , University of Glasgow , Glasgow , UK.
Sukanya
S
Gnanadesikan
a Institute of Cardiovascular and Medical Sciences , University of Glasgow , Glasgow , UK.
Simon
S
Kennedy
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007083:Iliac Artery / Q000187:drug effects / Q000502:physiology; D008297:Male; D009213:Myography; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D053657:Platelet-Rich Plasma / Q000166:cytology; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D046509:Tissue Culture Techniques; D019820:Xanthine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000975:Antioxidants; D010975:Platelet Aggregation Inhibitors; D019820:Xanthine; D000244:Adenosine Diphosphate; D003094:Collagen; D014969:Xanthine Oxidase; C471047:succinobucol; D011341:Probucol
Lipid peroxidation; platelet aggregation; succinobucol; superoxide