Experimental coronary artery thrombosis in the absence of thromboxane A2 synthesis: evidence for alternate pathways for coronary thrombosis.
The actions of the thromboxane synthetase inhibitor, U-63557A, were evaluated in vivo in anesthetized open-chest dogs by inducing left circumflex coronary artery (LCCA) thrombosis with low amperage electrical stimulation (100 microA for 6 h) of the intimal surface of the vessel, and ex vivo by assessing platelet aggregation and TXB2 production. U-63557A, 10 mg/kg + 5 mg/kg/h i.v., reduced ex vivo platelet aggregation in response to arachidonic acid (0.65 mM) by 93 +/- 2% (p less than 0.05, means +/- SEM), whereas the concurrent formation of TXB2 was decreased by 78 +/- 8% (p less than 0.05). TXB2 concentration also was reduced significantly in vivo as measured from coronary sinus blood samples; however, 6-keto-PGF1 alpha concentration was unchanged from predrug values. Despite the significant inhibition of platelet aggregation and TXB2 production, thrombus mass was not reduced: control, 32.0 +/- 5.9 mg (n = 7); U-63557A, 30.8 +/- 12.0 mg (n = 5, p = NS). These results suggest that U-63557A effectively inhibits TXA2 synthetase, but lacks antithrombotic activity in our experimental model. Therefore, substances other than TXA2 may be capable of mediating occlusive coronary artery thrombosis.
Hook
B G
BG
Schumacher
W A
WA
Lee
D L
DL
Jolly
S R
SR
Lucchesi
B R
BR
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy / Q000209:etiology*; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D013928:Thromboxane A2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000502:physiology*
D001572:Benzofurans; D005343:Fibrinolytic Agents; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase; C039936:furegrelate