Antithrombotic effects of the thromboxane A2 antagonist, SQ 28,668, in vitro and in the coronary circulation in vivo.
SQ 28,668 is a thromboxane receptor antagonist. In whole blood and platelet-rich plasma, micromolar concentrations of SQ 28,668 inhibited aggregation of human and porcine platelets induced by arachidonate and U-46,619, and the secondary phase of epinephrine-induced aggregation of human platelets. SQ 28,668 did not inhibit ADP-induced platelet aggregation and did not influence cAMP concentrations. High concentrations of SQ 28,668 inhibited platelet thromboxane synthase (IC50 = 660 microM), but SQ 28,668 did not inhibit cyclooxygenase or prostacyclin synthetase. In anesthetized pigs with pacing-induced tachycardia, placement of a critical stenosis at a focus of coronary vascular injury initiated a reproducible pattern of coronary blood flow reduction, reflecting thrombus formation at the site of injury. Treatment with SQ 28,668 (1.0 mg/kg, i.v.) abolished reductions in coronary blood flow in five of six pigs for 58 +/- 7 min and slowed the rate of blood flow reduction in the sixth. Before SQ 28,668 treatment, the rate of blood-flow reduction averaged 5.3 +/- 0.7 ml/min per min. Thirty and sixty minutes after treatment, the rates of blood-flow reduction averaged 0.6 +/- 0.6 and 2.1 +/- 1.0 ml/min per min, respectively (P less than 0.05). In control pigs, the rate of blood flow reduction before and 30 min after vehicle treatment averaged 5.7 +/- 2.0 and 5.5 +/- 1.6 ml/min per min, respectively (not significant). These findings indicate that SQ 28,668 is an effective antiplatelet agent in vitro and in vivo.
Ogletree
M L
ML
Department of Pharmacology, Squibb Institute für Medical Research, Princeton, New Jersey 08543-4000.
Harris
D N
DN
Heran
C L
CL
Phillips
M B
MB
Michel
I M
IM
Goldenberg
H J
HJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D005343:Fibrinolytic Agents; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013045:Species Specificity; D013552:Swine; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000378:metabolism
D001095:Arachidonic Acids; D005343:Fibrinolytic Agents; D011450:Prostaglandin Endoperoxides, Synthetic; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C050448:SQ 28668; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase