The effect of thromboxane receptor blockade versus thromboxane synthase inhibition on canine arterial graft patency.
This study compared the effects of a thromboxane synthase inhibitor, thromboxane receptor antagonist, and cyclooxygenase inhibitor in a canine arterial graft patency model. Fifty-six dogs were divided into a control (no treatment) and five treatment groups: thromboxane synthase inhibitor (U63557A; 15 mg/kg/tid); thromboxane receptor antagonist (SQ29548; 0.02 mg/kg/hr); high-dose aspirin (325 mg/day; low-dose aspirin (1 mg/kd/day; and aspirin plus dipyridamole (325 mg/day aspirin; 3 mg/kg/day dipyridamole). Drugs were orally administered except for thromboxane receptor antagonist, which was delivered intravenously by minosmotic pumps. After 24 hours of drug treatment, bilateral femoral artery prosthetic grafts (4 mm diameter x 7 cm; 1 polytetrafluoroethylene and 1 Dacron) were implanted. Patency was determined after 1 week. Dogs were classified before operation according to their epinephrine-enhanced arachidonate-stimulated platelet aggregation response. Polytetrafluoroethylene and Dacron graft patency rates were equivalent in all groups. Overall graft patency was significantly improved from 42% (control) to 94% by both high-dose aspirin and thromboxane receptor antagonist (p less than 0.001). Aspirin-dipyridamole also improved patency (83%; p less than 0.01 versus control), whereas thromboxane synthase inhibitor and low-dose aspirin were not effective. Baseline platelet aggregation was not predictive of patency. The drugs that promoted graft patency in this model either suppressed both thromboxane A2 and prostaglandin H2 formation (high-dose aspirin) or blocked their combined platelet receptor (thromboxane receptor antagonist). Thromboxane synthase inhibitor may be ineffective because prostaglandin H2 production is allowed. These data suggest that activation of the platelet thromboxane A2-prostaglandin H2 receptor is an essential event in early arterial graft thrombosis.
Bech
F R
FR
Section of Vascular Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH 03756.
Cronenwett
J L
JL
McDaniel
M D
MD
Ogletree
M L
ML
Freeman
D H
DH
D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004176:Dipyridamole / Q000494:pharmacology / Q000627:therapeutic use; D004285:Dogs; D005231:Fatty Acids, Unsaturated; D006083:Graft Occlusion, Vascular / Q000188:drug therapy / Q000517:prevention & control*; D006834:Hydrazines / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014654:Vascular Patency / Q000187:drug effects*
D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D004176:Dipyridamole; C045749:SQ 29548; D013930:Thromboxane-A Synthase; C039936:furegrelate; D001241:Aspirin