benzofurans and Graft-Occlusion--Vascular

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.

Topics: Animals; Aspirin; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Dipyridamole; Dogs; Fatty Acids, Unsaturated; Graft Occlusion, Vascular; Hydrazines; Male; Platelet Aggregation; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vascular Patency

The response of canine platelets to arachidonic acid (AA) stimulation was studied as a predictor of thrombotic potential. Fifty mongrel dogs underwent in vitro platelet aggregation studies with adenosine diphosphate (ADP), collagen, and AA used as inducing agents. Thirty-two dogs were selected on the basis of their response to AA stimulation. Platelet aggregation in response to AA stimulation occurred in 16 (responders) and 16 showed no aggregatory response (nonresponders). The animals were divided into four groups. Group I received no antiplatelet agents (control); group II received U-63,557A, a specific thromboxane synthetase inhibitor (TSI); group III received aspirin; and group IV received aspirin and TSI. Polytetrafluoroethylene grafts were implanted in the carotid and femoral arteries of the dogs in all four groups. Plasma thromboxane (TxB2) levels were drawn before drug treatment and 4 weeks after surgery. Platelet deposition on the luminal surface of the implanted grafts was studied in vivo with a technique that uses both 111In-labeled platelets and 99mTc-labeled red blood cells and was expressed as percentage of indium excess (%IE). Group I (control) dogs whose platelets aggregated in response to AA stimulation had significantly higher 24-hour platelet deposition (%IE) on the luminal surface of implanted grafts (p less than 0.02), lower 4-week graft patency (p less than 0.002), and higher plasma TxB2 levels (p less than 0.01) than those dogs whose platelets did not aggregate. In contrast to the results of AA stimulation, neither ADP nor collagen responsiveness was discriminatory for the thrombotic potential of canine arteries as measured by 24-hour platelet deposition (%IE), 4-week graft patency, or plasma TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Benzofurans; Blood Vessel Prosthesis; Dogs; Graft Occlusion, Vascular; Platelet Aggregation; Polytetrafluoroethylene; Thromboxane B2; Thromboxane-A Synthase

We evaluated the effect of a selective thromboxane synthetase inhibitor (TSI) on the patency of autogenous vein grafts in dogs. Treatment involved oral dosing (10 mg/kg bid) of TSI or placebo, combined with local treatment of the graft with TSI or placebo (papavarine) at the time of implantation. At harvest, two animals, one from each oral dosing group, had an occluded graft; both grafts had been locally treated with papavarine. We found no significant histopathologic difference between graft treatment groups. Attempts to estimate the effect of TSI dosing on the prostacyclin/thromboxane balance through radioimmunoassay analysis of graft perfusates were unsuccessful. As measured by in vitro platelet aggregation, oral TSI was found to alter platelet function, though not in a dose-dependent fashion, and the animals rebounded toward normal at 12 hours.

Topics: Animals; Benzofurans; Blood Vessel Prosthesis; Dogs; Graft Occlusion, Vascular; Iliac Artery; Jugular Veins; Male; Platelet Aggregation; Thromboxane-A Synthase; Vascular Patency

This study examined the effect of an orally active thromboxane (TXA2) synthetase inhibitor (TSI) on the patency, TXA2 production, and platelet accumulation of reversed autogenous vein grafts. Ten dogs received TSI (U-63557A) 10 mg/kg po q8 hr for 6 weeks, beginning 24 hr prior to surgery, while 15 control dogs were untreated. One jugular vein was harvested and stored in 37 degrees C saline for 1 hr to induce mild endothelial injury (stored). Normal and stored jugular vein grafts (8 cm) were then implanted in opposite femoral arteries while 3-cm segments of the same veins were implanted in the carotid arteries. Femoral graft flow was restricted with a 5 Fr distal arterial stenosis and patency determined by arteriography at 1, 2, 4, and 6 weeks. Vein graft endothelial surface TXB2 production was measured by RIA at graft implantation and in carotid grafts harvested at 1 week. 111In-labeled platelets were given iv 24 hr prior to carotid graft harvest to determine graft-platelet deposition. TSI treatment improved early (1 week) femoral vein graft patency from 63 to 89% (P less than 0.05), a trend that persisted for 6 weeks. Warm saline storage reduced 1-week graft patency from 83 to 63% (P less than 0.05), a difference that decreased with time. TSI treatment resulted in a marked decrease in TXB2 production, but was not associated with decreased 111In-labeled platelet deposition in carotid vein grafts. Warm saline storage increased graft-platelet deposition which was predominant at the arterial anastomoses. TSI treatment may improve early vein graft patency during the transient period of endothelial injury.

Topics: Animals; Benzofurans; Blood Platelets; Carotid Arteries; Dogs; Female; Femoral Artery; Graft Occlusion, Vascular; Jugular Veins; Male; Thromboxane B2; Thromboxane-A Synthase; Time Factors; Tissue Preservation; Transplantation, Autologous

The purpose of this study was to assess the success of endothelial cell-seeded and non-seeded small-diameter vascular grafts in dogs medicated with antiplatelet agents. Eighty dogs underwent bilateral carotid artery replacements with 6 cm lengths of 4 mm I.D. double-velour Dacron grafts. In each dog one graft was seeded with enzymatically derived autologous endothelial cells; the contralateral graft was nonseeded. The following anti-platelet medications were administered beginning 4 days preoperatively: aspirin (5 grains every day); dipyridamole (50 mg twice a day); aspirin plus dipyridamole (5 grains each day plus 50 mg twice a day); aspirin (1.25 grains every other day); ibuprofen (10 mg/kg/day); U-53,059, a cyclooxygenase inhibitor (3 mg/kg/day); and U-63557A, a thromboxane synthase inhibitor (10 mg/kg/day). Grafts were harvested 5 weeks postoperatively. Graft success was evaluated by patency, thrombus-free surface area, area endothelialized, and graft production of prostacyclin. None of the medications prevented neoendothelialization of seeded grafts. Mean patencies of endothelial cell-seeded grafts from medicated dogs were significantly greater than mean patencies of endothelial cell-seeded grafts from nonmedicated dogs. The cyclooxygenase inhibitors best maintained patency in nonseeded grafts. Thrombus-free surface areas of endothelial cell-seeded grafts from medicated dogs were significantly greater than from nonseeded control grafts from the medicated dogs. All medications impaired prostacyclin synthesis. We conclude that the combination of endothelial cell seeding plus antiplatelet medication is most efficacious in small-vessel grafting success and that high levels of prostacyclin production by vascular grafts are not necessary to maintain patency in dogs medicated with antiplatelet agents.

Topics: Animals; Aspirin; Benzofurans; Blood Platelets; Blood Vessel Prosthesis; Carotid Arteries; Dipyridamole; Dogs; Endothelium; Female; Graft Occlusion, Vascular; Ibuprofen; Male; Polyethylene Terephthalates; Random Allocation; Thrombosis; Thromboxane-A Synthase