The purpose of this study is to determine the ability of selective thromboxane (TXA2) synthetase inhibition or intra-arterial carbacyclin infuseion to improve arterial graft patency in dogs. In Part I of this study, th effect of an orally active, selective TXA2 synthetase inhibitor (U-63557A) will be compared with no treatment, low dose aspirin, and aspirin plus dipyridamole. The patency rates of autogenous jugular vein, polytetrafluoroethylene and Dacron femoral artery grafts will be assessed by arteriography for 8 weeks. Vein grafts will be modified by arterial outflow stenosis and endothelial damage caused by 37C saline storage, in order to simulate clinical conditions that reduce graft patency. Effects of these drug treatments of prostacyclin (PGI2) and TXA2 homeostasis will be measured by changes in platelet aggregation and serum levels of PGI2-TXA2 metabolites. Indium-111 labeled platelet imaging of prosthetic grafts and ex vivo In-111 counting of jugular vein grafts will allow correlation of drug treatment, platelet-graft deposition and graft patency. Vein graft and arterial production of PGI2 during drug treatment in both normal and endothelial damaged grafts will be measured by radio- immunoassay. Intimal fibroplasia at graft artery anastomoses will also be studied. In Part II of this study, a subcutaneously implanted, clinically tested infusion pump will be used to infuse carbacyclin, a chemically stable PGI2 analog, into the femoral artery, immediately proximal to one of bilateral femoral artery grafts. This route of administration eliminates unacceptable systemic side effects of intravenous PGI2 or carbacyclin infusion, but allows local vasodilation and potential anti-platelet effects. The patency rates of endothelial damaged jugular vein and Dacron grafts will be compared in treated and control (saline infused) animals. Regional blood flow of infused and non-infused contralateral hindlimbs will be compared by radiolabeled microsphere technique. Platelet-graft deposition will be measured by In-111 platelet imaging. Graft patency rates will be correlated with blood flow and platelet deposition to determine the relative importance of these predominant drug effects. The long term goal of this research is to identify pharmacologic methods to prolong arterial graft patency in selected patients who are at high risk for graft occlusion and limb loss.
