Effect of Endothelin-1 and Sarafotoxin S6b on Acute Platelet-Thrombus Formation in the Stenosed, Canine Coronary Artery
Endothelin-1 (ET-1), a recently discovered peptide produced by vascular endothelial cells, may play a role in the complex process of intravascular thrombus formation. The effect of ET-l or sarafotoxin S6b (a structural analogue of ET-l) on acute platelet-thrombus formation was examined in the stenosed canine coronary artery. A 70 - 80% stenosis was created by a plastic obstructor placed around the vessel. Endothelial cell and intimal damage were produced by compressing the vessel with vascular clamps. These conditions induced platelets to aggregate at the stenosed region, causing coronary blood flow to gradually decrease until it reached zero. At this point, the obstructor was mechanically agitated, dislodging the thrombus and restoring flow. A new platelet-thrombus then formed at the stenosed area, and the previous cycle was repeated. This repetitive flow pattern is referred to as cyclic flow reductions (CFRs). ET-1 and S6b (0.5 µg/kg, i.v. bolus) inhibited the development of an occlusive platelet-thrombus, as indicated by inhibition of CFRs. In addition, ET-l and S6b inhibited platelet-thrombus formation in dogs pretreated with aspirin (5 mg/kg), an inhibitor of prostacyclin (PGI2) production. PGI2 is a potent antiaggregatory agent also derived from the vascular endothelium. ET- 1 and S6b possess antithrombotic activity in vivo that is not due to the secondary release of PGI2. It is possible that the antithrombotic effects of ET-l demonstrated in this model may be due to a direct action of ET-l on platelets, or to endothelin-mediated release of other antiaggregtory factors.With honors.