Adenovirus-mediated transfer of COX-1 to angioplasty-injured carotid arteries was efficacious in augmenting PGI2 synthesis and was associated with an inhibition of thrombosis when a relatively high titer of adenovirus was instilled.

The goal of the present study was to demonstrate that intracoronary platelet deposition may trigger intense vasoconstriction of large epicardial coronary arteries in vivo and that this is largely mediated by thromboxane A2 and serotonin released by activated platelets. Cyclic flow variations (progressive declines in blood flow followed by sudden restorations of flow) due to recurrent intracoronary platelet activation and thrombus formation were induced by damaging the endothelium and placing a cylindrical constrictor on the left anterior descending coronary artery (LAD) in open-chest, anesthetized dogs. Coronary diameters were measured in vivo by means of ultrasonic crystals sutured on the LAD immediately distal to the constrictor (LADI) and 1 cm below (LAD2) and on the circumflex coronary artery (Cx). Coronary artery diastolic diameters were measured continuously before and during cyclic flow variations and after they were abolished by administration of LY53857, a serotonin-receptor antagonist (group 1, n =7), or SQ29548, a thromboxane-receptor antagonist (group 2, n = 7). During cyclic flow variations, at the nadir of coronary flow, LADI (a site of maximal platelet accumulation) cross-sectional area decreased by 52±10% and 38±6% in group 1 and 2 animals, respectively (p <0.001 compared with values recorded during a brief LAD occlusion obtained by a suture snare), whereas LAD2 (a site of minimal or no platelet accumulation) cross-sectional area did not differ from that recorded during the brief LAD occlusion. SQ29548 abolished cyclic flow variations in seven of seven dogs and LY53857 in six of seven, but they affected the increased coronary vasoconstriction differently: LADI cross-sectional area increased by 32±N6% of the control value in SQ29548-treated animals, whereas it returned to baseline dimension values in the LY53857-treated group as these interventions also abolished the cyclic flow variations. We conclude that a marked coronary vasoconstriction may be triggered by local platelet deposition and that thromboxane A2 and serotonin are mediators of this vasoconstriction. (Circulation 1989;79:154-166) It is currently believed that the pathophysiology of unstable angina is a primary reduction in coronary blood flow.

Cyclic variations in coronary blood flow (CFVs) in dogs with experimental coronary artery stenosis and endothelial injury appear to result primarily from the aggregation of platelets at the site of stenosis followed by dislodgement and distal embolization. Using this canine model, we tested the hypotheses: (a) that thrombin is an important mediator of CFVs in dogs with coronary stenoses and endothelial injury; (b) that inhibition of thrombin with heparin, or MCI-9038, a selective thrombin inhibitor, abolishes CFVs in this model; and (c) that abolition of CFVs by thrombin inhibition is time dependent. CFVs, produced in open-chest dogs by placing a flow-reducing plastic constrictor around the left anterior coronary artery, were monitored for either 30 min (group I) or 3 h (group II) before treatment with either heparin or 4-methyl-14N'-+(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) No. 3, 678-684, 1988. CORONARY THROMBOLYSIS has recently received great attention for its potential reduction of the1 extent of necrosis after myocardial ischemia. Thrombolysis can be accomplished by infusion of streptoki-

Tissue factor (TF), the initiator of blood coagulation and thrombosis, is up-regulated after vascular injury and in atherosclerotic states. Systemic administration of recombinant TF pathway inhibitor (TFPI) has been reported to decrease intimal hyperplasia after vascular injury and also to suppress systemic mechanisms of blood coagulation and thrombosis. Here we report that, in heritable hyperlipidemic Watanabe rabbits, adenoviral gene transfer of TFPI to balloon-injured atherosclerotic arteries reduced the extent of intimal hyperplasia by 43% (P < 0.05) compared with a control vector used at identical titer (1 ؋ 10 10 plaque-forming units͞ml). Platelet aggregation and coagulation studies performed 7 days after local gene transfer of TFPI failed to show any impairment in systemic hemostasis. At time of sacrifice, 4 weeks after vascular injury, the 10 Ad-TFPI treated carotid arteries were free of thrombi, whereas two control-treated arteries were occluded (P, not significant). These findings suggest that TFPI overexpressed in atherosclerotic arteries can regulate hyperplastic response to injury in the absence of changes in the hemostatic system, establishing a role for local TF regulation as target for gene transfer-based antirestenosis therapies. vascular smooth muscle cell ͉ thrombosis ͉ restenosis ͉ hypercholesterolemia ͉ atherosclerosis