Platelet-mediated obstruction of stenotic and endothelium-injured coronary arteries may be important in the abrupt progression from chronic stable to unstable coronary heart disease syndromes in patients. Transcardiac accumulation of thromboxane A2 and serotonin has been demonstrated in patients as chronic stable angina is converted to unstable angina. In this study in anesthetized open chest dogs with coronary artery stenosis and endothelial injury, thromboxane A2 and serotonin were shown to be important mediators of intermittent coronary obstruction caused by platelet aggregation and dynamic vasoconstriction. Furthermore, thromboxane A2 synthesis inhibitors and receptor antagonists and serotonin receptor antagonists, singly and together, provided substantial protection against repetitive platelet aggregation and dislodgment in canine models with coronary artery stenosis and endothelial injury even when systemic catecholamine concentrations were markedly elevated. These same observations apply in chronically instrumented, awake, unsedated dogs with coronary artery stenosis and endothelial injury in which recurrent platelet attachment and dislodgment cause cyclic flow alterations that may be prevented by thromboxane A2 synthesis inhibitors and receptor antagonists and serotonin receptor antagonists. Chronically instrumented dogs with coronary stenosis and endothelial injury in which recurrent platelet attachment and dislodgment occurred also developed neointimal proliferation of varying severity within 10 days to 3 weeks; the morphologic appearance of the neointimal proliferation was identical to that found in patients who develop restenosis after coronary angioplasty.