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Specific platelet mediators and the abrupt progression of coronary artery stenoses: experimental evidence and potential clinical implications
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FAILURE OF NITROGLYCERIN AND DILTIAZEM TO REDUCE PLATELET-MEDIATED VASOCONSTRICTION IN DOGS WITH CORONARY-ARTERY STENOSIS AND ENDOTHELIAL INJURY - FURTHER EVIDENCE FOR THROMBOXANE-A2 AND SEROTONIN AS MEDIATORS OF CORONARY-ARTERY VASOCONSTRICTION INVIVO
No full textPOTENTIAL USEFULNESS OF COMBINED THROMBOXANE-A2 AND SEROTONIN RECEPTOR BLOCKADE FOR PREVENTING THE CONVERSION FROM CHRONIC TO ACUTE CORONARY-ARTERY DISEASE SYNDROMES
No full textINHIBITION OF NEUTROPHIL ADHESION PROTEINS REDUCES NEOINTIMAL HYPERPLASIA FOLLOWING ARTERIAL INJURY IN RABBIT CAROTID ARTERIES
No full textENDOGENOUS AND EXOGENOUS NITRIC-OXIDE PROTECT AGAINST INTRACORONARY THROMBOSIS AND REOCCLUSION AFTER THROMBOLYSIS
No full textBackground Nitric oxide (NO), an endothelium-derived relaxing factor, plays an important role in regulating platelet activation. We evaluated the effect of NO in a canine model of intracoronary thrombosis, thrombolysis, and reocclusion. Methods and Results Before thrombosis was induced, 34 anesthetized dogs were treated with a continuous intracoronary infusion of saline (n=8); N-G-nitro-L-arginine (L-NNA, n=8), an inhibitor of NO synthetase; L-arginine (n=7), the precursor for NO; or sodium nitroprusside (SNP, n=11), an NO donor. Ten minutes after the infusion was begun, an electric current of 150 mu A was applied to the endothelium of coronary arteries to induce thrombosis. Occlusive thrombi developed in all dogs in the saline group (38+/-4 minutes) and the L-NNA group (30+/-6 minutes), in 6 of 7 dogs in the L-arginine group (81+/-18 minutes), and in 6 of 11 dogs in the SNP group (102+/-21 minutes) (P.05). After thrombolysis, coronary artery reocclusion developed in all reperfused dogs in the saline group (30+/-8 minutes) and in the L-NNA group (48+/-12 minutes), in 3 (of 4) reperfused dogs in the L-arginine group (123+/-26 minutes), and in 3 (of 4) reperfused dogs in the SNP group (128+/-19 minutes) (P<.01). The ex vivo platelet aggregation induced by collagen was inhibited after in vivo treatment with L-arginine or SNP. Conclusions Increasing NO production or giving an NO donor may inhibit platelet aggregation and delay intracoronary thrombus formation and reocclusion after thrombolysis
ROLE OF THROMBOXANE AND SEROTONIN AS MEDIATORS IN THE DEVELOPMENT OF SPONTANEOUS ALTERATIONS IN CORONARY BLOOD-FLOW AND NEOINTIMAL PROLIFERATION IN CANINE MODELS WITH CHRONIC CORONARY-ARTERY STENOSES AND ENDOTHELIAL INJURY
No full textPlatelet-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
ROLE OF NEW ANTIPLATELET AGENTS AS ADJUNCTIVE THERAPIES IN THROMBOLYSIS
No full textCoronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of th infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion
ENDOGENOUS NITRIC-OXIDE PROTECTS AGAINST PLATELET-AGGREGATION AND CYCLIC FLOW VARIATIONS IN STENOSED AND ENDOTHELIUM-INJURED ARTERIES
No full textBackground. This study was designed to test the hypothesis that endogenously produced nitric oxide protects against platelet aggregation and cyclic flow variations in stenosed and endothelium-injured arteries of mongrel dogs. Methods and Results. N(G)-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide formation, was administered at 5 mg/kg to 15 dogs after the left anterior descending coronary artery was mechanically injured and narrowed by external constrictors and to nine dogs before endothelial injury of the femoral artery and after injury and moderate arterial constriction. Treatment with L-NMMA resulted in cyclic How variations (as detected by external Doppler flow probes) in the left anterior descending artery of seven of 15 dogs and in the femoral artery of four of nine dogs after endothelial injury. L-Arginine, the precursor for nitric oxide synthesis, was administered at 60 mg/kg and abolished cyclic flow variations in each of the 11 dogs. D-Arginine did not change the L-NMMA-induced cyclic flow variations. Saline infusion did not induce or change cyclic flow variations in any of the animals. Acetylcholine (1, 10, and 100 mug/min; n=9) was administered in the femoral artery of nine additional dogs before and after endothelial injury in moderately stenosed femoral arteries. Acetylcholine did not induce cyclic flow variations in any animal; however, it did increase the severity of cyclic flow variations that developed in severely stenosed arteries. The diameter of the femoral artery was measured by intravascular ultrasound imaging. L-NMMA caused vasoconstriction of normal arteries, but no change was detected in endothelium-injured arteries. In contraSt, L-arginine caused vasodilation of normal arteries, but, again, no change was noted in endothelium-injured arteries. Acetylcholine dilated normal femoral arteries but constricted arteries with endothelial injury. In both in vitro and ex vivo platelet studies, L-NMMA enhanced platelet aggregation, whereas L-arginine significantly reduced platelet aggregation. D-Arginine and acetylcholine showed no effect on platelet aggregation. Conclusions. Promotion of nitric oxide production decreases platelet aggregation and may eliminate cyclic flow variations, whereas a reduction in nitric oxide formation enhances platelet aggregation and may induce cyclic flow variations. Acetylcholine causes vasoconstriction at the femoral arterial site of endothelial injury and may increase the severity of cyclic flow variations
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