Plasma P-selectin levels after angina increased significantly in patients with unstable angina but did not in patients with stable effort angina. These findings may contribute to understanding of the pathophysiology of the acute coronary syndrome of unstable angina.
Abstract-Platelet aggregation is inhibited through a negative feedback mechanism by the L-arginine/nitric oxide (NO) pathway found in platelets themselves. We have shown that long-term smoking impairs the bioactivity of platelet-derived NO (PDNO), resulting in an increased platelet aggregability. However, little is known about the relation between other coronary risk factors and PDNO release. Accordingly, this study was undertaken to examine whether other coronary risk factors are related to the impairment of PDNO bioactivity. We measured collagen-induced PDNO release with an NO-selective electrode in 61 subjects (mean age 47 years, range 24 to 74 years) who underwent complete physical and laboratory examinations. There was a significant inverse correlation between PDNO release and the number of coronary risk factors (rϭϪ0. Key Words: platelets Ⅲ nitric oxide Ⅲ risk factors Ⅲ atherothrombosis P latelets possess the functional L-arginine/nitric oxide (NO) pathway via constitutive NO synthase. 1,2 Platelet-derived NO (PDNO) increases the intraplatelet level of cGMP and inhibits platelet aggregation. 1 This modulation of platelet aggregation via the L-arginine/NO pathway is recognized as a negative-feedback mechanism to inhibit aggregation. 3,4 Using an NO-selective electrode, we 5 and others 6 directly measured PDNO release during platelet aggregation, which was potentiated by L-arginine and attenuated by inhibitors of NO synthase, indicating the existence of an L-arginine/NO pathway in human platelets. 1,7 PDNO has been shown to play a functional role in the inhibition of not only platelet activation but also platelet recruitment after aggregation. 8 Recently, we have shown that long-term smoking impairs PDNO release, resulting in an increased platelet aggregability. 5 However, little is known about the relation between other coronary risk factors and PDNO release. Accordingly, the present study was undertaken to investigate the hypothesis that other coronary risk factors impair platelet function and thereby affect PDNO release in subjects with major risk factors. Methods Study SubjectsThe study population consisted of 61 subjects who agreed to participate in the study. The subjects underwent complete routine physical and laboratory examinations, and their complete anamnesis was obtained. Of the 61 subjects, 42 were healthy volunteers, 12 had stable effort angina, and 7 had previous myocardial infarction. Medications, including long-acting nitrates, calcium channel blockers, -blockers, and ACE inhibitors, were withheld for Ն24 hours, and aspirin was withheld for Ն1 week before the study. None of the patients had received cholesterol-lowering agents. Patients with acute coronary syndromes, valvular heart diseases, or heart failure were excluded from the study. The present protocol was approved by our institutional ethic committee, and informed consent for the study was obtained from all patients. Definition of Coronary Risk FactorsCoronary risk factors in this study were determined according to the Sixth Report o...
Abstract-Cell adhesion molecules may play an important role in the disease process of acute coronary syndromes. We have shown a neutralizing anti-P-selectin monoclonal antibody and a sialyl Lewis x -containing oligosaccharide (SLe x -OS), an analogue of selectin ligand on leukocytes, reduce cyclic flow variations (CFVs) in a canine model of recurrent coronary arterial thrombosis, suggesting the important interaction between P-selectin and SLe x for the pathophysiology of these syndromes. However, the functional role of these adhesion molecules in the thrombotic process remains unclear. Therefore, we investigated effects of SLe x -OS on CFVs, platelet P-selectin expression, and morphology of the stenotic site in the same model. Anesthetized open-chest dogs (nϭ34) were randomly divided into 4 groups after developing CFVs. Dogs intravenously received saline or graded doses of SLe x -OS (5, 20, or 40 mg/kg bolus) infusion followed by a continuous infusion (5 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 ) for 60 minutes. By flow cytometric analysis, P-selectin expression on platelets after CFVs was significantly upregulated during CFVs. Immunohistochemical analysis revealed the incorporation of platelets with upregulated P-selectin within thrombi at the stenotic site. Microscopic observations revealed the presence of numerous platelets adhered to leukocytes at the stenotic site on the damaged endothelium. SLe x -OS significantly reduced CFVs, inhibited the P-selectin expression on platelets, and prevented the adherence of platelets and leukocytes. These findings further support the notion that the adhesive interaction between P-selectin on platelets and SLe x on leukocytes plays an important role in platelet-mediated thrombus formation in this model.
Abstract-We investigated whether platelet responsiveness to nitroglycerin (NTG) is maintained in long-term smokers and if not, the mechanism. In the absence or presence of NTG, intraplatelet reduced glutathione (GSH) levels and ADP-induced platelet aggregation and intraplatelet cGMP levels were measured in 10 long-term smokers and 10 age-matched nonsmokers. The intraplatelet GSH level was significantly lower in smokers than in nonsmokers (PϽ0.05).Platelet aggregation was dose-dependently inhibited by NTG in both groups; however, inhibition was significantly weaker in smokers. N-acetylcysteine (1 mmol/L), an exogenous thiol agent, significantly potentiated NTG-induced platelet inhibition in nonsmokers but not in smokers. The ADP-induced intraplatelet cGMP level was significantly greater in the presence of NTG in nonsmokers but not so in smokers. Because the effects of long-term smoking are multifactorial, a rabbit model was made by chronic administration of buthionine sulfoximine (BSO, nϭ6) to decrease intraplatelet GSH. The intraplatelet GSH level was significantly lower in BSO-treated rabbits than in saline-treated rabbits (PϽ0.001). The NTG-induced inhibition of platelet aggregation was significantly weaker in BSO rabbits. N-acetylcysteine-induced potentiation was not observed in BSO rabbits, whereas significant potentiation was found in saline rabbits. These findings were similar to those of long-term smokers. In contrast, the intraplatelet GSH-to-oxidized glutathione ratio, which represents the redox state of glutathione, was significantly lower in smokers than in nonsmokers, whereas no difference was found between saline rabbits and BSO rabbits. In conclusion, long-term smoking causes NTG resistance to aggregation in platelets, possibly through the depletion of intraplatelet GSH.
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