Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been proposed that atherosclerotic arteries produce less prostacyclin (PGI2) than nonatherosclerotic arteries do, thereby predisposing arteries to vasospasm and thrombosis in vivo. We reexamined this concept by measuring spontaneous as well as arachidonate-induced PGI2 biosynthesis in aortic segments from nonatherosclerotic and cholesterol-fed atherosclerotic New Zealand White rabbits. Thromboxane A2 (TXA2) generation was also measured. Formation of PGI2, as well as TXA2, as measured by radioimmunoassay (RIA) of their metabolites, was increased in atherosclerotic aortic segments relative to nonatherosclerotic segments (P less than or equal to 0.05) at 0, 5, 10, 15, and 30 min of incubation with arachidonate. Pretreatment of arterial segments with indomethacin inhibited PGI2 as well as TXA2 formation, whereas pretreatment with the selective TXA2 inhibitor OKY-046 inhibited only TXA2 release, thus confirming the identity of icosanoids. To confirm the RIA data, aortic segments were incubated with [14C]arachidonate prior to stimulation with unlabeled arachidonate. The uptake of arachidonate was similar, but the release of incorporated [14C]arachidonate was significantly (P less than or equal to 0.05) greater in atherosclerotic segments than in nonatherosclerotic ones. Conversions of released [14C]arachidonate to 6-keto[14C]prostaglandin F1 alpha and [14C]thromboxane B2 were similar in the two types of aortic segments. Thus, synthesis of PGI2 as well as TXA2 is increased in atherosclerosis, and this alteration in arachidonate metabolism is related to increased release of arachidonate.
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PMID:Increased prostacyclin and thromboxane A2 biosynthesis in atherosclerosis. 313 16

It is of great importance to clarify the role of thromboxane and prostacyclin in the process of atherosclerosis. In order to study this we induced atherosclerosis in rabbits through cholesterol feeding (1% w/w) for three to 12 weeks. After sacrifice the aorta was quickly removed and incubated. The in vitro thromboxane production measured as immunoreactive thromboxane B2 increased by 86 per cent in atherosclerotic vessels compared to control vessels (p less than 0.0005). The in vitro production of prostacyclin measured as immunoreactive 6-keto-prostaglandin F1 alpha showed a tendency to higher values in the atherosclerotic vessels compared to the control vessels (31%, p less than 0.025). This suggests that an increased thromboxane production rather than a decreased prostacyclin production might be important for the progression of atherosclerosis.
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PMID:Increased aortic thromboxane production in experimental atherosclerosis. 347 39

We studied the effects of smoking and nicotine on the production of proaggregatory thromboxane A2 (TxA2), antiaggregatory prostacyclin (epoprostenol, PGI2), and on lipid peroxidation in vivo and in vitro. In the in vivo study, serum concentrations of thromboxane B2 (TxB2), a stable metabolite of TxA2, increased immediately after smoking three cigarettes but not after smoking the equivalent amount of tobacco in a pipe, whereas serum lipid peroxide values did not change in either group. In vitro, nicotine (2 X 10(-3) mol/liter) inhibited pulmonary TxB2 production by 70% and simultaneously stimulated the production of 6-keto-prostaglandin F1 alpha, a stable metabolite of PGI2, by 40%, which suggest that nicotine does not exert its effect at the cyclooxygenase level. During aggregation in platelet-rich plasma, TxB2 production was inhibited by 53% with 2 X 10(-3) mol/liter of nicotine, and during whole blood clotting the inhibition was 34% with 2 X 10(-4) mol/liter of nicotine. Thus the rise in cigarette smokers' serum TxB2 was probably caused by some constituent of cigarette smoke other than nicotine. The increased production of TxA2 following cigarette smoking may provide one explanation for the increased incidence of atherosclerosis and its complications in cigarette smokers.
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PMID:Effects of smoking and nicotine on human prostacyclin and thromboxane production in vivo and in vitro. 351 66

Thromboxane A2 (TXA2) is mainly formed in thrombocytes. It promotes thrombocyte aggregation and contracts the blood vessels. TXA2 appears to be a specific physiological thrombotic agent. Synthesis of TXA2 is elevated in patients with diabetes mellitus of types I and II and in hypertensive patients. TXA2 has a half-life of about 30 s under physiological conditions. Prostacyclin (PGI2) is formed in the vessel walls. Its action is antagonistic to TXA2, that is, it inhibits platelet aggregation and dilates the blood vessels. Synthesis of PGI2 is depressed in the presence of the classical 4 main risk factors for atherosclerosis: arterial hypertension, hyperlipoproteinaemia, smoking and diabetes mellitus. PGI2 has a half-life of about 3 min under physiological conditions. Since TXA2 and PGI2 are very labile and thus extremely difficult to measure, it is at present usual to measure their stable metabolites thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Radioimmunological measurement (RIA) of TXB2 in plasma requires no preliminary work, but radioimmunological measurement of 6-keto-PGF1 alpha in plasma requires prior extraction and concentrating, since the concentration of 6-keto-PGF1 alpha in the plasma is usually below the detection limit of commercial RIA kits. This paper describes standardized conditions for drawing the blood sample, a simple method of extraction from plasma, and the reliability of two commercial RIA kits with 125I tracer in measuring TXB2 and 6-keto-PGF1 alpha in plasma.
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PMID:Routine measurement of thromboxane B2 and the prostacyclin metabolite 6-keto-prostaglandin F1 alpha in plasma. 377 54

Prostacycline may play a preventive role in the development of ischaemic complications of coronary atherosclerosis through its vasodilatory and platelet antiaggregant properties. Its biological instability makes it difficult to measure in the plasma; however, it is possible to determine plasma concentrations by radioimmune assay of one of its stable derivatives, 6-Keto-prostaglandin F1 alpha (6KPGF1 alpha). Systemic plasma concentrations at rest of 30 patients with severe atherosclerosis were not significantly different from those of healthy control subjects (7.5 +/- 6.5 vs 10 +/- 5 pg/ml). In addition ischaemia during exercise is not associated with significant variations; at rest 7.1 +/- 6 pg/ml in the "ischaemic" group (n = 20) compared to 7.6 +/- 6.4 pg/ml in the "non-ischaemic" group (n = 10); on effort: 9 +/- 10 pg/ml compared to 13.3 +/- 14 pg/ml. These results show that measuring the plasma 6KPGF1 alpha by peripheral vein blood sampling is of no use in the diagnosis of coronary atherosclerosis or of myocardial ischaemia on effort.
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PMID:[Endogenous prostacycline and coronaropathy. Plasma levels of 6-keto-PGF1 alpha]. 393 71

Prostacyclin is a potent vasodilator and platelet inhibitor produced by vascular endothelium. Endogenous production of prostacyclin under physiologic conditions is extremely low, far below the capacity of vascular tissue to generate this substance in response to stimulation in vitro. This may reflect a low frequency or intensity of stimulation of prostacyclin production. We postulated that if prostacyclin does act as an endogenous platelet-inhibitory agent, it should be produced in greater amounts in a clinical setting in which platelet-vascular interactions are likely to be increased. To test this hypothesis, we examined prostacyclin biosynthesis in patients with severe atherosclerosis and evidence of platelet activation in vivo. Excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha, a major urinary prostacyclin metabolite, was significantly higher in 9 patients with severe atherosclerosis and evidence of platelet activation (251 to 1859 pg per milligram of creatinine) than in 54 healthy volunteers (45 to 219 pg per milligram of creatinine; P less than 0.001). This difference represented an alteration in biosynthesis rather than in metabolism, since the fractional conversion of infused prostacyclin to the dinor metabolite was identical in both groups. Prostacyclin production may be low in healthy persons because there is almost no stimulus for its production but enhanced in patients with severe atherosclerosis as a consequence of platelet interactions with endothelium or other vascular insults. These observations are compatible with a role for prostacyclin as a local regulator of platelet-vascular interactions.
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PMID:Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. 623 83

Production of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and prostaglandin E2 (PGE2) was measured by radioimmunoassay in supernatants of isolated glomeruli from rats with streptozocin-induced diabetes and non-diabetic rats. Production of 6-oxo-PGF1 alpha by discs of aortas from these rats was measured at the same time. As shown before, aortic discs from diabetic rats produced significantly less 6-oxo-PGF1 alpha than aortic discs from non-diabetic rats (diabetic 1.99 +/- SEM 0.27 ng v non-diabetic 2.92 +/- 0.46 ng/mg net weight aorta; p less than 0.05). In contrast production of 6-oxo-PGF1 alpha by isolated glomeruli was not reduced in the diabetic rats (diabetic 77 +/- 7 pg v non-diabetic 70 +/- 8 pg/micrograms glomerular DNA). Similarly production of PGE2 was not diminished in the diabetic glomeruli (diabetic 1.20 +/- 0.15 ng v non-diabetic 0.91 +/- 0.12 ng/microgram glomerular DNA). It is concluded that regional differences in production of prostacyclin and 6-oxo-PGF1 alpha occur in experimental diabetes. Diminished prostacyclin production may contribute to the increased susceptibility of diabetic patients to atherosclerosis but is less likely to have a role in the pathogenesis of microangiopathy.
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PMID:Production of 6-oxo-prostaglandin F1 alpha and prostaglandin E2 by isolated glomeruli from normal and diabetic rats. 680 6

Plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 levels were determined to evaluate their role as predictive indicators for the development and progression of coronary atherosclerosis in young hypercholesterolemic swine. 32 young swine were randomly assigned to the control or atherogenic diet group for 10, 30, 90, or 180 days. Lipid profiles were obtained at the onset and repeated throughout the study. Radioimmunoassays of plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 were recorded at 10 day intervals in the 10 and 30 day subjects and at 30 day intervals in the 90 and 180 day subjects. Sections from the proximal left anterior descending coronary artery were classified based on their histological evidence of atherosclerosis by light microscopy. Hypercholesterolemia was positively correlated with development of coronary atherosclerosis (r = 0.704). However, plasma 6-keto-prostaglandin F1 alpha, thromboxane B2, and the thromboxane B2:6-keto-prostaglandin F1 alpha ratio were not found to be predictive indicators (p > 0.05) for the development or early progression of coronary atherosclerosis.
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PMID:Prostacyclin, thromboxane A2, and atherosclerosis in young hypercholesterolemic swine. 784 98

We studied 27 non-insulin-dependent diabetics without apparent atherosclerosis (AS) to investigate whether abnormal platelet function is related to asymptomatic atherosclerosis in diabetes mellitus. The degree of AS was quantitatively evaluated by determining the intimal plus medial thickness (IMT) of the carotid artery wall with ultrasound high-resolution B-mode imaging. Based on our previous finding that the upper threshold of the IMT was 1.1 mm in healthy subjects, the patients were divided into the AS-positive group with the IMT > 1.1 mm, (n = 17) and the AS-negative group with the IMT < 1.1 mm (n = 10). Among five variables measured as the factors concerned with thrombogenesis, only plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) were significantly higher in the AS-positive group than in the AS-negative group. Chronic administration of pentoxifylline (300 mg/day) significantly reduced the abnormally high plasma levels of beta-TG and PF4 in 7 patients of the AS-positive group to normal levels, without lowering the normal plasma beta-TG and PF4 levels in the remaining 10 patients. Pentoxifylline treatment did not affect the plasma levels of the 3 other variables, von Willebrand factor, 6-keto prostaglandin F1 alpha and thromboxane B2. This study suggests that the progress of atherosclerosis in diabetes mellitus is associated with in vivo platelet activation and platelet activation does not occur in diabetics without carotid atherosclerosis. Pentoxifylline may impede the vicious cycle in which atherosclerosis is accelerated by platelet activation.
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PMID:Platelet activation in diabetic patients with asymptomatic atherosclerosis. 795 14

The platelet-aggregatory response, platelet-release factors and markers of thrombin generation in vivo were studied prospectively in 53 patients participating in a randomized clinical trial evaluating the influence of nicardipine on the progression of coronary atherosclerosis. Coronary lesions were measured quantitatively and progression was defined as a decrease in minimum diameter by > or = 0.4 mm. At repeat angiography 24 months after study entry, 20 of the 53 patients had progression of 28 coronary narrowings. Only thrombin-induced enhanced platelet aggregation differentiated patients with from those without coronary disease progression, with an estimated odds ratio of 2.49 (95% confidence interval 1.10 to 5.66). The aggregatory response to adenosine diphosphate, collagen, epinephrine and platelet-activating factor were not different in the 2 groups of patients, nor were measurements of platelet factor 4, beta-thromboglobulin, thromboxane B2, 6-keto-prostaglandin F1 alpha and fibrinopeptide A. During 46.8 months of follow-up after repeat angiography, coronary events occurred in 11 of the 20 with and 6 of the 33 without progression (difference 37%, p = 0.013, confidence interval 11 to 63%). Those with coronary disease progression and an enhanced thrombin-induced platelet aggregation had a worse prognosis than those with no disease progression and a low thrombin-induced platelet aggregation. Thus, patients with coronary disease progression and future coronary events have an enhanced thrombin-induced platelet aggregation. This platelet abnormality may be a marker of increased risk and may play a causative role in the development of coronary events.
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PMID:Platelet aggregation, coronary artery disease progression and future coronary events. 810 46


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