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)

Differential inhibition of thromboxane A2 (TxA2) and prostacyclin (PGI2) biosynthesis has an antithrombotic potential, since it may change the TxA2/PGI2 formation ratio in a favourable direction. Very low doses of acetylsalicylic acid (ASA) have been demonstrated to elicit differential inhibition of TxA2 and PGI2 formation in healthy subjects; whether a similar effect can be obtained in patients with atherosclerosis is still an open question. We addressed this by analyzing the urinary excretion of the 2,3-dinor-metabolites of TxA2 (Tx-M) and PGI2 (PGI-M) in 10 patients with severe atherosclerosis during 10 consecutive days. The first three days were a basal period, under which no treatment was given. During the subsequent seven days a daily 50 mg oral dose of ASA was administered. In the basal state urinary Tx-M did not differ from that of PGI-M, the median excretion rates of the two eicosanoid metabolites being 526 (range 68-1490) and 562 (range 93-1970) pg/mg creatinine, respectively. During ASA treatment urinary Tx-M fell to a lower (p less than 0.001) level than PGI-M. Thus, during the last 5 days of ASA treatment the median excretion of Tx-M was depressed (p less than 0.001) to 148 (range 48-428) pg/mg creatinine, while that of PGI-M was decreased (p less than 0.01) to 313 (range 42-2658) pg/mg creatinine. These data indicate that a daily 50 mg dose of ASA inhibits cardiovascular formation of eicosanoids in patients with severe atherosclerosis and increased platelet TxA2 formation. Furthermore, this dose of ASA inhibits the formation of TxA2 more than that of PGI2.
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PMID:Differential inhibition of thromboxane A2 and prostacyclin synthesis by low dose acetylsalicylic acid in atherosclerotic patients. 210 95

RS-93427 is a potent, orally active prostacyclin-mimetic that is very rapidly absorbed but with generally long-lived actions in most species. It has antithrombotic, thrombolytic, and antivasospastic potential. Alone among several tested PGI-mimetics, it inhibits release of platelet mitogens more potently than its ability to inhibit aggregation. It also inhibits mitogen release from macrophages and vascular endothelial cells. RS-93427 is also potent at inhibiting macrophage accumulation of cholesteryl esters. These data suggest a broad spectrum of potential therapeutic utility for RS-93427 via the oral route. It might be useful both in acute manifestations of vascular occlusive disease involving thrombosis and vasospasm, in addition to the more chronic conditions involving intimal hyperplasia (as in arteriovenous grafts) and possibly frank atherosclerosis. Much work remains to be done, including examination of RS-93427 in chronic studies with various dosage forms, particularly in the study of atherosclerosis.
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PMID:Orally active prostacyclin-mimetic RS-93427: therapeutic potential in vascular occlusive disease associated with atherosclerosis. 295 59

Platelet activation, with subsequent formation of thromboxane A2 (TxA2), is thought to play a role in the development of arterial occlusion. In patients with severe atherosclerosis of the lower limbs, characterized by leg ulcers and rest pain, the basal formation of TxA2 and prostacyclin (PGI2) is increased. Corresponding data in patients with more moderate atherosclerosis of the lower limbs have not been reported. Since the capacity to physical exercise is not blunted in such patients proper evaluation of their TxA2-PGI2 synthesis should comprise not only assessment of the basal formation, but also TxA2/PGI2 biosynthesis during conditions of elevated cardiovascular activity. To address this, we analysed these eicosanoids in patients with a history of intermittent claudication. Urinary dinor-metabolites of TxB2 and PGI2 (Tx-M and PGI-M, respectively) were estimated by gas chromatography/negative ion-chemical ionization mass spectrometry in samples collected prior to, during and immediately after 20 min of severe treadmill exertion. The basal excretion of Tx-M was 105 +/- 26 pg/mg creatinine. It was not changed during exercise, but increased to 176 +/- 48 pg/mg creatinine (P less than 0.05) during the recovery. The basal excretion of PGI-M was 142 +/- 25 pg/mg creatinine. The PGI-M response to exercise varied from no change at all to a 30-fold increase, without any obvious correlation to experienced leg pain, walking distance or other recorded variables. During the recovery period the outflow of PGI-M was significantly higher than at rest (482 +/- 145 pg/mg creatinine; P less than 0.01). We conclude that in patients with intermittent claudication due to atherosclerosis (1) platelet activation does not occur during the course of the exercise, and (2) vascular prostacyclin formation can be dissociated from of TxA2 synthesis. The observed increase in PGI-M in some of the patients is suggested to reflect tissue ischaemia induced by the lack of adequate hyperaemia during exercise.
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PMID:Excretion of thromboxane A2 and prostacyclin metabolites during treadmill exercise in patients with intermittent claudication. 340 85

The pathogenesis of atherosclerosis, a major cause of age-related mortality, remains poorly understood. Although platelets and their products, including thromboxane A2, may be of importance in this process, little is known about eicosenoid biosynthesis and platelet function with increasing age. In order to address the hypothesis that platelet activation increases with age, we measured various indices of platelet function in a group of apparently healthy individuals over the age of 50 years. The circulating platelet aggregate ratio, plasma beta-thromboglobulin and threshold aggregating concentration of arachidonic acid were similar to those in healthy subjects aged less than 40 years. Although the bleeding time (168 +/- 24 vs 300 +/- 24 seconds) was significantly (p less than 0.001) shorter in the older volunteers this may be unrelated to platelet function and merely reflect age related changes in skin and/or vascular function. To further assess platelet and vascular function in vivo, we measured excretion of the major thromboxane and prostacyclin metabolites in urine, 2,3-donor-thromboxane B2 (Tx-M) and 2,3-dinor-6-keto-PGF1 alpha (PGI-M). Both Tx-M (223 +/- 22 vs 152 +/- 19 pg/mg creatinine; p less than 0.005) and PGI-M (198 +/- 21 vs 121 +/- 13 pg/mg creatinine; p less than 0.005) excretion were significantly higher in the older volunteers. These subtle but significant changes in eicosenoid biosynthesis are consistent with the presence of platelet activation in vivo increasing with age in apparently healthy individuals.
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PMID:Eicosenoid biosynthesis and platelet function with advancing age. 375 55

The levels of TxB2 and 6-keto-PGI alpha in the coronary sinus and thoracic aorta blood were determined in 14 patients with angina pectoris and signs of coronary atherosclerosis. 12 patients were involved in a dynamic study: before, during and 10 minutes after ischaemia-inducing atrial pacing. In all the patients atrial pacing resulted in a typical episode of angina, in 7 of them ST-segment depression of not less than 2 mm was seen on the ECG. In one patient arachidonic acid metabolites were evaluated during the control period and during a spontaneous episode of angina accompanied by ST-segment elevations. In 8 of 9 patients TxB2 was produced by the myocardium during atrial pacing. During monitored evaluation of arachidonic acid metabolites one patient with spontaneous angina demonstrated a gradual lowering of the 6-keto-PGI alpha, it being minimal by the beginning of the episode; TxB2 level increased more rapidly.
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PMID:[Thromboxane and prostacyclin in patients with stenocardia in induced and spontaneous ischemia of the myocardium]. 375 53

Prostacyclin (PGI2) synthesis seems to be one of the major physiological mechanisms involved in regulating platelet and vessel wall interactions. PGI2 is produced in large amounts by vascular endothelial cells, and vascular smooth muscle cells (SMC) also produce significant quantities. The capacity of SMC to produce PGI2, especially after endothelial injury, seems to be of importance. It is probably this type of situaton that is involved in the atherosclerotic process: experimental atherosclerosis in rabbits has been associated with a severe decrease in PGI, synthesis by arteries. Lipid peroxide accumulation within the arterial wall or in the plasma may also be involved in this process. Using arterial SMC in culture, we demonstrate here that, in comparison with healthy cultured cells, cells originating from atherosclerotic aorta have a decreased capacity to produce PGI2. The results were obtained using biological and radiochemical techniques and were confirmed by GC-MS. They suggest a potential role for PGI2 in inhibiting the atherosclerotic process.
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PMID:Prostacyclin production by cultured smooth muscle cells from atherosclerotic rabbit aorta. 699 46

Fibrinogen has been recognised in recent years as an independent risk factor in athero/thrombogenesis. However, the mechanism by which elevated fibrinogen translates into higher incidence of atherosclerosis is not known. One possible mechanism may be through the modification of fibrin. While it is already known that fibrin network is altered in disease states like peripheral vascular disease, diabetes, hypercholesterolaemia and myocardial infarction, the influence of altered fibrin network structure on growth and function of endothelial cells (EC) and fibroblasts (FB) requires investigation. Fibrin network structure in plasma clots was modified by changing pH and characterised using established biophysical methods. PGI(2), von Willebrand Factor (vWF), t-PA and PAI-1 were measured to evaluate changes in cell function induced by modified fibrin structure. In general, networks composed of thin fibres induced growth over their entire layer. Networks composed of thick fibres and open matrix promoted infiltration of cells into gel matrix and growth of macrovascular structures. Furthermore, thin fibres promoted a more prothrombotic environment as observed from changes in cell biochemical function. Fibrin, whilst initially acting as a scaffolding for cellular and biochemical processes, may also alter cell function and determine the progress of atherosclerosis.
Atherosclerosis 1997 Feb 28
PMID:Interaction of endothelial cells and fibroblasts with modified fibrin networks: role in atherosclerosis. 906 11

1. Chronic inhibition of nitric oxide synthase (NOS) provokes a hypertensive state which has been shown to be angiotensin II (Ang-II) dependent. In addition to raising blood pressure, NOS inhibition also causes leukocyte adhesion. The present study was designed to define the role of Ang-II in hypertension and in the leukocyte-endothelial cell interactions induced by acute NOS or cyclo-oxygenase (COX) inhibition using intravital microscopy within the rat mesenteric microcirculation. 2. While pretreatment with an Ang-II AT(1) receptor antagonist (losartan) reversed the prompt increase in mean arterial blood pressure (MABP) caused by indomethacin, it had no effect on the increase evoked by systemic L-NAME administration. 3. Pretreatment with losartan inhibited the leukocyte rolling flux, adhesion and emigration which occurs after 60 min NOS inhibition by 83, 80 and 70% respectively, and returned leukocyte rolling velocity to basal levels. 4. Losartan significantly reduced the leukocyte-endothelial cell interaction elicited by COX inhibition. In contrast, leukocyte recruitment induced by acute mast cell activation was not inhibited by losartan. 5. AT(1) receptor blockade also prevented the drop in haemodynamic parameters such as mean red blood cell velocity (V(mean)) and shear rate caused by NOS and COX inhibition. 6. In this study, we have demonstrated a clear role for Ang-II in the leukocyte-endothelial cell interactions and haemodynamic changes which arise in the absence of NO or prostacyclin (PGI(2)). This is of interest since leukocyte recruitment, which culminates in the vascular lesions that occur in hypertension, atherosclerosis and myocardial ischemia-reperfusion injury, might be prevented using AT(1) Ang-II receptor antagonists.
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PMID:Angiotensin II is involved in nitric oxide synthase and cyclo-oxygenase inhibition-induced leukocyte-endothelial cell interactions in vivo. 1115 20

By dietary manipulation of rats with n-3 polyunsaturated fatty acids (PUFAs), platelets and endothelium-containing aortic tissue were obtained with decreased levels of arachidonate and increased levels of eicosapentaenoate and docosahexaenoate. These diet-induced changes were accompanied by a reduced formation of thromboxane A(2) (TXA(2)) and prostaglandin I(2) (PGI(2)) in platelets and aortic tissue, respectively. When platelets were incubated with autologous, aorta-derived PGI(2), the dietary modulation of PGI(2) generation had a stronger effect on the activation process than the dietary effect on TXA(2) generation. The platelet-inhibiting effect of PGI(2) was independent of the type of agonist and involved both TXA(2)-dependent and -independent activation responses. PGI(2) also inhibited the agonist-induced formation of TXA(2). In addition, the platelet-inhibitory effect of PGI(2) was more prolonged in time than the brief, stimulatory effect of TXA(2). We conclude that, in the thromboxane-prostaglandin balance of platelet activation, PGI(2) plays a more prominent role than TXA(2). Furthermore, dietary n-3 PUFAs appear to influence platelet activation more by reducing formation of endothelial PGI(2) than by decreasing autocrine-produced TXA(2). Thus, in rats, the proposed antithrombotic effect of fish oil is unlikely to be caused by an altered thromboxane-prostaglandin balance.
Atherosclerosis 2001 Feb 01
PMID:Modulation of rat platelet activation by vessel wall-derived prostaglandin and platelet-derived thromboxane: effects of dietary fish oil on thromboxane-prostaglandin balance. 1116 68

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.
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PMID:Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. 1124 83


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