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)

Fresh rings of arteries and veins obtained from surgical specimens generated an unstable substance, prostacyclin (prostaglandinx, [P.G.X]) WHICH IS A POTENT INHIBITOR OF PLATELET AGGREGATION. The spontaneous generation of prostacyclin as well as its generation from exogenous arachidonic acid was inhibit by incubation of the tissues with a prostaglandin-synthetase inhibitor such as indomethacin, whilst the generation induced by prostaglandin endoperoxides was not. 15-Hydroperoxyarachidonic acid (a lipid hydroperoxide) inhibited the generation of prostacyclin in all three situations. It is postulated that prostacyclin is important for prevention of deposition of platelets on the vessel wall and that the inhibition or prevention of the generation of prostacyclin is important in the genesis of diseases, especially those in which increased lipid peroxidation occurs, such as atherosclerosis.
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PMID:Human arterial and venous tissues generate prostacyclin (prostaglandin x), a potent inhibitor of platelet aggregation. 6 57

Prostaglandins (PG) are highly unsaturated, cyclic fatty acids with 20 carbon atoms which are biosynthesized from dihomo-gamma-linolenic, arachidonic and eicosapentaenoic acids. These fatty acids are either ingested or are biosynthesized from linoleic and linolenic acids, respectively. The PG-precursor fatty acids are liberated from membrane phospholipids by phospholipase A and are converted to prostaglandins by the multienzyme complex PG-synthetase. The activity of the PG-system is influenced by extracellular hormonal, neural and mechanical stimuli and by intracellular factors such as ion-concentration and activity of the enzymes adenyl- and guanylcyclase. Prostaglandins are tissue hormones or autacoids which act on their receptors near their site of synthesis and degradation. The prostaglandin family constitutes a group of more than 10 natural occurring compounds showing a variety of biological actions. In arteries and veins the different PG:s have vasodilating as well as vasoconstricting effects. In addition, they are involved in the regulation of vascular smooth muscle proliferation. Within the kidney PG:s have vascular and tubular actions. They antagonize the effect of ADH, mediate renin secretion and are involved in the control of electrolyte balance. In the regulation of platelet aggregation and platelet adhesion PG:s have opposite functions: Prostacyclin which is synthesized in the vascular wall antagonizes the aggregating action of Thromboxane A2 which is formed in the platelets. A defect or an imbalance in the production of PG:s in the vascular wall, in platelets or in the kidney is assumed to play a pathogenetic role in a variety of cardiovascular and renal diseases such as in hypertension, atherosclerosis, persistent ductus arteriosus and Bartter's syndrome.
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PMID:[Prostaglandins in cardiovascular and renal function. Biochemical, physiological and clinical findings (author's transl)]. 10 97

Intact platelets from atherosclerotic rabbits release more thromboxane B2 (TXB2) and 12-hydroxyeicosatetraenoic acid (HETE) than platelets from normal rabbits following incubation with [14C]arachidonic acid (AA). In contrast, no difference is found between homogenates of platelets from normal and atherosclerotic animals. PGI2 stimulates cAMP accumulation and inhibits TXB2 formation more potently in intact platelets from atherosclerotic than from normal rabbits, but has no effect on AA metabolism in homogenised platelets.
Atherosclerosis 1979 Jun
PMID:Prostacyclin-dependent differences in TXA2 formation by platelets from normal and atherosclerotic rabbits. 22 90

Experimental atherosclerosis in rabbits induced by feeding a standard atherogenic diet for 4 months resulted in an increased sensitivity of platelets to the proaggregatory action of collagen and ADP. Treatment with dipyridamole (3 x 10 mg/day i.m.) for 4 weeks normalized platelet loss in atherosclerotic rabbits and abolished the increased sensitivity to proaggregatory collagen, but not to ADP. Dipyridamole treatment lowered basal as well as PGI2-induced cAMP levels below values seen in platelets from normal rabbits, but the stimulation by PGI2 relative to basal cAMP levels was not affected or even increased by dipyridamole treatment. Dipyridamole did not affect the increased sensitivity of platelets from atherosclerotic rabbits to the antiaggregatory action of PGI2, indicating that dipyridamole decreased absolute cAMP levels, probably due to reduction of the adenine nucleotide pool in platelets without affecting the adenylate cyclase function. Dipyridamole enhanced atherosclerotic plaque formation in arterial walls. Basal as well as PGI2-stimulated cAMP content was lower in homogenates from atherosclerotic than from normal aortic tissue. Dipyridamole-treated animals showed a further decrease in basal as well as PGI2-stimulated cAMP content of the aortic tissue, suggesting that this decrease in cAMP content may be linked to the enhanced proliferative activity seen in artherosclerotic plaque formation.
Atherosclerosis 1979 Jul
PMID:Effects of dipyridamole in experimental atherosclerosis. Action on PGI2, platelet aggregation and atherosclerotic plaque formation. 22 6

Experimental atherosclerosis in rabbits was associated with a suppression of prostacyclin generation from exogenous arachidonic acid by the coronary vascular bed. The spontaneous formation of prostacyclin by incubated rings of mesenteric artery was also diminished. These results suggest that in atherosclerosis an impaired activity of the endothelial prostacyclin synthexizing system contributes to the intra-arterial formation of thrombi.
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PMID:The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits. 34 Dec 24

Experimental atherosclerosis in rabbits was associated with increased aggregation of their platelets to arachidonic acid, and with increased generation of thromboxane A2 by their platelet-rich plasma. A heightened susceptibility of platelets to the anti-aggregatory action of prostacyclin against the ADP-induced aggregation was also observed. It is concluded that in advance atherosclerosis the platelet system is hypersensitive to biologically active metabolites of arachidonic acid.
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PMID:Experimental atherosclerosis in rabbits: platelet aggregation, thromboxane A2 generation and anti-aggregatory potency of prostacyclin. 34 Dec 25

Recently two local hormones, thromboxane A2 (TXA2) and prostacyclin (PGI2) have been discovered. These hormones are labile metabolites of arachidonic acid. TXA2 is generated by blood platelets, while PGI2 is produced by vascular endothelium. TXA2 is a potent vasoconstrictor. It also initiates the release reaction, followed by platelet aggregation. PGI2 is a vasodilator, especially potent in coronary circulation. It also inhibits platelet aggregation by virtue of stimulation of platelet adenyl cyclase. Common precursors for both hormones are cyclic endoperoxides PGG2 and PGH2, being formed by cyclooxygenation of arachidonic acid. This last enzymic reaction is more efficient in platelets than in vascular endothelium, and therefore the generation of PGI2 by vasuclar wall is accelerated by an interaction between platelets and endothelial cells. During this interaction platelets supply the endothelial PGI2 synthetase with their cyclic endoperoxides. The newly formed PGI2 repels the platelets from the intima. When PGI2 synthetase is irreversibly inactivated by low concentration of lipid peroxides, then the platelets are not rejected but stick to the endothelium, generate TXA2 and mature thrombi are formed. A balance between formation and release of PGI2, TXA2 and/or cyclic endoperoxides in circulation is of utmost importance for the control of intra-arterial thrombi formation and possibly plays a role in the pathogenesis of atherosclerosis.
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PMID:A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation. 36 54

Metabolism of arachidonic acid (AA) was studied in perfused lungs and kidneys of normal and atherosclerotic rabbits by determination of PGE2, PGF2 alpha and the stable metabolites of PGI2 (6-keto-PGF1 alpha) and TXA2 (TXB2). PGI2 was the main AA metabolite formed by normal lungs and kidneys. Atherosclerosis reduced the formation of PGI2 by about 50 % in both organs. TXA2 formation was similarily decreased in lungs. In kidneys, the decrease in PGI2 formation was accompanied by an increase in PGE2 formation.
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PMID:Atherosclerosis decreased prostacyclin formation in rabbit lungs and kidneys. 38 29

Atherosclerosis is complicated by thrombosis and it has been suggested that a decreased prostacyclin and/or an increased thromboxane release from the vascular wall could play a part in this process. There are few reports dealing with determinations of prostanoid release from physiologically perfused normal and atherosclerotic vessel walls or from perfused atherosclerotic hearts. Therefore, fourteen rabbits were given 2% cholesterol added to the diet for 26 weeks, which led to atherosclerosis, verified by scanning electron microscopy. Five animals died, and in the surviving nine, as well as from ten healthy rabbits, the aorta was excised. The vessels were perfused with pulsatile flow at physiologic pressure five times for fifteen minutes with the addition of arachidonic acid to the last perfusate. Prostacyclin and thromboxane were determined as their stable degradation products 6-keto-PGF1 alpha and TxB2 by radio-immuno assay. Atherosclerotic and normal animals had the same initial release of prostacyclin but in the atherosclerotic animals the release did not decline with time as it did in the normal animals. The response to arachidonic acid was also higher in the atherosclerotic group. The release of thromboxane was not altered in the atherosclerotic group compared to the control group. It is concluded that prostacyclin release from aortas is altered in rabbits with diet-induced atherosclerosis compared to normal rabbit aortas, but that vascular thromboxane production is not.
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PMID:Diet-induced atherosclerosis in rabbits alters vascular prostacyclin release. 129 29

Recent clinical studies have shown that calcium channel blockers can retard and possibly reduce the angiographic progression of coronary artery disease. Calcium channel blockers also inhibit dietary-induced atherosclerosis in animal models of this disease. In this study, we delineate potential cellular and molecular mechanisms by which nicardipine, a dihydropyridine calcium antagonist, may alter lipoprotein and cholesterol trafficking, affect the regulatory signal transduction pathways involved in accelerating cholesteryl ester (CE) catabolism in vascular smooth muscle cells, and modulate cell-cell interactions of vascular and inflammatory cells. We demonstrate in arterial smooth muscle cells that nicardipine increases 1) LDL binding, uptake, and degradation, 2) RNA transcript levels for the LDL receptor, 3) CE catabolic activity, 4) PGI2 release, and 5) RNA transcript levels for cyclooxygenase. Furthermore, nicardipine blocked cytokine-induced monocyte adhesion to endothelial cells and smooth muscle cells. Taken together, these findings support the hypothesis that nicardipine may function as an anti-atherosclerotic agent by promoting CE catabolism and cholesterol clearance and by reducing monocyte adhesion to the activated endothelium.
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PMID:Dihydropyridine calcium antagonist modulates cholesterol metabolism and eicosanoid biosynthesis in vascular cells. 131 89


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