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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central noradrenaline (NA) and adrenaline (A) turnover in 15--16-week-old stroke prone, spontaneously hypertensive (sp-SH) female rats in an advanced stage of hypertension was found to differ from that of normotensive Wistar-Kyoto (WKy) control rats. The catecholamine (CA) levels were measured after inhibition of dopamine-beta-hydroxylase (DBH) or phenylethanolamine-N-methyltransferase (PNMT). in the hypertensive rats the dopamine (DA) and NA levels and the NA turnover were reduced in the hypothalamus, while in the dorsal part of the caudal medulla oblongata NA levels and A turnover were reduced. Changes in hypothalamic DA and NA mechanisms and in A mechanisms in medulla oblongata may therefore be of importance in the blood pressure regulation of sp-SH rats.
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PMID:Catecholamine turnover changes in hypothalamus and dorsal midline area of the caudal medulla oblongata of spontaneously hypertensive rats. 53 May 33

The potential role of adrenaline, both circulating and in the central nervous system, in the maintenance of high blood pressure was examined in stroke-prone spontaneously hypertensive rats (SHRSP). alpha-Monofluoromethyldopa, a long-lasting inhibitor of dopa decarboxylase, was used to induce rapid depletion of central and peripheral catecholamine stores. Subsequent inhibition of phenylethanolamine-N-methyltransferase (PNMT) allowed the gradual restoration of dopamine and noradrenaline but not adrenaline, resulting in a greater relative depletion of adrenaline. Adrenaline was almost totally depleted in the circulation and peripheral tissues. The resting level of blood pressure, however, was unaffected, excepting after administration of a vasopressin (AVP) antagonist. Moreover, there was no reduction in the magnitude of acute pressor responses to electrical stimulation of the rostral ventrolateral medulla oblongata (C1 area), despite extensive loss of adrenaline from the brainstem and spinal cord. The results suggest that adrenaline contributes to the resting level of blood pressure but that its loss can be offset by the pressor activity of AVP. Thus neither central nor peripheral adrenaline stores appear to be essential for the maintenance of hypertension or for centrally-evoked vasoconstriction in adult SHRSP.
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PMID:Effects of depleting central and peripheral adrenaline stores on blood pressure in stroke-prone spontaneously hypertensive rats. 194 21

1. We have studied the number and distribution of adrenaline synthesizing nerve cells in the medulla oblongata of the rat, using a combination of immunofluorescence to visualize the enzyme phenylethanolamine-N-methyltransferase (PNMT) and catecholamine fluorescence to detect central catecholamines. 2. The distribution of adrenaline synthesizing nerve cells was similar in normotensive (Wistar Kyoto) rats, spontaneous hypertensive rats, and stroke-prone rats. Few of the cells visualized by PNMT immunofluorescence were detected by the Faglu fluorescence method for catecholamines. The C1 (ventrolateral) and C2 (dorsomedial) groups of PNMT cells were anatomically distinct from the A1 and A2 groups of catecholamine fluorescent cells and lay rostral to these cells within the medulla. There was a third group of adrenaline synthesizing cells close to the midline in the rostral medulla, and we have called this the C3 group. 3. There was a 32% increase in the number of PNMT cells in the medulla of 4-week-old stroke-prone rats. 4. PNMT enzyme activity in a cross-segment of the medulla containing the adrenaline synthesizing cells was also increased by 30% in both spontaneous hypertensive rats and stroke-prone rats.
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PMID:Adrenaline synthesizing nerve cells in the medulla of normotensive and hypertensive rats. 703 37

1. We have studied the number of phenylethanolamine-N-methyltransferase (PNMT)-containing nerve cells in the medulla and the activity of PNMT in the medulla, spinal cord and hypothalamus of the rat. 2. At 4 weeks of age there was an increase in the number of PNMT cells counted in the medulla of the spontaneously hypertensive rat (SHR; 21%, P less than 0.01) and the stroke-prone spontaneously hypertensive rat (SHR-SP; 22%, P less than 0.01) compared with the Wistar--Kyoto (WKY) control rat. 3. At 4 months of age there were no significant differences in the number of medullary PNMT cells in two normotensive strains (WKY and Fisher rats), two genetically hypertensive strains (SHR and SHR-SP) and in DOCA--salt hypertensive rats. 4. In four week old rats the activity of PNMT was increased by about 50% in the spinal cord and medulla of the SHR and SHR-SP compared with the WKY rats, and immunotitration experiments suggest that this is due to an increased concentration of enzyme. 5. At 4 months of age there were no increases in PNMT activity of either genetically hypertensive rats or DOCA--salt hypertensive rats.
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PMID:Adrenaline neurons and PNMT activity in the brain and spinal cord of genetically hypertensive rats and rats with DOCA--salt hypertension. 731 27

Although hyperhomocysteinemia has been recognized recently as a prevalent risk factor for myocardial infarction and stroke, the mechanisms by which it accelerates arteriosclerosis have not been elucidated, mostly because the biological effects of homocysteine can only be demonstrated at very high concentrations and can be mimicked by cysteine, which indicates a lack of specificity. We found that 10-50 microM of homocysteine (a range that overlaps levels observed clinically) but not cysteine inhibited DNA synthesis in vascular endothelial cells (VEC) and arrested their growth at the G1 phase of the cell cycle. Homocysteine in this same range had no effect on the growth of vascular smooth muscle cells (VSMC) or fibroblasts. Homocysteine decreased carboxyl methylation of p21(ras) (a G1 regulator whose activity is regulated by prenylation and methylation in addition to GTP-GDP exchange) by 50% in VEC but not VSMC, a difference that may be explained by the ability of homocysteine to dramatically increase levels of S-adenosylhomocysteine, a potent inhibitor of methyltransferase, in VEC but not VSMC. Moreover, homocysteine-induced hypomethylation in VEC was associated with a 66% reduction in membrane-associated p21(ras) and a 67% reduction in extracellular signal-regulated kinase 1/2, which is a member of the mitogen-activated protein (MAP) kinase family. Because the MAP kinases have been implicated in cell growth, the p21(ras)-MAP kinase pathway may represent one of the mechanisms that mediates homocysteine's effect on VEC growth. VEC damage is a hallmark of arteriosclerosis. Homocysteine-induced inhibition of VEC growth may play an important role in this disease process.
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PMID:Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. 931 59

Homocystinuria, an inherited disease in which plasma levels of homocysteine are high, was discovered in the sixties and it soon became clear that the affected patients had striking features of generalized atherosclerosis. The most common causes of death were arterial and venous thrombosis, stroke, or myocardial infarction. Observations in this human model of hyperhomocysteinemia led to studies in the general population whose findings suggest - though not conclusively- that homocysteine is a cardiovascular risk factor. The same is true for patients with chronic renal failure who almost always have moderate to severe high blood homocysteine levels. Homocysteine accumulates in relation to the concentration of its precursor, S-adenosylhomocysteine, a powerful competitive transmethylation inhibitor. Inhibition of a methyltransferase required to repair damaged proteins has actually been detected in uremic patients' red blood cells. However, in view of the multiple, widespread metabolic roles of S-adenosylmethionine-dependent methyltransferases, in many organs and tissues including the vascular endothelium, hypomethylation is currently interpreted as one of homocysteine's most important mechanisms of action. Various biological compounds, including small molecules and nucleic acids, as well as proteins, which are involved in the pathophysiology of thrombosis and atherosclerosis, are all potential targets of hypomethylation. Epidemiological studies and experimental models tend to confirm that homocysteine is both a cardiovascular risk factor and a uremic toxin, acting through different mechanisms.
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PMID:Homocysteine, a new cardiovascular risk factor, is also a powerful uremic toxin. 1049 66

The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation of NMDA receptors could contribute to neuronal damage in homocystinuria and HH(e). Since HH(e) is associated with certain neurodegeneratives diseases, in the present review, the molecular mechanisms involved in neurotoxicity due to Hcy are discussed.
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PMID:[Hyperhomocysteinemia: atherothrombosis and neurotoxicity]. 1079 37

The vitamins folic acid, B12 and B6 and B2 are the source of coenzymes which participate in one carbon metabolism. In this metabolism, a carbon unit from serine or glycine is transferred to tetrahydrofolate (THF) to form methylene-THF. This is either used as such for the synthesis of thymidine, which is incorporated into DNA, oxidized to formyl-THF which is used for the synthesis of purines, which are building blocks of RNA and DNA, or it is reduced to methyl-THF which used to methylate homocysteine to form methionine, a reaction which is catalyzed by a B12-containing methyltransferase. Much of the methionine which is formed is converted to S-adenosylmethionine (SAM), a universal donor of methyl groups, including DNA, RNA, hormones, neurotransmitters, membrane lipids, proteins and others. Because of these functions, interest in recent years has been growing particularly in the area of aging and the possibility that certain diseases that afflict the aging population, loss of cognitive function, Alzheimer's disease, cardiovascular disease, cancer and others, may be in part explained by inadequate intake or inadequate status of these vitamins. Homocysteine, a product of methionine metabolism as well as a precursor of methionine synthesis, was shown recently to be a risk factor for cardiovascular disease, stroke and thrombosis when its concentration in plasma is slightly elevated. There are now data which show association between elevated plasma homocysteine levels and loss of neurocognitive function and Alzheimer's disease. These associations could be due to a neurotoxic effect of homocysteine or to decreased availability of SAM which results in hypomethylation in the brain tissue. Hypomethylation is also thought to exacerbate depressive tendency in people, and for (colorectal) cancer DNA hypomethylation is thought to be the link between the observed relationship between inadequate folate status and cancer. There are many factors that contribute to the fact that the status of these vitamins in the elderly is inadequate. These factors are in part physiological such as the achlorhydria which affects vitamin B12 absorption and in part socioeconomic and habitual. We need more studies to confirm that these vitamins have important functions in the etiology of these diseases. We also need to establish if these diseases can be prevented or diminished by proper nutrition starting at a younger age.
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PMID:Folate, vitamin B12 and vitamin B6 and one carbon metabolism. 1181 80

There is evidence that vascular risk factors contribute to the pathology of Alzheimer's disease. Increased concentrations of circulating homocysteine are associated with vascular risk factors and Alzheimer's disease but the mechanisms involved are unclear. Homocysteine inhibits the hydrolysis of S-adenosylhomocysteine (SAH) which is a product inhibitor of S-adenosylmethionine (SAM) dependent methyltransferase reactions. It has been shown previously that SAH inhibits phosphatidylethanolamine N-methyltransferase (PEMT) in the liver. The activity of PEMT in the liver plays an important role in the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) and the delivery of essential polyunsaturated fatty acids (PUFAs) to peripheral tissues. In the present study, the plasma concentrations of SAH, SAM and homocysteine and the erythrocyte composition of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and their respective polyunsaturated fatty acid concentrations were determined in 26 patients with Alzheimer's disease and compared to those in 29 healthy control subjects. There was a significant increase in the plasma concentrations of SAH (p<0.001) and homocysteine (p<0.001) and a significant increase in the plasma concentrations of SAM (p<0.001) in the Alzheimer's patients. A significant positive correlation was found between the plasma concentrations of SAH and homocysteine (r=0.738, p<0.001). There was a negative correlation between the plasma concentrations of homocysteine and the ratio of SAM/SAH (r=-0.637, p<0.01). There was a significant decrease in the erythrocyte content of PC (p<0.001) and an increase in the erythrocyte content of PE (p<0.001) in the Alzheimer's patients. Plasma SAH concentrations were negatively related to erythrocyte PC concentrations (r=-0.286, p<0.01) and positively related to erythrocyte PE concentrations (r=0.429, p<0.001). The erythrocyte PC from Alzheimer's patients had a significant depletion of docosahexaenoic acid (DHA) (p<0.001) while there was no significant difference in the DHA content of erythrocyte PE. There was a significant negative correlation between plasma SAH and the DHA composition of erythrocyte PC (r=-0.271, p<0.001). This data may reflect the inhibition of hepatic PEMT activity by SAH in Alzheimer's disease. The decreased mobilization of DHA from the liver into plasma and peripheral tissues may increases the risk of atherosclerosis and stroke leading to chronic cerebral hypoperfusion. The evidence suggests that a metabolic link between the increased production of SAH and phospholipid metabolism may contribute to cerebrovascular and neurodegenerative changes in Alzheimer's disease.
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PMID:A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer's disease. 1699 49

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function.
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PMID:Hyperhomocysteinemia in uremia--a red flag in a disrupted circuit. 1970 80


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