Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium channel blockers are a group of drugs used for the treatment of hypertension. Carbonic anhydrase (CA) I detected in vascular smooth muscle and in other cells in the organism has a major role in the acid-base balance and in vascular processes. Our previous work has proven that verapamil inhibits CA activity by a direct mechanism of action. Starting from our results in this article we studied in vitro and in vivo the effect of calcium channel blockers (verapamil and amlodipine) on erythrocyte CA I, on vascular smooth muscles CA I, and on arterial blood pressure values in human and in animals. Our in vitro and in vivo results have proved that verapamil and amlodipine are strong CA I inhibitors both in human erythrocytes and also in vascular smooth muscles in animals. In humans, calcium channel blockers studied here progressively reduce arterial blood pressure in hypertensive subjects, in parallel with progressive lowering of erythrocyte CA I activity in the normal range in normotensive subjects. From our point of view verapamil and amlodipine possess a dual mechanism of action: the first well-known action consists of their action on calcium channels. The second mechanism, suggested by us, directly acts on the vascular smooth muscle CA I isozyme, so that its inhibition should ensure an adequate pH for calcium ions transport through the channels, having as result vasodilation. This double mechanism could explain the hypotensive effect of verapamil and amlodipine, with a mechanism that partially dependent on CA I inhibition.
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PMID:Calcium channel blockers reduce blood pressure in part by inhibiting vascular smooth muscle carbonic anhydrase I. 1110 Dec

Neurofilaments (NFP) are components of neuronal cytoskeleton involved primarily in axonal transport and in the regulation of dynamic activities of nerve cells. NFP consist of three subunits denominated high- (200 kDa, NFP-H), intermediate- (160 kDa, NFP-I), and low-molecular weight (68 kDa, NFP-L) neurofilament proteins. Their function and polymerization depends on phosphorylation status, and is regulated by Ca2+ influx. Ca2+ overload enhances degradation of NFP and may compromise axonal transport. An increased susceptibility to ischemia occurs in hypertension, which is also a cause of brain damage. In this study, the expression of phosphorylated NFP (P-NFP) was investigated in the brain of spontaneously hypertensive rats (SHR) using immunohistochemical techniques with antibodies against the phosphorylated epitope of NFP RT-97. Microanatomical analysis included frontal cortex, occipital cortex, hippocampus and cerebellar cortex. The effect of long-term treatment with the dihydropyridine-type Ca2+ antagonist nicardipine on the expression of P-NFP was investigated as well. In hypertension a decreased P-NFP immunoreactivity was observed in frontal and occipital cortex, in the CA1 subfield of hippocampus and in the dentate gyrus, but not in the CA3 subfield of hippocampus or in the cerebellar cortex. Treatment with a daily dose of 3 mg/kg of nicardipine and 10 mg/kg of hydralazine significantly reduced systolic pressure in SHR. The above dose of nicardipine and to a lesser extent a non-hypotensive dose of the compound (0.1 mg/kg/day), but not hydralazine, increased P-NFP immunoreactivity in the cerebral cortex and hippocampus, except the CA3 subfield. The possibility that rescued P-NFP immunoreactivity by treatment with nicardipine depends on improved brain perfusion caused by the compound and/or by countering neuronal Ca2+ overload is discussed.
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PMID:Effect of nicardipine treatment on the expression of neurofilament 200 KDa immunoreactivity in the brain of spontaneously hypertensive rats. 1127 May 80

Hypertension is a main risk factor for cerebrovascular disease, including vascular dementia. The present study was designed to evaluate if hypertension-dependent changes of the hippocampus of spontaneously hypertensive rats (SHR) of different ages were related with those occurring in vascular dementia. The hippocampus was chosen as the brain area involved in learning and memory. Systolic pressure was slightly increased in 2-month-old SHR in comparison with age-matched normotensive Wistar-Kyoto (WKY) rats and augmented progressively with age in SHR. No microanatomical changes were observed in the hippocampus of SHR of 2 months in comparison with age-matched WKY rats. A limited decrease of white matter volume was observed in 4-month-old SHR. In SHR of 6 months, a reduction of grey matter volume both in the CA1 subfield and in the dentate gyrus occurred. Evaluation of phosphorylated 200-kDa neurofilament immunoreactivity revealed a decreased immune reaction area in the CA1 subfield of 6-month-old SHR compared to age-matched WKY rats and no changes in the expression and localization of the dendritic marker microtubule associated protein (MAP)-2. In 6-month-old SHR, an increase of glial fibrillary acidic protein (GFAP)-expression was found by Western blot analysis. Immunohistochemistry revealed an increase in number (hyperplasia), but not in size of astrocytes. These findings indicate the occurrence of cytoskeletal breakdown and astroglial changes primarily in the CA1 subfield of the hippocampus of SHR of 6 months. The occurrence in the hippocampus of SHR of regressive changes and astroglial reaction similar to those occurring in neurodegenerative disorders with cognitive impairment suggests that they represent an animal model of vascular dementia.
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PMID:The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia? 1179 40

Dihydropyridine (DHP)-type Ca2+ antagonists block primarily L-type Ca2+ channels and are used in the therapy of hypertension. They were also proposed for the treatment of several central nervous system disorders. In brain, these compounds bind both neuronal and vascular Ca2+ channels, but no studies have evaluated comparatively their density at neuronal and vascular level. This study has analyzed the pharmacological profile and the anatomical localization of L-type Ca2+ channels in rat frontal cortex, hippocampus and in forebrain pial and intracerebral arteries by radioligand binding assay and high resolution light microscope autoradiography. The DHP derivative [3H]nicardipine was used as a radioligand. Binding of [3H]nicardipine was consistent with the labeling of L-type Ca2+ channels. In frontal cortex, the highest density of binding sites was found in nerve cell body region, followed by the neuropil and the wall of intracerebral arteries. In hippocampus, the density of binding sites was higher in the nerve cell body region than in the neuropil of CA1, CA3, and CA4 subfields. In the dentate gyrus, a higher density of silver grains was developed in neuropil than in nerve cell body of granule neurons. With the exception of dentate gyrus, neuronal binding sites were more expressed than vascular binding sites in the hippocampus. In pial arteries [3H]nicardipine binding density decreased concomitant with the reduction of vessel diameter, whereas in intracerebral arteries [3H]nicardipine binding density displayed an opposite pattern. The above findings indicate that in brain the density of neuronal L-type Ca2+ channels was significantly higher than that of vascular ones. This may account for more pronounced neuronal than vascular effects after pharmacological manipulation of cerebral Ca2+ channels.
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PMID:Neuronal populations of rat cerebral cortex and hippocampus expressed a higher density of L-type Ca 2+ channel than corresponding cerebral vessels. 1245 Feb 46

Umbilical cord occlusion (UCO), a known risk factor for perinatal brain damage, causes severe fetal asphyxia leading to oxidative stress, lipid peroxidation, and cell death. We have determined the effects of two 10-min UCO on the distribution of the lipid peroxidation marker 4-hydroxynonenal (4-HNE) and the activated form of the apoptosis marker caspase-3 in the brains of late-gestation fetal sheep. UCO caused asphyxia, hypertension, and bradycardia, but these parameters normalized 2 h after the occlusion. At postmortem, 48 h after the second UCO there were significantly higher numbers of 4-HNE-positive cells in all layers of the hippocampus and cerebellum, the parietal cortex, substantia nigra, caudate nucleus, putamen, and thalamus compared with control brains. 4-HNE immunoreactivity was also found in white matter tracts of the subcallosal bundle, external medullary lamina, reticular thalamic nucleus, and cerebellar fiber tracts only in UCO brains. Double-labeling identified these cells as predominantly neurons and astrocytes, with oligodendrocytes showing lower levels of 4-HNE immunoreactivity. After UCO, the number of caspase-3-immunopositive cells was increased significantly in the hippocampal CA1, molecular layer and dentate gyrus, ventrolateral thalamic nucleus, substantia nigra, putamen, and cerebellar granular and molecular layers compared with controls. Double-labeling revealed caspase-3 immunoreactivity was mainly in neurons, and to lesser extent in astrocytes and oligodendrocytes. Pyknotic cell numbers were significantly increased in hippocampal CA1 and CA3, parietal cortex, caudate nucleus, putamen, and cerebellar Purkinje cells after UCO. These data indicate that brief asphyxia induces widespread lipid peroxidation involving all cell types of the fetal brain and apoptosis in both neurons and glia.
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PMID:Lipid peroxidation, caspase-3 immunoreactivity, and pyknosis in late-gestation fetal sheep brain after umbilical cord occlusion. 1476 19

Alpinae Oxyphyllae Fructus (Alpinia oxyphylla MIQ) (Korean name Ik-Jj-In) is a medicinal plant used in Korea for the treatment of various symptoms accompanying hypertension and cerebrovascular disorders. The present study was performed to investigate the effects of Alpinae Oxyphyllae Fructus water-extracts (AOF) on a cultured primary neuron cell system, cell cytotoxicity and lipid peroxidation in Abeta treatment conditions. Cell killing was significantly enhanced by addition of increasing concentrations of Abeta. Pretreatment of AOF attenuated in cell killing enhanced by increasing concentrations of Abeta. Abeta-induced cell death was protected by the application of water extract of AOF in a dose-dependent manner, and concentrations of 50 to 100 micro g/ml had a significant effect compared to exposure of Abeta only. AOF has been shown to protect primary cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. The evidence indicated that AOF protects neurons against ischemia-induced cell death. Oral administration of AOF into mice prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous AOF was also confirmed by counting synapses in the hippocampal CA1 region. The presence of AOF in neuron cultures did not repress a NMDA receptor-mediated increase in intracellular Ca(2+), but rescued the neurons from NO-induced death. AOF may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.
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PMID:Protective effects of alpinae oxyphyllae fructus (Alpinia oxyphylla MIQ) water-extracts on neurons from ischemic damage and neuronal cell toxicity. 1502 67

All components of the renin-angiotensin system are localized in the brain. However, because renin is present in very low concentrations, the mechanism by which angiotensin II is formed in the brain remains unclear. We previously reported the development of 2 transgenic mouse models using sensitive reporters, enhanced green fluorescent protein (eGFP) and beta-galactosidase (beta-Gal), to examine the cellular localization of renin and angiotensinogen in the mouse brain. To determine whether renin and angiotensinogen are coexpressed or present in neighboring cells in the rostral ventrolateral medulla (RVLM) and other cardiovascular control regions of the brain, we produced and examined double-transgenic mice, which express eGFP driven by the renin promoter (REN-1c/eGFP) and beta-gal driven by the human angiotensinogen promoter (hAGT/beta-gal). Using these reporter transgenes as sensitive markers for renin and angiotensinogen expression, we conclude that both proteins are coexpressed in the parabrachial nucleus and central nucleus of the amygdala and are in adjacent cells in the RVLM, reticular formation, bed nucleus of the stria terminalis, subfornical organ, and CA1-3 region. These data suggests that, in these areas, both renin and angiotensinogen are in close proximity providing the potential for the local formation of angiotensin I either intracellularly, when there is colocalization, or in the interstitium, when they are in juxtaposed cells.
Hypertension 2004 May
PMID:Adjacent expression of renin and angiotensinogen in the rostral ventrolateral medulla using a dual-reporter transgenic model. 1503 61

The influence of hypertension associated with diabetes on cerebrovascular and frontal cortex or hippocampus microanatomy was investigated in 20-week-old spontaneously hypertensive rats (SHR) in which diabetes was induced by treatment with streptozotocin (STZ) and in control or STZ-diabetic age-matched normotensive Wistar Kyoto (WKY) rats. At the beginning of experiment, systolic pressure values were similar in WKY rats either control, or exposed to STZ and remarkably higher in control or STZ-treated SHR. Systolic pressure values increased in the different animal groups examined along the course of experiment. Blood glucose levels were increased in either STZ-WKY rats or -SHR compared to WKY rats and SHR respectively. The main changes occurring in pial and intracerebral arteries of SHR and STZ-SHR were thickening of the arterial wall accompanied by luminal narrowing. In medium sized pial arteries of STZ-WKY rats luminal narrowing and a decreased thickness of arterial wall were noticeable. Intracerebral arteries of STZ-WKY diabetic rats showed a not homogeneous sensitivity of different sized branches. The volume of zones III and IV of frontal cortex was decreased in SHR and STZ-SHR compared to control WKY rats. The number of nerve cells in these cerebrocortical layers was decreased to a similar extent in SHR. STZ-WKY rats or STZ-SHR compared to control WKY rats. In dentate gyrus, followed by the CA1 subfield of hippocampus, decreased volume and number of neurons were found in SHR and STZ-SHR compared to control WKY rats. The occurrence of astrogliosis was observed in hypertensive, diabetic or hypertensive plus diabetic rats. The above findings indicate the occurrence of cerebrovascular and brain microanatomical changes in SHR and to a lesser extent in STZ-diabetic rats compared to control normotensive and normoglicemic WKY rats. Association of hypertension and diabetes caused more pronounced changes than in the single disease models. These results support the view that hypertension and diabetes affect the structure of cerebrovascular tree and of brain and that association of the two diseases results in an increased risk of target-organ damage, involving brain.
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PMID:Cerebrovascular and brain microanatomy in spontaneously hypertensive rats with streptozotocin-induced diabetes. 1519 86

Control of blood pressure protects from the development of cerebrovascular lesions and vascular dementia (VaD). This study has assessed the influence of treatment with the dihydropyridine-type Ca2+ antagonist nicardipine on brain microanatomical changes in spontaneously hypertensive rats (SHR). SHR were treated from 16th to 26th week of age with hypotensive (3 mg/Kg/day) or non-hypotensive (0.1 mg/Kg/day) doses of nicardipine, with the non-dihydropyridine-type vasodilator hydralazine (10 mg/kg/day) or with vehicle (control group). Untreated age-matched Wistar Kyoto (WKY) rats were used as a normotensive reference group. Brain volume, number of neurons, glial fibrillary-acidic protein (GFAP)-immunoreactive astrocytes and neurofilament 200 KDa (NFP)-immunoreactivity (IR) were assessed in frontal and occipital cortex, hippocampus and striatum. A decrease of volume and number of nerve cells and a loss of NFP-IR was found in the frontal and occipital cortex and in the CA1 subfield of hippocampus and in the striatum of SHR. Treatment with nicardipine countered microanatomical changes occurring in SHR, whereas hydralazine displayed a less pronounced effect. Comparatively, the non-hypotensive dose of nicardipine was less active than the hypotensive one. The observation that equihypotensive doses of nicardipine or hydralazine did not protect brain in the same way from hypertensive brain damage suggests that lowering blood pressure is per se not enough for affording neuroprotection. The demonstration of neuroprotective effect of nicardipine suggests an use of the compound in situations in which hypertension is accompanied by the risk of brain damage.
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PMID:Treatment with nicardipine protects brain in an animal model of hypertension-induced damage. 1519 89

Obese Zucker rat (OZR) is a genetic model of obesity with noninsulin-dependent diabetes and hypertension. The OZR exhibit hyperinsulinemia, hyperlipidmia, and high circulating glucocorticoid levels. We have shown previously that long-term potentiation (LTP) is impaired in the CA1 region of the hippocampus of OZR. In the present work, although electrophysiological recording from anesthetized OZR hippocampus showed impaired LTP in the CA1, an intact LTP was recorded in the dentate gyrus (DG) region of the hippocampus of the same OZR. Thus, LTP is differentially impaired in the CA1 compared with the DG region of OZR hippocampus. Immunoblotting was used to investigate the molecular mechanism responsible for impairment of LTP in the CA1 but not in the DG region. Analysis revealed reduction in the levels of phosphorylated calcium-dependent calmodulin kinase II (P-CaMKII) and total CaMKII in the CA1 region of OZR. However, in the DG region, reduction was observed only in the levels of total CaMKII, with no change in P-CaMKII levels. The ratio of P-CaMKII to total CaMKII was increased in the DG but not in the CA1 area of hippocampus of OZR. Although unchanged in the CA1, calcineurin levels were significantly reduced in the DG of OZR. These findings suggest that the DG might possess a compensatory mechanism whereby calcineurin levels are reduced to allow sufficient P-CaMKII to produce an apparently normal LTP in the DG area of OZR hippocampus.
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PMID:Impairment of long-term potentiation in the CA1, but not dentate gyrus, of the hippocampus in Obese Zucker rats: role of calcineurin and phosphorylated CaMKII. 1628 Jun 4


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