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)

We recently reported that the heparin (Hep) III domain of fibronectin contains the H2 cell adhesion site in repeat III5 which binds activated alpha4 integrins. We have now further characterized the heparin and cell binding activities of this domain. A recombinant fragment containing repeats III4-III5 (FN-III4-5) induced Jurkat cell adhesion upon integrin activation with Mn2+ or TS2/16 monoclonal antibody (anti-beta1). Adhesion of Mn2+-treated cells to FN-III4-5 or FN-III5 fragments was inhibited by chondroitinase ABC and ACII but not by the anti-alpha4 monoclonal antibody HP2/1. In contrast, HP2/1 completely blocked adhesion of TS2/16-treated cells while chondroitinase had a partial (FN-III4-5) or minor (FN-III5) effect. Thus, the role of each receptor depended on the stimulus used to activate alpha4 beta1. The combination of HP2/1 and chondroitinase at dilutions which did not inhibit when used individually abolished adhesion of Mn2+ or TS2/16-treated cells to both fragments, indicating a cooperative effect between alpha4beta1 and chondroitin sulfate proteoglycans (CSPG). Furthermore, we have identified a 20-amino acid sequence in III5 (HBP/III5) which binds heparin and induces cell adhesion via CSPG exclusively. Although soluble HBP/III5 was a poor inhibitor, when combined with H2, it abolished adhesion to FN-III4-5 and FN-III5 fragments. These results establish that adhesion to the Hep III domain involves the cooperation of activated alpha4 beta1 and CSPG and show that HBP/III5 is a novel heparin and CSPG-binding site contributing to cell adhesion to this domain.
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PMID:Cooperative role for activated alpha4 beta1 integrin and chondroitin sulfate proteoglycans in cell adhesion to the heparin III domain of fibronectin. Identification of a novel heparin and cell binding sequence in repeat III5. 986 21

Preeclampsia (PE) is a leading cause of maternal hypertension in pregnancy, fetal growth restriction, premature birth, and fetal and maternal mortality (1). Activation and dysfunction of the maternal and fetal endothelium in PE may be the consequence of increased oxidative stress associated with circulating lipid peroxides (2-4), and in cases of severe maternal hypertension, uterine and umbilical artery waveforms are abnormal (5). We have investigated PE-associated abnormalities in the regulation of intracellular Ca2+ ([Ca2+]i) and cyclic guanosine monophosphate (cGMP) production (index of nitric oxide [NO]) in human fetal umbilical vein endothelial cells. Basal [Ca2+]i was slightly elevated in PE cells, whereas agonist-stimulated Ca2+ entry was reduced in cells from PE compared with normal term or age-matched preterm pregnancies. Furthermore, PE cells exhibited a decreased permeability to Ba2+ but an increased permeability to Mn2+ and Gd3+, suggesting that PE is associated with phenotypic alterations in fetal endothelial cation channel(s). Basal and histamine-stimulated cGMP levels were elevated in PE compared with preterm or normal cells, implying an increased NO production in PE. However, immunoblots for endothelial NO synthase (eNOS) and soluble guanylyl cyclase (sGC) revealed reduced eNOS expression in PE and preterm cells, with negligible changes in sGC levels. This study provides important and novel insights into abnormalities of fetal endothelial cells isolated from women with PE, reveal ing an altered cation membrane permeability and activity of eNOS-sGC pathway. As these changes are sustained in culture in vitro, this may reflect long-term "programming" of the fetal cardiovascular system.
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PMID:Preeclampsia is associated with altered Ca2+ regulation and NO production in human fetal venous endothelial cells. 1192 25

Maternal undernutrition during critical periods of organ development is known to impair fetal growth and predispose to the development of adulthood diseases, such as hypertension, coronary heart disease and type II diabetes that are linked to low birth weight and are characterized by endothelial dysfunction. Increased oxidative stress, in rats submitted to intrauterine undernutrition, provides a potential explanation for the endothelial dysfunction development. The aim of this study was to determine the oxidative stress and its consequence on mesenteric arteriolar responses to vasoactive agents in offspring from diet-restricted dams. For this, female pregnant Wistar rats were fed either normal or 50% of normal intake diets, during the whole gestational period. In male offspring, arterial blood pressure was determined by the tail cuff method in anesthetized rats, mesenteric arteriolar reactivity and superoxide anion generation were studied using intravital microscopy and superoxide dismutase activity was determined in mesentery by spectrophotometric assay. Intrauterine undernutrition induced hypertension, decreased vasodilation to acetylcholine and bradykinin but did not alter the responses to sodium nitroprusside. Topical application of superoxide dismutase and superoxide dismutase mimetic manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin significantly improved the altered arteriolar responses to acetylcholine and bradykinin. A decreased superoxide dismutase activity and an increased superoxide anion concentration were observed in the offspring of diet-restricted dams. This study shows for the first time that intrauterine undernutrition enhances oxidative stress in vivo and relates this to the impaired endothelium-dependent vasodilation.
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PMID:Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. 1235 11

We previously reported that inhibition of epidermal growth factor receptor tyrosine kinase activity attenuates renal arteriolar contractile responses to angiotensin II. We performed the present experiments to determine if epidermal growth factor receptor tyrosine kinase activity contributes to the afferent arteriolar intracellular [Ca2+] response to angiotensin II. Afferent arterioles were dissected from rat kidney and intracellular [Ca2+] was monitored with the use of fura-2. In normal Ringer's bath containing 1.5 mmol/L Ca2+, basal intracellular [Ca2+] averaged 95+/-7 nmol/L and 100 nmol/L angiotensin II caused a rapid rise (peak Delta=75+/-10 nmol/L) that waned to a plateau averaging 24+/-5 nmol/L above baseline. Pretreatment with 100 nmol/L AG1478 (epidermal growth factor receptor tyrosine kinase inhibitor) reduced both the peak and the plateau stages of the angiotensin II response (peak Delta=42+/-7 nmol/L; plateau Delta=8+/-4 nmol/L). A structurally unrelated epidermal growth factor receptor tyrosine kinase inhibitor also suppressed the peak response to angiotensin II, whereas tyrosine phosphatase inhibition enhanced the plateau phase of the response. In the presence of 100 nmol/L extracellular Ca2+, the angiotensin II response was characterized by a peak of diminished magnitude (Delta=49+/-10 nmol/L; P<0.05 versus the response in normal Ringer's bath) with no plateau, and this response was unaffected by AG1478. Moreover, angiotensin II stimulation of divalent cation influx (Mn2+ quench of fura-2 fluorescence) was decreased significantly by AG1478. We conclude that epidermal growth factor receptor tyrosine kinase activity contributes to the afferent arteriolar intracellular [Ca2+] response to angiotensin II and that this process involves promotion of Ca2+ influx.
Hypertension 2002 Nov
PMID:Angiotensin II triggers EGFR tyrosine kinase-dependent Ca2+ influx in afferent arterioles. 1241 65

Carbon monoxide (CO) is formed during the degradation of haeme by haeme oxygenase (HO). As well as being an important signalling molecule and vasodilator, CO also possesses antihypertensive, anti-inflammatory and antiapoptotic qualities and protects against ischaemic tissue injury. Several approaches have been used to investigate the therapeutic potential of CO, ranging from direct administration of CO gas to the use of prodrugs, which generate CO upon metabolism. A novel approach involves the use of specific CO carriers, which will release measurable, controllable and effective amounts of CO into biological systems. Transitional metal carbonyls based around iron, manganese or ruthenium have recently been developed as CO-releasing molecules (CO-RMs) that, under appropriate conditions, will release CO. Such molecules have been shown to provide cardioprotection in both ex vivo and in vivo experiments. To date, CO-RMs have been largely incompatible with biological systems in that they are only soluble in organic solvents or have to be preactivated either by physical or chemical stimuli. However, the recent development of water-soluble CO-RMs has provided new opportunities to investigate the pharmacological and biological features of CO without such confounding influences. CORM-3, a novel water-soluble CO-RM, has recently been used to confirm the cardioprotective actions of CO. In this issue of British Journal of Pharmacology, Foresti and co-workers report that CORM-3 delivers CO, produces aortic vasodilation ex vivo and reduces blood pressure in vivo via modulation of the same cGMP and potassium channels utilised by endogenous and exogenous CO. These findings suggest that CORM-3 has the potential for use as a modulator of vascular function and hypertension. However, the use of water-soluble CO-RMs raises several questions of their own which will need to be addressed if CO-RMs are to be of future use therapeutically.
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PMID:Water-soluble carbon monoxide-releasing molecules: helping to elucidate the vascular activity of the 'silent killer'. 1514 42

Oxidative stress because of an excessive production of superoxide anion (O2*-) is associated with hypertension. The present study evaluated the hypothesis that in the rostral ventrolateral medulla (RVLM), where the premotor neurons for the maintenance of vascular vasomotor activity are located, increased O2*- contributes to hypertension in spontaneously hypertensive rats (SHR) by modulating the cardiovascular depressive actions of nitric oxide (NO). Compared with normotensive Wistar-Kyoto (WKY) rats, SHR manifested significantly increased basal O2*- production, along with reduced manganese superoxide dismutase (MnSOD) expression and activity, in the RVLM. The magnitude of hypotension, bradycardia, or suppression of sympathetic neurogenic vasomotor tone elicited by microinjection bilaterally into the RVLM of a membrane-permeable SOD mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (MnTBAP), was also significantly larger in SHR. Transfection bilaterally into the RVLM of adenoviral vectors encoding endothelial nitric oxide synthase resulted in suppression of arterial pressure, heart rate, and sympathetic neurogenic vasomotor tone in both WKY rats and SHR. Microinjection of MnTBAP into the RVLM of SHR further normalized those cardiovascular parameters to the levels of WKY rats. We conclude that an elevated level of O2*- in the RVLM is associated with hypertension in SHR. More importantly, this elevated O2*- may contribute to hypertension by reducing the NO-promoted cardiovascular depression.
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PMID:Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. 1564 47

Moderate ethanol consumption is known to reduce the risk of cardiovascular diseases; however, chronic high dose ethanol ingestion causes cardiovascular injuries including hypertension. The dose response of ethanol-induced hypertension and associated oxidative stress response has not been well established. This study investigated the dose response of ethanol on blood pressure (BP), nitric oxide (NO) and antioxidants in the plasma of the rat. Male Fisher rats (200-250 g) were divided into five groups of six animals each and treated as follows: (1) control (5% sucrose, orally) daily for 12 weeks; (2) 20-30% ethanol (1 g kg-1, orally) daily for 12 weeks; (3) 20-30% ethanol (2 g kg-1, orally) daily for 12 weeks; (4) 20-30% ethanol (4 g kg-1, orally) daily for 12 weeks; (5) 20-30% ethanol (6 g kg-1, orally) daily for 12 weeks. The BP (systolic, diastolic and mean) was recorded every week through tail-cuff method. The animals were sacrificed 12 weeks after treatments and blood was collected and analyzed. Systolic and mean BP were slightly decreased with 1 g kg-1 dose but significantly elevated with 2, 4 and 6 g kg-1 doses 7-12 weeks after ethanol ingestion. Whereas diastolic BP was significantly elevated with 4 and 6 g kg-1 doses 8-12 weeks after ethanol ingestion. Blood alcohol levels were significantly elevated with 4 and 6 g kg-1 dose of ethanol for 12 weeks. Ethanol dose-dependency increased plasma malondialdehyde (MDA) and protein carbonyl levels, while nitric oxide (NO), ratio of reduced to oxidized glutathione (GSH/GSSG) and antioxidant enzymes: copper/zinc-superoxide dismutase (CuZn-SOD) and manganese (Mn)-SOD, catalase (CAT) and glutathione peroxidase (GSH-Px) activities were decreased 12 weeks post-treatment. The data suggested that ethanol induces hypertension at higher doses by depleting NO and antioxidants and increasing oxidative tissue injury in rats.
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PMID:Dose response of alcohol-induced changes in BP, nitric oxide and antioxidants in rat plasma. 1568 47

Eleven metal elements in niuhuang jiangya wan, including sodium, calcium, magnesium, potassium, iron, chromium, manganese, nickel, cadmium, copper and zinc, were determined by flame atomic absorption spectrophotometer. The results showed that there are rich metal elements in niuhuang jiangya wan and provided useful data for discussing the relation between trace elemtnts in niuhuang jiangya wan and cure for high blood pressure.
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PMID:[Determination of 11 metal elements in niuhuang jiangya wan by atomic absorption spectrophotometer]. 1581 77

Recent studies have suggested that the calcium antagonists have an antiatherogenic antioxidant property. The effects of the calcium antagonists on reactive oxygen species (ROS)-related enzymes, however, remain unknown. We hypothesized that the calcium antagonists inhibit oxidative stress in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) through the ROS-scavenging enzymes known as superoxide dismutases (SODs). Male 12-week-old Wister-Kyoto rats (WKY) and SHRSP were used for the study. SHRSP were randomized and treated for 6 weeks with a vehicle, amlodipine (5 mg/kg/day), or enalapril (10 mg/kg/day). NAD(P)H oxidase activity was measured by a luminescence assay, and SOD activity was measured spectrophotometrically. Protein expressions were analyzed by immunoblots. Both drugs showed equipotent effects on systolic blood pressure, left ventricular hypertrophy and fibrosis, the wall-to-lumen ratio, the manganese SOD activity, ROS, and the endothelial NO synthase expression in the SHRSP hearts. Furthermore, amlodipine significantly restored copper/zinc-containing SOD (Cu/ZnSOD) expression and its activity in SHRSP hearts to a level equal to that of WKY more effectively than did enalapril (p <0.05), whereas enalapril downregulated NAD(P)H oxidase activity more than did amlodipine (p <0.05) in the SHRSP hearts. Furthermore, amlodipine restored Cu/ZnSOD expression and its activity in SHRSP hearts to a level equal to that in WKY hearts, and this restoration was significantly more effective than that by enalapril (p <0.05); on the other hand, enalapril induced a greater downregulation of NAD(P)H oxidase activity in SHRSP hearts than did amlodipine (p <0.05). Thus, amlodipine may inhibit vascular remodeling and oxidative stress in the SHRSP heart by efficiently upregulating Cu/ZnSOD, suggesting that the calcium antagonist may exhibit an antiatherogenic antioxidative action beyond blood-pressure lowering through the restoration of Cu/ZnSOD activity in the heart in cases of hypertension.
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PMID:Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats. 1582 70

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.
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PMID:Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. 1641 Apr 2


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