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Douglas R Seals - One of the best experts on this subject based on the ideXlab platform.
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nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice
Aging Cell, 2016Co-Authors: Natalie De Picciotto, Amy L Sindler, Lindsey B Gano, Lawrence C Johnson, Shinichiro Imai, Christopher R Martens, Kathryn F Mills, Douglas R SealsAbstract:We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD + intermediate, increases arterial SIRT1 activity and reverses age‐associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid Artery Endothelium‐dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)‐mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age‐associated impairment in EDD was restored in OC by the superoxide (O2−) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s−1 vs. 337 ± 3 cm s−1) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic Artery stiffness, compared with YC. OC had greater aortic O2− production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen‐I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO‐mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s−1) and EM (3694 ± 315 kPa), normalized O2− production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen‐I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD + threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age‐related arterial dysfunction by decreasing oxidative stress.
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mitochondria targeted antioxidant mitoq ameliorates age related arterial endothelial dysfunction in mice
The Journal of Physiology, 2014Co-Authors: Rachel A Giosciaryan, Amy L Sindler, Melanie C Zigler, Timothy J Larocca, Michael P Murphy, Douglas R SealsAbstract:Key points The development of age-related arterial endothelial dysfunction, a key antecedent of increased cardiovascular disease (CVD) risk, is mediated largely by reduced nitric oxide bioavailability as a consequence of oxidative stress. Mitochondria are critical signalling organelles in the vasculature, which, when dysregulated, become a source of excessive reactive oxygen species; the role of mitochondria-derived oxidative stress in age-related vascular dysfunction is unknown. We show that a mitochondria-targeted antioxidant, MitoQ, ameliorates vascular endothelial dysfunction in old mice and that these improvements are associated with the normalization of mitochondria-derived oxidative stress and markers of arterial mitochondrial health. These results indicate that mitochondria-derived oxidative stress is an important mechanism underlying the development of age-related vascular endothelial dysfunction and therefore may be a promising therapeutic target. Mitochondria-targeted antioxidants represent a novel strategy for preserving healthy vascular endothelial function in primary ageing and preventing age-related CVD in humans. Abstract Age-related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age-related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria-targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid Artery Endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability (P < 0.05). Acute (ex vivo) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on Endothelium-independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD). Our results suggest that mitochondria-derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria-targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age-related CVD.
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weight loss alone improves conduit and resistance Artery endothelial function in young and older overweight obese adults
Hypertension, 2008Co-Authors: Gary L Pierce, Stacy D Beske, Brooke R Lawson, Kara L Southall, Francoise J Benay, Anthony J Donato, Douglas R SealsAbstract:Obesity is associated with vascular endothelial dysfunction, as indicated by impaired Endothelium-dependent dilation. Presently there is no direct evidence that energy intake–restricted weight loss alone improves conduit or resistance Artery Endothelium-dependent dilation, the mechanisms involved, or whether improvements differ with patient age. A total of 40 overweight or obese (body mass index: ≥25 2 ) nondiabetic men and women aged 21 to 69 years completed 12 weeks of reduced energy intake (n=26; 15 male) or attention control (n=14; 9 male) and 4 weeks of weight maintenance (randomized trial). Energy intake restriction reduced estimated total energy intake (33%), body weight (10.5%), total and abdominal body fat, plasma leptin, oxidized low-density lipoprotein, and improved several metabolic risk factors. Brachial Artery flow-mediated dilation was increased by 30% (6.0±0.7% versus 7.9±0.7%Δ; P =0.01; n=17). Peak forearm blood flow during intrabrachial Artery infusion of acetylcholine was increased by 26% (16.8±1.4 versus 21.1±1.9 mL/100 mL per minute; P r =−0.46; P N G -monomethyl-l-arginine. Improvements in Endothelium-dependent dilation were not related to age: mean increases in subjects >50 years of age were similar to or greater than those
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Xanthine oxidase does not contribute to impaired peripheral conduit Artery Endothelium-dependent dilatation with ageing
Journal of Physiology, 2006Co-Authors: Iratxe Eskurza, Zachary D. Kahn, Douglas R SealsAbstract:Vascular oxidative stress is the key mechanism involved in the age-related decline in Endothelium-dependent dilatation (EDD). We tested the hypothesis that xanthine oxidase (XO), a major vascular source of reactive oxygen species, contributes to the impairment in EDD with ageing. At baseline, brachial Artery flow-mediated dilatation (FMD) was 55% lower in older (n = 9, 64 +/- 2 years, 8M/1F, mean +/- S.E.M.) versus young (n = 9, 26 +/- 1 years, 8M/1F) healthy adults (3.41 +/- 0.44 versus 7.53 +/- 0.67%, P < 0.001), whereas Endothelium-independent dilatation (EID; sublingual nitroglycerin) did not differ between groups. Plasma oxidized low-density lipoprotein (oxi-LDL), a measure of systemic oxidative stress, was greater at baseline in the older subjects (58.3 +/- 5.9 versus 46.8 +/- 2.4 U l(-1), P < 0.05) and inversely correlated with baseline FMD (r = - 0.54; P < 0.05). Acute administration of allopurinol, a competitive inhibitor of XO, reduced plasma uric acid concentrations similarly in both groups (P < 0.001), but did not affect FMD, EID, or oxi-LDL in either group. Vascular endothelial protein expression of XO (immunofluorescence) was not different in antecubital venous cells from the young and older subjects (0.56 +/- 0.12 versus 0.68 +/- 0.19 XO intensity/human umbilical vein endothelial cell intensity, P = 0.49). We conclude that XO does not contribute to oxidative stress-associated reductions in peripheral conduit Artery EDD with ageing in humans, possibly due to an absence of age-associated up-regulation of endothelial XO.
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effect of acute and chronic ascorbic acid on flow mediated dilatation with sedentary and physically active human ageing
The Journal of Physiology, 2004Co-Authors: Iratxe Eskurza, Douglas R Seals, Kevin D Monahan, Jed A RobinsonAbstract:Peripheral conduit Artery flow-mediated dilatation decreases with ageing in humans. The underlying mechanisms and efficacy of preventive strategies are unknown. Brachial Artery flow-mediated dilatation was determined at baseline and after ascorbic acid (vitamin C) intravenous infusion and chronic supplementation (500 mg day−1 for 30 days) in three groups of healthy men: young sedentary (n= 11; 25 ± 1 years, mean ±s.e.m.), older sedentary (n= 9; 64 ± 2), and older endurance-exercise trained (n= 9; 64 ± 2). At baseline, flow-mediated dilatation (normalized for the hyperaemic stimulus) was ∼45% lower in the older (0.015 ± 0.001) versus young (0.028 ± 0.004) sedentary men (P 15-fold in all groups and restored flow-mediated dilatation in the sedentary older men (to 0.023 ± 0.002; P > 0.1 versus other groups), with no effects in the other two groups. Oral ascorbic acid supplementation did not affect flow-mediated dilatation in any group. Brachial Artery Endothelium-independent dilatation (sublingual nitroglycerin) did not differ among the groups at baseline nor change with ascorbic acid administration. These results provide the first evidence for an important role of oxidative stress in both the impairment in peripheral conduit Artery flow-mediated dilatation with sedentary human ageing and the preservation of flow-mediated dilatation with physically active ageing.
Ronald R Magness - One of the best experts on this subject based on the ideXlab platform.
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uterine Artery leptin receptors during the ovarian cycle and pregnancy regulate angiogenesis in ovine uterine Artery endothelial cells
Biology of Reproduction, 2017Co-Authors: Rosalina Villalon Landeros, Vladimir E Vargas, Gladys E Lopez, Jing Zheng, Ronald R MagnessAbstract:Leptin regulates body weight, reproductive functions, blood pressure, endothelial function, and fetoplacental angiogenesis. Compared to the luteal phase, the follicular phase and pregnancy are physiological states of elevated estrogen, angiogenesis, and uterine blood flow (UBF). Little is known concerning regulation of uterine Artery (UA) angiogenesis by leptin and its receptors. We hypothesized that (1) ex vivo expression of leptin receptors (LEPR) in UA Endothelium (UAendo) and UA vascular smooth muscle (UAvsm) is elevated in pregnant versus nonpregnant (Luteal and Follicular) sheep; (2) in vitro leptin treatments differentially modulate mitogenesis in uterine Artery endothelial cells from pregnant (P-UAECs) more than in nonpregnant (NP-UAECs) ewes; and (3) LEPR are upregulated in P-UAECs versus NP-UAECs in association with leptin activation of phospho-STAT3 signaling. Local UA adaptations were evaluated using a unilateral pregnant sheep model where prebreeding uterine horn isolation (nongravid) restricted gravidity to one horn. Immunolocalization revealed LEPR in UAendo and UAvsm from pregnant and nonpregnant sheep. Contrary to our hypothesis, western analysis revealed that follicular UAendo and UAvsm LEPR were greater than luteal, nongravid, gravid, and control pregnant. Compared to pregnant groups, LEPR were elevated in renal Artery Endothelium of follicular and luteal sheep. Leptin treatment significantly increased mitogenesis in follicular phase NP-UAECs and P-UAECs, but not luteal phase NP-UAECs. Although UAEC expression of LEPR was similar between groups, leptin treatment only activated phospho-STAT3 in follicular NP-UAECs and P-UAECs. Thus, leptin may play an angiogenic role particularly in preparation for the increased UBF during the periovulatory period and subsequently to meet the demands of the growing fetus.
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ca2 i signaling vs enos expression as determinants of no output in uterine Artery Endothelium relative roles in pregnancy adaptation and reversal by vegf165
American Journal of Physiology-heart and Circulatory Physiology, 2011Co-Authors: Derek S Boeldt, Ronald R Magness, Ian M BirdAbstract:Pregnancy is a time of greatly increased uterine blood flow to meet the needs of the growing fetus. Increased uterine blood flow is also observed in the follicular phase of the ovarian cycle. Simul...
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simultaneous imaging of ca2 i and intracellular no production in freshly isolated uterine Artery endothelial cells effects of ovarian cycle and pregnancy
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Ronald R Magness, Ian M BirdAbstract:Pregnancy and the follicular phase of the ovarian cycle show elevation of uterine blood flow and associated increases in uterine Artery Endothelium (UAE) endothelial nitric oxide (NO) synthase (eNO...
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pregnancy and ovarian steroid regulation of angiotensin ii type 1 and type 2 receptor expression in ovine uterine Artery Endothelium and vascular smooth muscle
Endothelium-journal of Endothelial Cell Research, 2005Co-Authors: Jeremy A Sullivan, Ronald R Magness, Heidi L Rupnow, Jacqueline M Cale, Ian M BirdAbstract:Although pregnancy is clearly associated with refractoriness to infused angiotensin II (AII) in the uteroplacental unit, there is still dispute over the mechanism by which angiotensin type 1 and type 2 receptors (AT1R and AT2R) may mediate this response in the uterine Artery. This is in large part due to incomplete knowledge of levels of AT1R and AT2R expression and function in uterine Artery Endothelium (UA Endo) in the nonpregnant (NP) and pregnant (P) states, combined with the disagreement on whether AII may act through release of adrenomedullary catecholamines. The authors have previously described an increase in AT1R in UA Endo but not UA vascular smooth muscle (VSM) during pregnancy as compared to the nonpregnant intact ewe. Herein they report that the pregnancy-associated increase in AT1R expression in UA Endo is regulated by ovarian steroids. Using a recently developed antibody to AT2R, the authors now show there is no change in AT2R in UA Endo or VSM associated with ovarian function, and although...
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endothelial vasodilator production by uterine and systemic arteries v effects of ovariectomy the ovarian cycle and pregnancy on prostacyclin synthase expression
Prostaglandins & Other Lipid Mediators, 2000Co-Authors: Ronald R Magness, Charles R Shideman, Deirdre A Habermehl, Jeremy A Sullivan, Ian M BirdAbstract:Prostacyclin (PGI2) is a potent vasodilator, the level of which is increased during pregnancy, and is the main eicosanoid of which production is elevated in the Endothelium and vascular smooth muscle (VSM) of both uterine and omental (systemic) arteries. We tested the hypothesis that during physiologic states that have high uterine blood flow, such as pregnancy and the follicular phase of the ovarian cycle (versus luteal phase and ovariectomized ewes), there is an increased level of prostacyclin synthase (PGIS) expression in ovine uterine and omental Artery Endothelium and VSM. To investigate this, the cellular localization and PGIS protein expression level in uterine and systemic arteries was examined by immunohistochemistry as well as by Western immunoblot analysis of endothelial-isolated protein and denuded vessels (VSM). Whole uterine, but not omental (systemic), arteries from the pregnant ewes showed an increase (P < 0.001) in PGIS expression. Further localization of PGIS protein by immunohistochemistry and quantification by Western analysis showed PGIS to be somewhat higher in the uterine Artery VSM (69 ± 7%) than Endothelium (31 ± 7%). PGIS protein levels in uterine and omental Artery endothelial isolated protein were not altered by ovariectomy or the ovarian cycle, although they were both significantly elevated by pregnancy. Uterine and omental Artery VSM PGIS expression levels also were not altered by ovariectomy or the ovarian cycle, whereas PGIS expression, in uterine but not omental Artery VSM showed a significant elevation during pregnancy. Thus, the rise in PGI2 production by uterine arteries observed in ovine pregnancy is paralleled by an elevation in PGIS expression in both Endothelium and VSM, whereas those seen in omental arteries is associated with increases in endothelial PGIS.
Ian M Bird - One of the best experts on this subject based on the ideXlab platform.
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ca2 i signaling vs enos expression as determinants of no output in uterine Artery Endothelium relative roles in pregnancy adaptation and reversal by vegf165
American Journal of Physiology-heart and Circulatory Physiology, 2011Co-Authors: Derek S Boeldt, Ronald R Magness, Ian M BirdAbstract:Pregnancy is a time of greatly increased uterine blood flow to meet the needs of the growing fetus. Increased uterine blood flow is also observed in the follicular phase of the ovarian cycle. Simul...
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simultaneous imaging of ca2 i and intracellular no production in freshly isolated uterine Artery endothelial cells effects of ovarian cycle and pregnancy
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Ronald R Magness, Ian M BirdAbstract:Pregnancy and the follicular phase of the ovarian cycle show elevation of uterine blood flow and associated increases in uterine Artery Endothelium (UAE) endothelial nitric oxide (NO) synthase (eNO...
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pregnancy and ovarian steroid regulation of angiotensin ii type 1 and type 2 receptor expression in ovine uterine Artery Endothelium and vascular smooth muscle
Endothelium-journal of Endothelial Cell Research, 2005Co-Authors: Jeremy A Sullivan, Ronald R Magness, Heidi L Rupnow, Jacqueline M Cale, Ian M BirdAbstract:Although pregnancy is clearly associated with refractoriness to infused angiotensin II (AII) in the uteroplacental unit, there is still dispute over the mechanism by which angiotensin type 1 and type 2 receptors (AT1R and AT2R) may mediate this response in the uterine Artery. This is in large part due to incomplete knowledge of levels of AT1R and AT2R expression and function in uterine Artery Endothelium (UA Endo) in the nonpregnant (NP) and pregnant (P) states, combined with the disagreement on whether AII may act through release of adrenomedullary catecholamines. The authors have previously described an increase in AT1R in UA Endo but not UA vascular smooth muscle (VSM) during pregnancy as compared to the nonpregnant intact ewe. Herein they report that the pregnancy-associated increase in AT1R expression in UA Endo is regulated by ovarian steroids. Using a recently developed antibody to AT2R, the authors now show there is no change in AT2R in UA Endo or VSM associated with ovarian function, and although...
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endothelial vasodilator production by uterine and systemic arteries v effects of ovariectomy the ovarian cycle and pregnancy on prostacyclin synthase expression
Prostaglandins & Other Lipid Mediators, 2000Co-Authors: Ronald R Magness, Charles R Shideman, Deirdre A Habermehl, Jeremy A Sullivan, Ian M BirdAbstract:Prostacyclin (PGI2) is a potent vasodilator, the level of which is increased during pregnancy, and is the main eicosanoid of which production is elevated in the Endothelium and vascular smooth muscle (VSM) of both uterine and omental (systemic) arteries. We tested the hypothesis that during physiologic states that have high uterine blood flow, such as pregnancy and the follicular phase of the ovarian cycle (versus luteal phase and ovariectomized ewes), there is an increased level of prostacyclin synthase (PGIS) expression in ovine uterine and omental Artery Endothelium and VSM. To investigate this, the cellular localization and PGIS protein expression level in uterine and systemic arteries was examined by immunohistochemistry as well as by Western immunoblot analysis of endothelial-isolated protein and denuded vessels (VSM). Whole uterine, but not omental (systemic), arteries from the pregnant ewes showed an increase (P < 0.001) in PGIS expression. Further localization of PGIS protein by immunohistochemistry and quantification by Western analysis showed PGIS to be somewhat higher in the uterine Artery VSM (69 ± 7%) than Endothelium (31 ± 7%). PGIS protein levels in uterine and omental Artery endothelial isolated protein were not altered by ovariectomy or the ovarian cycle, although they were both significantly elevated by pregnancy. Uterine and omental Artery VSM PGIS expression levels also were not altered by ovariectomy or the ovarian cycle, whereas PGIS expression, in uterine but not omental Artery VSM showed a significant elevation during pregnancy. Thus, the rise in PGI2 production by uterine arteries observed in ovine pregnancy is paralleled by an elevation in PGIS expression in both Endothelium and VSM, whereas those seen in omental arteries is associated with increases in endothelial PGIS.
Coen D A Stehouwer - One of the best experts on this subject based on the ideXlab platform.
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association between global leukocyte dna methylation renal function carotid intima media thickness and plasma homocysteine in patients with stage 2 4 chronic kidney disease
Nephrology Dialysis Transplantation, 2008Co-Authors: Prabath W B Nanayakkara, Coen D A Stehouwer, Jessica Kieftede C Jong, Frans J Van Ittersum, Margreet R Olthof, Rob Kok, Henk J Blom, Coen Van Guldener, Piet M Ter Wee, Yvo M SmuldersAbstract:Background. Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD. The aims of this study in patients with stage 2-4 CKD were (1) to assess the association between renal function and DNA methylation, (2) to assess the association between DNA methylation and two markers of atherosclerosis [common carotid intima-media thickness (CCA-IMT)] and brachial Artery Endothelium-dependent, flow-mediated dilatation (BA-FMD) and (3) to examine the effect of a multi-step treatment strategy on DNA methylation. Methods. In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study (ATIC-study), 93 patients with stage 2-4 CKD were included. In a randomized, double-blind, placebo-controlled design, the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months. DNA methylation was assessed using tandem mass spectrometry. CCA-IMT and BA-FMD were assessed using B-mode ultrasonagraphy. Results. At baseline, global DNA methylation was not associated with the estimated glomerular filtration rate (P = 0.32) or with CCA-IMT (P = 0.62) or BA-FMD (P = 0.51). No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function. Conclusion. In patients with stage 2-4 CKD, global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD. A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients. These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2-4 CKD. © The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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aggressive antihypertensive therapy based on hydrochlorothiazide candesartan or lisinopril as initial choice in hypertensive type ii diabetic individuals effects on albumin excretion endothelial function and inflammation in a double blind randomized clinical trial
Journal of Human Hypertension, 2005Co-Authors: Miranda T Schram, Jos W R Twisk, F J Van Ittersum, A Spoelstrade M Man, R A J M Van Dijk, Casper G Schalkwijk, Richard G Ijzerman, Coen D A StehouwerAbstract:We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals. A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mmHg. After titration, patients were treated for 12 months. Mean blood pressures changed from 157/93, 151/94 and 149/93 at baseline to 135/80, 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups. About 70% reached target blood pressures. However, only 45% had blood pressures <130/85 mmHg. Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased (GEE regression coefficients, -2.40 mg/24 h (P<0.001), -85 ng/ml (P=0.01) and -50 ng/ml (P=0.02)), but brachial Artery Endothelium-dependent and -independent vasodilation and levels of von Willebrand factor and C-reactive protein did not change (GEE regression coefficients, 0.21 mm (P=0.07), 0.04 mm (P=0.43), 0.04 IU/ml (P=0.33) and -1.15 mg/l (P=0.64)). No differences in outcome variables between treatment groups were observed. These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult. Aggressive antihypertensive therapy can improve urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals, regardless of the type of antihypertensive therapy used.
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microalbuminuria is associated with impaired brachial Artery flow mediated vasodilation in elderly individuals without and with diabetes further evidence for a link between microalbuminuria and endothelial dysfunction the hoorn study
Kidney International, 2004Co-Authors: Coen D A Stehouwer, Ronald M A Henry, Jacqueline M Dekker, G Nijpels, Robert J Heine, L M BouterAbstract:Microalbuminuria is associated with impaired brachial Artery, flow-mediated vasodilation in elderly individuals without and with diabetes: Further evidence for a link between microalbu- minuria and endothelial dysfunction—The Hoorn Study. Background. Extensive endothelial dysfunction (i.e., affect- ing many aspects of endothelial function) has been hypothe- sized to explain why microalbuminuria (MA) is associated with cardiovascular disease risk. However, it is not clear whether MA is specifically associated with impaired endothelial nitric oxide (NO) synthesis in individuals without and with type 2 diabetes. Methods. We did a population-based study in 645 individu- als (mean age 68 years; 248 with normal glucose metabolism, 137 with impaired glucose metabolism, and 260 with type 2 di- abetes) and investigated associations of MA (present (urinary albumin-creatinine ratio ≥2 mg/mmol) versus absent, and in four categories (<2, ≥ 2t o 5,≥ 5t o 10,≥10 mg/mmol)) with ul- trasonically measured brachial Artery Endothelium-dependent, flow-mediated (FMD; an estimate of endothelial NO synthesis) and Endothelium-independent, nitroglycerin-induced vasodila- tion (NID). Results. FMD was 0.12 mm in the presence of MA (N = 93; 49 with diabetes), and 0.18 in its absence (P = 0.002). After adjustment for age, sex, baseline arterial diameter, and other potential confounders, FMD was 0.038 mm (95% CI, 0.001 to 0.075) lower in the presence of MA (P = 0.04), and decreased linearly across MA categories (by 0.027 mm (0.007 to 0.046) per category increase of MA; P = 0.007). NID was similar in individ- uals with and without MA. Results were similar in individuals without and with diabetes. Conclusion. Microalbuminuria is linearly associated with im- paired Endothelium-dependent, flow-mediated vasodilation in elderly individuals without and with diabetes. These findings support the concept that impaired endothelial nitric oxide syn- thesis plays a role in the association of microalbuminuria with cardiovascular disease risk.
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long term homocysteine lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial Artery Endothelium dependent vasodilation or carotid Artery stiffness a 2 year randomized placebo controlled trial
Arteriosclerosis Thrombosis and Vascular Biology, 2001Co-Authors: Robert A J M Van Dijk, J A Rauwerda, Mieke Steyn, Jos W R Twisk, Coen D A StehouwerAbstract:Homocysteine is associated with atherothrombotic disease, which may be mediated through associations of homocysteine levels with blood pressure, endothelial function, or arterial stiffness. In a placebo-controlled, randomized clinical trial, we measured blood pressure, brachial Artery Endothelium-dependent vasodilation, and common carotid Artery stiffness in 158 clinically healthy siblings of patients with premature atherothrombotic disease at baseline and after 1 and 2 years of homocysteine-lowering treatment with folic acid (5 mg) plus pyridoxine (250 mg). Intention-to-treat analyses limited to participants (n=130) who underwent at least 1 measurement after the baseline visit showed that compared with placebo, treatment with folic acid plus pyridoxine was associated with a 3.7-mm Hg (95% CI −6.8 to −0.6 mm Hg) lower systolic and a 1.9-mm Hg (95% CI −3.7 to −0.02 mm Hg) lower diastolic blood pressure over the 2-year trial period. Together with the decreased occurrence of abnormal exercise electrocardiography tests reported previously, our results support the hypothesis that homocysteine-lowering treatment with folic acid plus pyridoxine has beneficial vascular effects. Because no effects could be demonstrated on brachial Artery Endothelium-dependent vasodilation or on common carotid Artery stiffness, the present study does not support the hypothesis that the cardiovascular effects of homocysteine are mediated through these factors, at least in clinically healthy individuals.
M P Burnham - One of the best experts on this subject based on the ideXlab platform.
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characterization of a charybdotoxin sensitive intermediate conductance ca2 activated k channel in porcine coronary Endothelium relevance to edhf
British Journal of Pharmacology, 2002Co-Authors: Rostislav Bychkov, Ah Weston, M P Burnham, Gillian R Richards, Gillian Edwards, Michel Feletou, Paul M VanhoutteAbstract:This study characterizes the K+ channel(s) underlying charybdotoxin-sensitive hyperpolarization of porcine coronary Artery Endothelium. Two forms of current-voltage (I/V) relationship were evident in whole-cell patch-clamp recordings of freshly-isolated endothelial cells. In both cell types, iberiotoxin (100 nM) inhibited a current active only at potentials over +50 mV. In the presence of iberiotoxin, charybdotoxin (100 nM) produced a large inhibition in 38% of cells and altered the form of the I/V relationship. In the remaining cells, charybdotoxin also inhibited a current but did not alter the form. Single-channel, outside-out patch recordings revealed a 17.1±0.4 pS conductance. Pipette solutions containing 100, 250 and 500 nM free Ca2+ demonstrated that the open probability was increased by Ca2+. This channel was blocked by charybdotoxin but not by iberiotoxin or apamin. Hyperpolarizations of intact Endothelium elicited by substance P (100 nM; 26.1±0.7 mV) were reduced by apamin (100 nM; 17.0±1.8 mV) whereas those to 1-ethyl-2-benzimidazolinone (1-EBIO, 600 μM, 21.0±0.3 mV) were unaffected (21.7±0.8 mV). Substance P, bradykinin (100 nM) and 1-EBIO evoked charybdotoxin-sensitive, iberiotoxin-insensitive whole-cell perforated-patch currents. A porcine homologue of the intermediate-conductance Ca2+-activated K+ channel (IK1) was identified in endothelial cells. In conclusion, porcine coronary Artery endothelial cells express an intermediate-conductance Ca2+-activated K+ channel and the IK1 gene product. This channel is opened by activation of the EDHF pathway and likely mediates the charybdotoxin-sensitive component of the EDHF response. Keywords: Endothelium, EDHF, hyperpolarization, calcium-activated potassium channels, charybdotoxin, iberiotoxin, apamin, IK1 gene product Introduction The vascular Endothelium controls vessel tone by releasing nitric oxide (Furchgott & Zawadzki, 1980) and prostacyclin (Moncada & Vane, 1979) as well as by a third pathway which involves hyperpolarization of the vascular smooth muscle (reviewed by Busse et al., 2002). This ‘Endothelium-dependent hyperpolarizing factor (EDHF)' pathway is inhibited by a combination of the toxins apamin and charybdotoxin, but not apamin and iberiotoxin (Corriu et al., 1996; Zygmunt & Hogestatt, 1996; Petersson et al., 1997; Chataigneau et al., 1998; Edwards et al., 1998; 2000). Given the specificities of these toxins (reviewed by Garcia et al., 1991; Castle, 1999), small- and intermediate-conductance Ca2+-activated K+ channels (SKCa and IKCa, respectively) but not large-conductance Ca2+-activated K+ channels (BKCa) are implicated in the EDHF pathway. In the vasculature, SKCa and IKCa are expressed in endothelial cells (Sakai, 1990; Marchenko & Sage, 1996; Kohler et al., 2000; Burnham et al., 2002) but not in smooth muscle cells with the contractile phenotype while BKCa are mainly expressed in myocytes (Zygmunt et al., 1997; Neylon et al., 1999; Quignard et al., 2000). Furthermore, the combination of apamin and charybdotoxin blocks EDHF-mediated vasodilatation if selectively applied to the Endothelium and inhibits the hyperpolarization of the endothelial cells produced by acetylcholine or bradykinin (Edwards et al., 1998; 2000; Doughty et al., 1999; Ohashi et al., 1999). Finally, the increase in endothelial intracellular calcium concentration, provoked by the agonist, is not inhibited by the two toxins (Ghisdal & Morel, 2001). Altogether, these experimental results suggest that the hyperpolarization of the endothelial cells is the critical initiating step in the EDHF-mediated responses (Quignard et al., 2000; Edwards et al., 2000; Busse et al., 2002) and that apamin plus charybdotoxin exert their effects at this site (Edwards et al., 1998). In an earlier study, in porcine coronary Artery endothelial cells, an apamin-sensitive K+ channel which is likely to be involved in the EDHF response was proposed to be an SKCa containing the SK3 subunit (Burnham et al., 2002). The purpose of the present study was, in the same cells, to characterize the K+ channels sensitive to charybdotoxin which are also involved in EDHF-mediated responses.
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characterization of an apamin sensitive small conductance ca2 activated k channel in porcine coronary Artery Endothelium relevance to edhf
British Journal of Pharmacology, 2002Co-Authors: M P Burnham, Ah Weston, Rostislav Bychkov, Gillian R Richards, Michel Feletou, Paul M Vanhoutte, Gerald E EdwardsAbstract:The apamin-sensitive small-conductance Ca2+-activated K+ channel (SKCa) was characterized in porcine coronary arteries. In intact arteries, 100 nM substance P and 600 μM 1-ethyl-2-benzimidazolinone (1-EBIO) produced endothelial cell hyperpolarizations (27.8±0.8 mV and 24.1±1.0 mV, respectively). Charybdotoxin (100 nM) abolished the 1-EBIO response but substance P continued to induce a hyperpolarization (25.8±0.3 mV). In freshly-isolated endothelial cells, outside-out patch recordings revealed a unitary K+ conductance of 6.8±0.04 pS. The open-probability was increased by Ca2+ and reduced by apamin (100 nM). Substance P activated an outward current under whole-cell perforated-patch conditions and a component of this current (38%) was inhibited by apamin. A second conductance of 2.7±0.03 pS inhibited by d-tubocurarine was observed infrequently. Messenger RNA encoding the SK2 and SK3, but not the SK1, subunits of SKCa was detected by RT – PCR in samples of Endothelium. Western blotting indicated that SK3 protein was abundant in samples of Endothelium compared to whole arteries. SK2 protein was present in whole Artery nuclear fractions. Immunofluorescent labelling confirmed that SK3 was highly expressed at the plasmalemma of endothelial cells and was not expressed in smooth muscle. SK2 was restricted to the peri-nuclear regions of both endothelial and smooth muscle cells. In conclusion, the porcine coronary Artery Endothelium expresses an apamin-sensitive SKCa containing the SK3 subunit. These channels are likely to confer all or part of the apamin-sensitive component of the Endothelium-derived hyperpolarizing factor (EDHF) response. British Journal of Pharmacology (2002) 135, 1133–1143; doi:10.1038/sj.bjp.0704551
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characterization of an apamin sensitive small conductance ca2 activated k channel in porcine coronary Artery Endothelium relevance to edhf
British Journal of Pharmacology, 2002Co-Authors: M P Burnham, Ah Weston, Rostislav Bychkov, Gillian R Richards, Michel Feletou, Paul M Vanhoutte, Gillian EdwardsAbstract:The apamin-sensitive small-conductance Ca2+-activated K+ channel (SKCa) was characterized in porcine coronary arteries. In intact arteries, 100 nM substance P and 600 μM 1-ethyl-2-benzimidazolinone (1-EBIO) produced endothelial cell hyperpolarizations (27.8±0.8 mV and 24.1±1.0 mV, respectively). Charybdotoxin (100 nM) abolished the 1-EBIO response but substance P continued to induce a hyperpolarization (25.8±0.3 mV). In freshly-isolated endothelial cells, outside-out patch recordings revealed a unitary K+ conductance of 6.8±0.04 pS. The open-probability was increased by Ca2+ and reduced by apamin (100 nM). Substance P activated an outward current under whole-cell perforated-patch conditions and a component of this current (38%) was inhibited by apamin. A second conductance of 2.7±0.03 pS inhibited by d-tubocurarine was observed infrequently. Messenger RNA encoding the SK2 and SK3, but not the SK1, subunits of SKCa was detected by RT – PCR in samples of Endothelium. Western blotting indicated that SK3 protein was abundant in samples of Endothelium compared to whole arteries. SK2 protein was present in whole Artery nuclear fractions. Immunofluorescent labelling confirmed that SK3 was highly expressed at the plasmalemma of endothelial cells and was not expressed in smooth muscle. SK2 was restricted to the peri-nuclear regions of both endothelial and smooth muscle cells. In conclusion, the porcine coronary Artery Endothelium expresses an apamin-sensitive SKCa containing the SK3 subunit. These channels are likely to confer all or part of the apamin-sensitive component of the Endothelium-derived hyperpolarizing factor (EDHF) response. Keywords: EDHF, porcine coronary Artery, Endothelium, apamin, 1-EBIO, SK1, SK2, SK3 Introduction In the combined presence of inhibitors of nitric oxide and prostacyclin synthesis, ligands such as acetylcholine, substance P and bradykinin or increases in luminal flow still evoke vasodilation (Nagao & Vanhoutte, 1991; Zhang et al., 1994; Petersson et al., 1997; Izzard & Heagerty, 1999). Under these conditions, vessel relaxation is Endothelium-dependent and is believed to be generated through the action of an Endothelium-derived hyperpolarizing factor (EDHF; Garland et al., 1995; Feletou & Vanhoutte, 2000; Edwards & Weston, 2001a). Microelectrode experiments have shown that the critical initiating step in the EDHF pathway is endothelial cell hyperpolarization and that this component is sensitive to a combination of the toxins apamin and charybdotoxin (Edwards et al., 1998; 2000) but not apamin and iberiotoxin (Corriu et al., 1996; Zygmunt & Hogestatt, 1996; Petersson et al., 1997; Chataigneau et al., 1998; Edwards et al., 1998; 2000). Iberiotoxin and charybdotoxin are two scorpion venom-derived peptides but while the former is selective for large-conductance Ca2+-activated K+ channels (BKCa), the latter also inhibits the intermediate-conductance Ca2+-activated K+ channel (IKCa) and some voltage-dependent potassium channels (Garcia et al., 1991). Apamin is a selective inhibitor of the small-conductance Ca2+-activated K+ channel (SKCa; Castle, 1999). Together with other lines of evidence, these observations have led to the hypothesis that the inhibition of EDHF by apamin plus charybdotoxin is due to their inhibition of SKCa and IKCa located on the vascular Endothelium (Edwards et al., 1998). Three SKCa subunits (SK1, SK2 and SK3) have been cloned which all form apamin-sensitive channels when expressed in Xenopus oocytes or mammalian cells (Kohler et al., 1996; Hosseini et al., 1999; Shah & Haylett, 2000; Strobaek et al., 2000; Grunnet et al., 2001a). The objective of the present study was to characterize further the apamin-sensitive component of the EDHF pathway in the porcine left anterior descending coronary Artery. Patch-clamp and sharp microelectrode techniques were used to measure K+ currents and membrane potential changes, respectively, in freshly-isolated endothelial cells and whole vessels. In addition, RT – PCR and Western blotting techniques coupled with immunofluorescence histochemistry were employed to identify and localize K+ channel proteins in the cells of this Artery. A preliminary account of some of these observations has been presented (Burnham et al., 2001). Data obtained concerning the endothelial IKCa will be reported in a separate study.
