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Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial.
Chen, J, Hamm, LL, Bundy, JD, Kumbala, DR, Bodana, S, Chandra, S, Chen, CS, Starcke, CC, Guo, Y, Schaefer, CM, et al
Clinical journal of the American Society of Nephrology : CJASN. 2020;(11):1566-1575
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Abstract
BACKGROUND AND OBJECTIVES Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. RESULTS Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. CONCLUSIONS This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.
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The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.
van Bommel, EJM, Muskiet, MHA, van Baar, MJB, Tonneijck, L, Smits, MM, Emanuel, AL, Bozovic, A, Danser, AHJ, Geurts, F, Hoorn, EJ, et al
Kidney international. 2020;(1):202-212
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.
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Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers.
Yang, L, Cheriyan, J, Gutterman, DD, Mayer, RJ, Ament, Z, Griffin, JL, Lazaar, AL, Newby, DE, Tal-Singer, R, Wilkinson, IB
Chest. 2017;(3):555-563
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BACKGROUND Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo. METHODS Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination. The effects of GSK2256294 on EET-mediated vasodilation in human resistance arteries were assessed in vitro and in vivo in a phase I clinical trial in healthy overweight smokers. RESULTS Compared with control groups, there was reduced vasodilation with bradykinin (P = .005), a blunted effect of fluconazole on bradykinin-induced vasodilation (P = .03), and a trend toward reduced basal EET/dihydroxyepoxyeicosatrienoic acid ratio in patients with COPD (P = .08). A similar pattern was observed in overweight smokers. In vitro, 10 μM GSK2256294 increased 11,12-EET-mediated vasodilation compared with vehicle (90% ± 4.2% vs 72.6% ± 6.2% maximal dilatation) and shifted the bradykinin half-maximal effective concentration (EC50) (-8.33 ± 0.172 logM vs -8.10 ± 0.118 logM; P = .001 for EC50). In vivo, 18 mg GSK2256294 improved the maximum bradykinin response from 338% ± 46% before a dose to 566% ± 110% after a single dose (P = .02) and to 503% ± 123% after a chronic dose (P = .003). CONCLUSIONS GSK2256294 attenuates smoking-related EET-mediated endothelial dysfunction, suggesting potential therapeutic benefits in patients with COPD. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01762774; URL: www.clinicaltrials.gov.
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The LargPAD Trial: Phase IIA evaluation of l-arginine infusion in patients with peripheral arterial disease.
Kashyap, VS, Lakin, RO, Campos, P, Allemang, M, Kim, A, Sarac, TP, Hausladen, A, Stamler, JS
Journal of vascular surgery. 2017;(1):187-194
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OBJECTIVE Endothelial function is improved by l-arginine (l-arg) supplementation in preclinical and clinical studies of mildly diseased vasculature; however, endothelial function and responsiveness to l-arg in severely diseased arteries is not known. Our objective was to evaluate the acute effects of catheter-directed l-arg delivery in patients with chronic lower extremity ischemia secondary to peripheral arterial disease. METHODS The study enrolled 22 patients (45% male) with peripheral arterial disease (mean age, 62 years) requiring lower extremity angiography. Endothelium-dependent relaxation of patent but atherosclerotic superficial femoral arteries was measured using a combination of intravascular ultrasound (IVUS) imaging and a Doppler FloWire (Volcano Corporation, Rancho Cordova, Calif) during the infusion of incremental acetylcholine (10-6 to 10-4 molar concentration) doses. Patients received 50 mg (n = 3), 100 mg (n = 10), or 500 mg (n = 9) l-arg intra-arterially, followed by repeat endothelium-dependent relaxation measurement (limb volumetric flow). IVUS-derived virtual histology of the culprit vessel was also obtained. Endothelium-independent relaxation was measured using a nitroglycerin infusion. Levels of nitrogen oxides and arginine metabolites were measured by chemiluminescence and mass spectrometry, respectively. RESULTS Patients tolerated limb l-arg infusion well. Serum arginine and ornithine levels increased by 43.6% ± 13.0% and 23.2% ± 10.3%, respectively (P < .005), and serum nitrogen oxides increased by 85% (P < .0001) after l-arg infusion. Average vessel area increased by 6.8% ± 1.3% with l-arg infusion (acetylcholine 10-4; P < .0001). Limb volumetric flow increased in all patients and was greater with l-arg supplementation by 130.9 ± 17.6, 136.9 ± 18.6, and 172.1 ± 24.8 mL/min, respectively, for each cohort. Maximal effects were seen with l-arg at 100 mg (32.8%). Arterial smooth muscle responsiveness to nitroglycerin was intact in all vessels (endothelium-independent relaxation, 137% ± 28% volume flow increase). IVUS-derived virtual histology indicated plaque volume was 14 ± 1.3 mm3/cm, and plaque stratification revealed a predominantly fibrous morphology (46.4%; necrotic core, 28.4%; calcium, 17.4%; fibrolipid, 6.6%). Plaque morphology did not correlate with l-arg responsiveness. CONCLUSIONS Despite extensive atherosclerosis, endothelial function in diseased lower extremity human arteries can be enhanced by l-arg infusion secondary to increased nitric oxide bioactivity. Further studies of l-arg as a therapeutic modality in patients with endothelial dysfunction (ie, acute limb ischemia) are warranted.
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Folic acid ingestion improves skeletal muscle blood flow during graded handgrip and plantar flexion exercise in aged humans.
Romero, SA, Gagnon, D, Adams, AN, Moralez, G, Kouda, K, Jaffery, MF, Cramer, MN, Crandall, CG
American journal of physiology. Heart and circulatory physiology. 2017;(3):H658-H666
Abstract
Skeletal muscle blood flow is attenuated in aged humans performing dynamic exercise, which is due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole body heating through nitric oxide-dependent mechanisms. However, it is unclear whether folic acid improves vasodilation in other vascular beds during conditions of increased metabolism (i.e., exercise). The purpose of this study was to test the hypothesis that folic acid ingestion improves skeletal muscle blood flow in aged adults performing graded handgrip and plantar flexion exercise via increased vascular conductance. Nine healthy, aged adults (two men and seven women; age: 68 ± 5 yr) performed graded handgrip and plantar flexion exercise before (control), 2 h after (acute, 5 mg), and after 6 wk (chronic, 5 mg/day) folic acid ingestion. Forearm (brachial artery) and leg (superficial femoral artery) blood velocity and diameter were measured via Duplex ultrasonography and used to calculate blood flow. Acute and chronic folic acid ingestion increased serum folate (both P < 0.05 vs. control). During handgrip exercise, acute and chronic folic acid ingestion increased forearm blood flow (both conditions P < 0.05 vs. control) and vascular conductance (both P < 0.05 vs. control). During plantar flexion exercise, acute and chronic folic acid ingestion increased leg blood flow (both P < 0.05 vs. control), but only acute folic acid ingestion increased vascular conductance (P < 0.05 vs. control). Taken together, folic acid ingestion increases blood flow to active skeletal muscle primarily via improved local vasodilation in aged adults.NEW & NOTEWORTHY Our findings demonstrate that folic acid ingestion improves blood flow via enhanced vascular conductance in the exercising skeletal muscle of aged humans. These findings provide evidence for the therapeutic use of folic acid to improve skeletal muscle blood flow, and perhaps exercise and functional capacity, in human primary aging.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/folic-acid-and-exercise-hyperemia-in-aging/.
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Assessing the effects of a short-term green tea intervention in skin microvascular function and oxygen tension in older and younger adults.
Wasilewski, R, Ubara, EO, Klonizakis, M
Microvascular research. 2016;:65-71
Abstract
Green tea consumption has been associated with a reduction in cardiovascular disease risk factors. However, there is little evidence examining its potential differing effect between younger and older populations, whilst little is known on its effect on the circulatory system when oxygen demand is higher. Therefore the aim of this study was to evaluate the short-term effects of green tea consumption on microvascular functioning in both an older and younger population. Fifteen young [24 (4.0)] and fifteen older [61 (4.0)] participants, consumed two cups of green tea daily for 14days. We used Laser Doppler Flowmetry (LDF) to assess cutaneous microvascular function and Transcutaneous Oxygen monitoring (TcPO2) to assess skin oxygen tension. Systolic and diastolic blood pressure were also assessed on both visits. We observed significant improvements in axon-mediated microvascular vasodilation for the younger group [1.6 (0.59) vs 2.05 (0.72), p<0.05] and the older group [1.25 (0.58) vs 1.65 (0.5) p<0.05]. Improvements in skin oxygen tension were also noted for both groups in both noted TcPO2 measures (i.e. 1.25 (0.58) vs 1.65 (0.5) (p<0.05), for ΔTcPO2max for the older group, between visits) respectively. Improvements were also observed for systolic blood pressure in both the younger [120 (10) vs 112 (10), p<0.05] and older group [129 (12) v 124 (11), p<0.001]. In conclusion, we observed statistically-significant improvements in microvascular function and skin oxygen tension. Our results suggest that green tea may prove beneficial as a dietary element in lifestyle interventions aiming to lower cardiovascular disease risk, in both older and younger populations.
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Acute ascorbic acid ingestion increases skeletal muscle blood flow and oxygen consumption via local vasodilation during graded handgrip exercise in older adults.
Richards, JC, Crecelius, AR, Larson, DG, Dinenno, FA
American journal of physiology. Heart and circulatory physiology. 2015;(2):H360-8
Abstract
Human aging is associated with reduced skeletal muscle perfusion during exercise, which may be a result of impaired endothelium-dependent dilation and/or attenuated ability to blunt sympathetically mediated vasoconstriction. Intra-arterial infusion of ascorbic acid (AA) increases nitric oxide-mediated vasodilation and forearm blood flow (FBF) during handgrip exercise in older adults, yet it remains unknown whether an acute oral dose can similarly improve FBF or enhance the ability to blunt sympathetic vasoconstriction during exercise. We hypothesized that 1) acute oral AA would improve FBF (Doppler ultrasound) and oxygen consumption (V̇o2) via local vasodilation during graded rhythmic handgrip exercise in older adults (protocol 1), and 2) AA ingestion would not enhance sympatholysis in older adults during handgrip exercise (protocol 2). In protocol 1 (n = 8; 65 ± 3 yr), AA did not influence FBF or V̇o2 during rest or 5% maximal voluntary contraction (MVC) exercise, but increased FBF (199 ± 13 vs. 248 ± 16 ml/min and 343 ± 24 vs. 403 ± 33 ml/min; P < 0.05) and V̇o2 (26 ± 2 vs. 34 ± 3 ml/min and 43 ± 4 vs. 50 ± 5 ml/min; P < 0.05) at both 15 and 25% MVC, respectively. The increased FBF was due to elevations in forearm vascular conductance (FVC). In protocol 2 (n = 10; 63 ± 2 yr), following AA, FBF was similarly elevated during 15% MVC (∼ 20%); however, vasoconstriction to reflex increases in sympathetic activity during -40 mmHg lower-body negative pressure at rest (ΔFVC: -16 ± 3 vs. -16 ± 2%) or during 15% MVC (ΔFVC: -12 ± 2 vs. -11 ± 4%) was unchanged. Our collective results indicate that acute oral ingestion of AA improves muscle blood flow and V̇o2 during exercise in older adults via local vasodilation.
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Acute dietary nitrate supplementation enhances compensatory vasodilation during hypoxic exercise in older adults.
Casey, DP, Treichler, DP, Ganger, CT, Schneider, AC, Ueda, K
Journal of applied physiology (Bethesda, Md. : 1985). 2015;(2):178-86
Abstract
We have previously demonstrated that aging reduces the compensatory vasodilator response during hypoxic exercise due to blunted nitric oxide (NO) signaling. Recent evidence suggests that NO bioavailability can be augmented by dietary nitrate through the nitrate-nitrite pathway. Thus we tested the hypothesis that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise, particularly in older adults. Thirteen young (25 ± 1 yr) and 12 older (64 ± 2 yr) adults performed rhythmic forearm exercise at 20% of maximum voluntary contraction during normoxia and hypoxia (∼80% O2 saturation); both before (control) and 3 h after beetroot juice (BR) consumption. Forearm vascular conductance (FVC; ml·min(-1)·100 mmHg(-1)) was calculated from forearm blood flow (ml/min) and blood pressure (mmHg). Compensatory vasodilation was defined as the relative increase in FVC due to hypoxic exercise (i.e., % increase compared with respective normoxic exercise trial). Plasma nitrite was determined from venous blood samples obtained before the control trials and each of the exercise trials (normoxia and hypoxia) after BR. Consumption of BR increased plasma nitrite in both young and older adults (P < 0.001). During the control condition, the compensatory vasodilator response to hypoxic exercise was attenuated in older compared with young adults (3.8 ± 1.7% vs. 14.2 ± 1.2%, P < 0.001). Following BR consumption, compensatory vasodilation did not change in young (13.7 ± 3.3%, P = 0.81) adults but was substantially augmented in older adults (11.4 ± 2.1%, P < 0.01). Our data suggest that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise in older but not young adults.
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Peripheral Microvascular Vasodilatory Response to Estradiol and Genistein in Women with Insulin Resistance.
Wenner, MM, Taylor, HS, Stachenfeld, NS
Microcirculation (New York, N.Y. : 1994). 2015;(5):391-9
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OBJECTIVE E2 enhances vasodilation in healthy women, but vascular effects of the phytoestrogen GEN are still under investigation. IR compromises microvascular function. We therefore examined the interaction of E2 , GEN, and IR on microvascular vasodilatory responsiveness. METHODS We hypothesized that E2 and GEN increase microvascular vasodilation in healthy women (control, n = 8, 23 ± 2 year, BMI: 25.9 ± 2.9 kg/m2) but not in women with IR (n = 7, 20 ± 1 year, BMI: 27.3 ± 3.0 kg/m2). We used the cutaneous circulation as a model of microvascular vasodilatory function. We determined CVC with laser Doppler flowmetry and beat-to-beat blood pressure during local cutaneous heating (42 °C) with E2 or GEN microdialysis perfusions. Because heat-induced vasodilation is primarily an NO-mediated response, we examined microvascular vasodilation with and without L-NMMA. RESULTS In C, E2 enhanced CVC (94.4 ± 2.6% vs. saline 81.6 ± 4.2% CVCmax , p < 0.05), which was reversed with L-NMMA (80.9 ± 7.8% CVCmax , p < 0.05), but GEN did not affect vasodilation. Neither E2 nor GEN altered CVC in IR, although L-NMMA attenuated CVC during GEN. CONCLUSIONS Our study does not support improved microvascular responsiveness during GEN exposure in healthy young women, and demonstrates that neither E2 nor GEN improves microvascular vasodilatory responsiveness in women with IR.
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[Possibilities of Correction of Endothelial Dysfunction at the Background of Combined Antihypertensive Therapy in Patients With Arterial Hypertension and Type 2 Diabetes].
Statsenko, ME, Derevianchenko, MV
Kardiologiia. 2015;(3):17-20
Abstract
AIM: To evaluate the impact of a 12-week combined antihypertensive therapy with enalapril + indapamide on endothelial dysfunction in patients with arterial hypertension (AH) and diabetes mellitus (DM) type 2. MATERIALS AND METHODS 30 patients with AH stage II-III and DM type 2 age from 40 to 65 years were included into research. The combined antihypertensive therapy with enalapril 28.6 ± 1.9 + indapamide 2.5 ± 0 mg/day was assigned for 12 weeks. We studied endothelial function by determining the concentration of NO metabolites and endothelin-1 in serum and urine, the results of occlusion test. RESULTS After 12-week therapy, 100% of the patients achieved BP goals. There was no impairment of carbohydrate metabolism. Endothelial function was improved in hypertensive patients with T2DM: there were increases in both serum and urinary NO production (by 381 and 48.2%, respectively) and decreases in urinary endothelin-1 secretion (by 56.3%). The number of patients with normal microcirculation increased from 13.3 to 53.3% (p < 0.001) by reducing the number of patients with abnormal (hyperemic and stagnant-stasic) types of microcirculation. CONCLUSION Twelve-week treatment with the combined antihypertensive medication. The combined antihypertensive therapy with enalapril + indapamide is highly effective and safe for recovering endothelial function in hypertensive patients with T2DM.