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Oral L-Arginine (5 g/day) for 14 Days Improves Microcirculatory Function in Healthy Young Women and Healthy and Type 2 Diabetes Mellitus Elderly Women.
Costa, G, Shushanof, M, Bouskela, E, Bottino, D
Journal of vascular research. 2022;(1):24-33
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Abstract
OBJECTIVE The aim of this study was to investigate the effect of oral supplementation with L-arginine on serum biochemical profile, blood pressure, microcirculation, and vasoreactivity/endothelial function in young controls, and elderly women with and without type 2 diabetes mellitus (T2DM). METHODS Healthy young (n = 25), healthy elderly (n = 25), and elderly women with type 2 diabetes mellitus (T2DME, n = 23, glycated Hb ≥6.4% and mean of 7.7 years for duration of the disease), aged 18-30 and older than 65 years, respectively, were included in the study. All patients underwent biochemical analysis (fasting glycemia and lipidogram), arterial blood pressure, nailfold videocapillaroscopy (capillary diameters, functional capillary density [FCD], peak red blood cell velocity [RBCVmax] after 1 min ischemia, time to reach peak RBCV [TRBCVmax]), and venous occlusion plethysmography (vasoreactivity), before and after 14 days of oral supplementation with L-arginine (5 g/day). RESULTS L-Arginine did not change fasting glycemia and lipidogram, but it decreased systolic, diastolic, and mean arterial pressure in elderly women, increased RBCVmax in all groups, and did not decrease TRBCVmax in T2DME. Capillary diameters and FCD remained unchanged in all groups. L-Arginine improved vasoreactivity during reactive hyperemia and after sublingual nitroglycerin (0.4 mg) in all groups. CONCLUSION L-Arginine supplementation (5g/day during 14 days) was able to improve vascular/microvascular health in the elderly women with or without T2DM.
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Acute consumption of flavanol-rich cocoa beverage improves attenuated cutaneous microvascular function in healthy young African Americans.
Kim, K, Brothers, RM
Microvascular research. 2020;:103931
Abstract
Flavanols have beneficial effects on vascular health and we have recently demonstrated that cerebral vasodilatory capacity in healthy young African Americans (AA) is improved with acute flavanol intake relative to aged-matched Caucasian Americans (CA). However, whether the positive benefits of acute flavanol consumption would also be present in the cutaneous microvascular circulation of AA remains unknown. Thus, we hypothesized that acute consumption of flavanol-rich cocoa (FC) would improve the previously reported reduced cutaneous microvascular responses to local heating in young AA. Seven AA and seven CA participated in this double-blind crossover study. Data were collected on two different days, separated by a minimum of one week. Two intradermal microdialysis membranes were inserted in the forearm and each site was randomly assigned to receive lactated Ringer's solution or NO synthase (NOS) inhibitor. Participants were randomly assigned to consume either a non-flavanol containing (NF) beverage or FC beverage. Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flux/mean arterial pressure and normalized as % maximal CVC (%CVCmax). The difference in %CVCmax between the Ringer's site and NOS inhibited site was calculated to assess NO contribution (Δ %CVCmax). In the Ringer's site, acute consumption of FC beverage improved %CVCmax during 39 °C heating when compared to NF beverage in AA (NF: 36 ± 6 vs. FC: 47 ± 5%CVCmax; P < .01) while there was similar %CVCmax during 39 °C heating between beverages in CA (NF: 55 ± 4 vs. FC: 59 ± 5%CVCmax; P = .40). During 39 °C heating, NO contribution was significantly higher with FC beverage than NF beverage in AA (NF: 27 ± 5 vs. FC: 35 ± 4 Δ %CVCmax; P = .03) while there was similar NO contribution between beverages in CA (NF: 42 ± 4 vs. FC: 45 ± 4 Δ %CVCmax; P = .36). This data suggests that acute consumption of FC could be a therapeutic solution to improve an attenuated microvascular function in young AA.
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Apocynin and Tempol ameliorate dietary sodium-induced declines in cutaneous microvascular function in salt-resistant humans.
Ramick, MG, Brian, MS, Matthews, EL, Patik, JC, Seals, DR, Lennon, SL, Farquhar, WB, Edwards, DG
American journal of physiology. Heart and circulatory physiology. 2019;(1):H97-H103
Abstract
It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer's (n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol (n = 22), and 100 µM apocynin (n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine (n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVCmax); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2 %CVCmax; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin (P < 0.01) and Tempol (P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS (P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. NEW & NOTEWORTHY High-sodium diets have deleterious effects on vascular function, likely mediating, in part, the increased cardiovascular risk associated with a high sodium intake. Local infusion of apocynin and Tempol improved microvascular function in salt-resistant adults on a high-salt diet, providing evidence that reactive oxygen species contribute to impairments in microvascular function from high salt. This study provides insight into the blood pressure-independent mechanisms by which dietary sodium impairs vascular function. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/dietary-sodium-oxidative-stress-and-microvascular-function/ .
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The acute influence of sucrose consumption with and without vitamin C co-ingestion on microvascular reactivity in healthy young adults.
West, S, Smail, O, Bond, B
Microvascular research. 2019;:103906
Abstract
BACKGROUND Sugar sweetened beverages (SSB) are a major source of dietary sugar and a public health concern. Glucose consumption acutely influences microvascular reactivity in healthy adults, possibly via oxidative stress. The purpose of this study was to observe the acute influence of a more relevant dose of sucrose on microvascular reactivity, and to identify whether this response is influenced by the amount of vitamin C typically contained in SSB. METHODS Thirteen ostensibly healthy adults (8 male, 5 female) performed three 1-day trials in a randomized order; the consumption of 300 ml water (control; CON), or 300 ml water with 50 g sucrose (SUGAR) or 50 g sucrose with 160 mg of vitamin C (VITC). Near infrared spectroscopy was used to determine peak reactive hyperaemia (PRH), the rate of desaturation (Slope 1) and reperfusion (Slope 2), and the total area under the reperfusion curve versus time (TRH) following 5 min of forearm cuff occlusion before and 30, 60, 90 and 120 min after test drink consumption. RESULTS SUGAR and VITC significantly increased the total area under the curve versus time for plasma glucose (P < 0.05 for both). No changes in microvascular reactivity were observed between trials, although VITC increased Slope 1 compared to both SUGAR and CON 30 and 60 min post drink (P < 0.05 for both). CONCLUSION The consumption of a sugar load representative of commercially available SSB did not influence microvascular reactivity. The co-ingestion of Vitamin C also failed to influence microvascular reactivity, but did increase the rate of oxygen extraction.
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Attenuated cutaneous microvascular function in healthy young African Americans: Role of intradermal l-arginine supplementation.
Kim, K, Hurr, C, Patik, JC, Matthew Brothers, R
Microvascular research. 2018;:1-6
Abstract
It has been established that endothelial function in conduit vessels is reduced in young African Americans (AA) relative to Caucasian Americans (CA). However, less is known regarding endothelial function in microvasculature of young AA. We hypothesized that microvascular function in response to local heating of skin is attenuated in young AA relative to age-matched CA due largely to the lack of NO bioavailability, which is in turn improved by intradermal l-arginine supplementation and/or inhibition of arginase. Nine AA and nine CA adults participated in this study. Participants were instrumented with four microdialysis membranes in the cutaneous vasculature of one forearm and were randomly assigned to receive 1) lactated Ringer's solution as a control site; 2) 20 mM NG-nitro-l-arginine (l-NAME) to inhibit NO synthase activity; 3) 10 mM l-arginine to local supplement l-arginine; or 4) a combination of 5.0 mM (S)-(2‑boronoethyl)-l-cysteine-HCL (BEC) and 5.0 mM Nω-hydroxy-nor-l-arginine (nor-NOHA) at a rate of 2.0 μl/min to locally inhibit arginase activity. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux divided by mean arterial pressure. All CVC data were presented as a percentage of maximal CVC (%CVCmax) that was determined by maximal cutaneous vasodilation induced by 44 °C heating plus sodium nitroprusside administration. The response during the 42 °C local heating plateau was blunted in the AA at the control site (CA: 84 ± 12 vs. AA: 62 ± 6 vs. %CVCmax; P < 0.001). This response was improved in AA at the l-arginine site (Control: 62 ± 6 vs. l-arginine: 70 ± 18%CVCmax; P < 0.05) but not in the arginase inhibited site (Control: 62 ± 6 vs. Arginase inhibited: 62 ± 13%CVCmax; P = 0.91). In addition, the AA group had an attenuated NO contribution to the plateau phase during 42 °C local heating relative to the CA group (CA: 56 ± 14 vs. AA: 44 ± 6 Δ %CVCmax; P < 0.001). These findings suggest that 1) cutaneous microvascular function in response to local heating is blunted in young AA when compared to age-matched young CA; 2) this attenuated response is partly related to decrease in NO bioavailability in young AA; and 3) a local infusion of l-arginine, but not arginase inhibition, improves cutaneous microvascular responses to local heating in young AA relative to CA.
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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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Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms.
Stanhewicz, AE, Alexander, LM, Kenney, WL
Clinical science (London, England : 1979). 2015;(2):159-67
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Abstract
Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms.
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The REFLO-STEMI trial comparing intracoronary adenosine, sodium nitroprusside and standard therapy for the attenuation of infarct size and microvascular obstruction during primary percutaneous coronary intervention: study protocol for a randomised controlled trial.
Nazir, SA, Khan, JN, Mahmoud, IZ, Greenwood, JP, Blackman, DJ, Kunadian, V, Been, M, Abrams, KR, Wilcox, R, Adgey, AA, et al
Trials. 2014;:371
Abstract
BACKGROUND Microvascular obstruction (MVO) secondary to ischaemic-reperfusion injury is an important but underappreciated determinant of short- and longer-term outcome following percutaneous coronary intervention (PCI) treatment of ST-elevation myocardial infarction (STEMI). Several small studies have demonstrated a reduction in the degree of MVO utilising a variety of vasoactive agents, with adenosine and sodium nitroprusside (SNP) being most evaluated. However, the evidence base remains weak as the trials have had variable endpoints, differing drug doses and delivery. As such, the results regarding benefit are conflicting. METHODS The REperfusion Facilitated by LOcal adjunctive therapy in STEMI (REFLO-STEMI) trial is a multicentre, prospective, randomised, controlled, open label, study with blinded endpoint analysis: Patients presenting within 6 h of onset of STEMI and undergoing planned primary PCI (P-PCI) with TIMI 0/1 flow in the infarct-related artery (IRA) and no significant bystander coronary artery disease on angiography, are randomised into one of three groups: PCI with adjunctive pharmacotherapy (intracoronary adenosine or SNP) or control (standard PCI). All receive Bivalirudin anticoagulation and thrombus aspiration. The primary outcome is infarct size (IS) (determined as a percentage of total left ventricular mass) measured by cardiac magnetic resonance imaging (CMRI) undertaken at 48 to 72 h post P-PCI. Secondary outcome measures include MVO (hypoenhancement within infarct core) on CMRI, angiographic markers of microvascular perfusion and MACE during 1-month follow-up. The study aims to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in IS). DISCUSSION The REFLO-STEMI study has been designed to address the weaknesses of previous trials, which have collectively failed to demonstrate whether adjunctive pharmacotherapy with adenosine and/or SNP can reduce measures of myocardial injury (infarct size and MVO) and improve clinical outcome, despite good basic evidence that they have the potential to attenuate this process. The REFLO-STEMI study will be the most scientifically robust trial to date evaluating whether adjunctive therapy (intracoronary adenosine or SNP following thrombus aspiration) reduces CMRI measured IS and MVO in patients undergoing P-PCI within 6 h of onset of STEMI. TRIAL REGISTRATION Trial registered 20th November 2012: ClinicalTrials.gov Identifier NCT01747174.
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Oral clopidogrel improves cutaneous microvascular function through EDHF-dependent mechanisms in middle-aged humans.
Dahmus, JD, Bruning, RS, Kenney, WL, Alexander, LM
American journal of physiology. Regulatory, integrative and comparative physiology. 2013;(4):R452-8
Abstract
Platelet P₂Y₁₂-ADP and COX-1 receptor inhibition with oral clopidogrel (CLO) and low-dose aspirin (ASA), respectively, attenuates reflex-mediated cutaneous vasodilation, but little is known about how these medications affect local vasodilatory signaling. Reactive hyperemia (RH) results in vasodilation that is mediated by sensory nerves and endothelium-derived hyperpolarization factors (EDHF) through large-conductance calcium-activated potassium channels, whereas slow local heating (LH) elicits vasodilation largely through the production of nitric oxide (NO). We hypothesized that CLO and ASA would attenuate locally mediated cutaneous vasodilation assessed by RH and LH (0.5°C/min). In a randomized, cross-over, double-blind placebo-controlled study, nine healthy men and women (56 ± 1 yr) took CLO (75 mg), ASA (81 mg), and placebo for 7 days. Skin blood flow was measured (laser-Doppler flowmetry, LDF) and cutaneous vascular conductance (CVC) was calculated (LDF/mean arterial pressure) and normalized to maximal CVC (%CVCmax: 43°C and 28 mM sodium nitroprusside). RH response parameters, including area under the curve (AUC), total hyperemic response (THR), and the decay constant tau (λ) were calculated. NO-dependent vasodilation during LH was assessed by calculating the difference in %CVCmax between a control site and an NO synthase-inhibited site (10 mM l-NAME: intradermal microdialysis). CLO augmented the AUC and THR (AUCclo = 3,783 ± 342; THRclo = 2,306 ± 266% CVCmax/s) of the RH response compared with ASA (AUCASA = 3,101 ± 325; THRASA = 1,695 ± 197% CVCmax/s) and placebo (AUCPlacebo = 3,000 ± 283; THRPlacebo = 1,675 ± 170% CVCmax/s; all P < 0.0001 vs. CLO). There was no difference in the LH response or calculated NO-dependent vasodilation among treatments (all P > 0.05). Oral CLO treatment augments vasodilation during RH but not LH, suggesting that CLO may improve cutaneous microvascular function.
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The effect of acute administration of statins on coronary microcirculation during the pre-revascularization period in patients with myocardial infraction.
Paraskevaidis, IA, Iliodromitis, EK, Ikonomidis, I, Rallidis, L, Hamodraka, E, Parissis, J, Andoniadis, A, Tzortzis, S, Anastasiou-Nana, M
Atherosclerosis. 2012;(1):184-9
Abstract
UNLABELLED The beneficial effects of statin pretreatment as well as of staccato reperfusion (SR) on myocardium have been demonstrated in patients undergoing cardiac interventions. In this study, we compared the effects of the acute statin administration prior to percutaneous coronary intervention (PCI) with the effects of staccato or abrupt reperfusion on coronary microcirculation in patients with myocardial infarction (MI). METHODS We randomly assigned 47 patients who had ST-elevation or non-ST-elevation MI 48 h prior to PCI, into three groups: staccato reperfusion (consisting of 6 periods of 10-s balloon inflation/deflation) plus statin therapy (SRSG), statin therapy plus abrupt reperfusion (SG), and abrupt reperfusion alone (ARG). Myocardial contrast echocardiography (MCE) was performed to assess the blood volume (A), velocity (β) and flow (A × β) of the segments associated with the PCI-treated artery the day following intervention and 30 days after. LV end-diastolic (EDV) and systolic volumes (ESVs), wall motion score index (WMSI) were evaluated. RESULTS Compared to ARG, SRSG and SG resulted in a greater improvement in A, β and A × β (F = 20.6, p < 0.001 for A, F = 3.5, p = 0.03 for β and F = 11.3, p < 0.001 for A × β for the overall effect of intervention) as well as a greater decrease of WMSI, EDV and ESV (p < 0.01) one month post-PCI. The changes of all echocardiography markers were greater in SRSG than SG (p < 0.01). The % changes in ESV correlated with the corresponding % changes in MCE indices in SRSG and SG (p < 0.05). CONCLUSION The acute statin administration prior to reperfusion either alone or in synergy with staccato reperfusion ameliorates coronary microcirculatory dysfunction in patients with myocardial infarction.