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Microvascular Function (microvascular + function)
Kinds of Microvascular Function Selected AbstractsImpairment of Coronary Microvascular Function in Patients with Neurally Mediated SyncopePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 2p1 2003JAW-WEN CHEN CHEN, J.-W., et al.: Impairment of Coronary Microvascular Function in Patients with Neurally Mediated Syncope.Recent evidence suggests that myocardial ischemia may occur in patients with neurally mediated syncope and normal coronary angiograms. This study was conducted to evaluate if coronary microvascular function is impaired in such patients. Coronary hemodynamic studies and head-up tilt table tests (HUTs) were performed on 30 consecutive patients with normal coronary angiograms and recurrent syncope. Another ten subjects with atypical chest pain and no evidence of myocardial ischemia or syncope served as a control. Great cardiac vein flow (GCVF) and coronary sinus flow (CSF) were measured by the thermodilution method at baseline and after dipyridamole infusion (0.56 mg/kg IV for 4 minutes). Coronary flow reserve (CFR), derived from CSF and GCVF, was significantly lower in the 15 patients with positive HUT than in the other 15 patients with negative HUT (1.75 ± 0.48vs2.64 ± 0.8, P < 0.01and2.29 ± 0.45vs3.07 ± 0.63, P < 0.01, respectively). Ischemic-like ECG was noted during treadmill exercise test in 40% of the former and in 7% of the latter group(P = 0.01). There was no significant difference in CFR between patients with negative HUT and control subjects. Coronary microvascular function was impaired in syncopal patients with positive HUT and relatively preserved in those with negative HUT, suggesting the possible linkage between coronary microvascular dysfunction and the development of neurally mediated syncope. (PACE 2003; 26[Pt. I]:605,612) [source] Diet-induced obesity in Sprague,Dawley rats causes microvascular and neural dysfunctionDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2010Eric P. Davidson Abstract Background The objective of this study was to determine the effect of diet-induced obesity (DIO) on microvascular and neural function. Methods Rats were fed a standard or high fat diet for up to 32 weeks. The following measurements were carried out: vasodilation in epineurial arterioles using videomicroscopy, endoneurial blood flow using hydrogen clearance, nerve conduction velocity using electrical stimulation, size,frequency distribution of myelinated fibres of the sciatic nerve, intraepidermal nerve fibre density using confocal microscopy and thermal nociception using the Hargreaves method. Results Rats fed a high fat diet for 32 weeks developed sensory neuropathy, as indicated by slowing of sensory nerve conduction velocity and thermal hypoalgesia. Motor nerve conduction velocity and endoneurial blood flow were not impaired. Mean axonal diameter of myelinated fibres of the sciatic nerve was unchanged in high fat-fed rats compared with that in control. Intraepidermal nerve fibre density was significantly reduced in high fat-fed rats. Vascular relaxation to acetylcholine and calcitonin gene-related peptide was decreased and expression of neutral endopeptidase (NEP) increased in epineurial arterioles of rats fed a high fat diet. In contrast, insulin-mediated vascular relaxation was increased in epineurial arterioles. NEP activity was significantly increased in the skin of the hindpaw. Markers of oxidative stress were increased in the aorta and serum of high fat-fed rats but not in epineurial arterioles. Conclusion Chronic obesity causes microvascular and neural dysfunction. This is associated with increased expression of NEP but not oxidative stress in epineurial arterioles. NEP degrades vasoactive peptides, which may explain the decrease in microvascular function. Copyright © 2010 John Wiley & Sons, Ltd. [source] Does aerobic fitness influence microvascular function in healthy adults at risk of developing Type 2 diabetes?DIABETIC MEDICINE, Issue 4 2005A. R. Middlebrooke Abstract Aim To investigate whether aerobic fitness is associated with skin microvascular function in healthy adults with an increased risk of developing Type 2 diabetes. Methods Twenty-seven healthy normal glucose-tolerant humans with either a previous diagnosis of gestational diabetes or having two parents with Type 2 diabetes and 27 healthy adults who had no history of diabetes were recruited. Maximal oxygen uptake was assessed using an incremental exercise test to exhaustion. Skin microvascular function was assessed using laser Doppler techniques as the maximum skin hyperaemic response to a thermal stimulus (maximum hyperaemia) and the forearm skin blood flow response to the iontophoretic application of acetylcholine (ACh) and sodium nitroprusside. Results Maximal oxygen uptake was not significantly different in the ,at-risk' group compared with healthy controls. Maximum hyperaemia was reduced in those ,at risk' (1.29 ± 0.30 vs. 1.46 ± 0.33 V, P = 0.047); however, the peak response to acetylcholine or sodium nitroprusside did not differ in the two groups. A significant positive correlation was demonstrated between maximal oxygen uptake and maximum hyperaemia (r = 0.52, P = 0.006 l/min and r = 0.60, P = 0.001 ml/kg/min) and peak ACh response (r = 0.40, P = 0.04 l/min and r = 0.47, P = 0.013 ml/kg/min) in the ,at-risk' group when expressed in absolute (l/min) or body mass-related (ml/kg/min) terms. No significant correlations were found in the control group. Conclusions In this ,at-risk' group with skin microvascular dysfunction maximal oxygen uptake was not reduced compared with healthy controls. However, in the ,at-risk' group alone, individuals with higher levels of aerobic fitness also had better microvascular and endothelial responsiveness. [source] Free fatty acids exert a greater effect on ocular and skin blood flow than triglycerides in healthy subjectsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2004M. Bayerle-Eder Abstract Background, Free fatty acids (FFAs) and triglycerides (TGs) can cause vascular dysfunction and arteriosclerosis. Acute elevation of plasma FFA and TG concentration strongly increase ocular and skin blood flow. This study was designed to discriminate whether FFA or TG independently induce hyperperfusion by measuring regional and systemic haemodynamics. Methods, In a balanced, randomized, placebo-controlled, double-blind, three-way, crossover study nine healthy subjects received either Intralipid® (Pharmacia and Upjohn, Vienna, Austria) with heparin, Intralipid® alone or placebo control. Pulsatile choroidal blood flow was measured with laser interferometry, retinal blood flow and retinal red blood cell velocity with laser Doppler velocimetry, and skin blood flow with laser Doppler flowmetry during an euglycaemic insulin clamp. Results, A sevenfold increase of FFA during Intralipid®/heparin infusion was paralleled by enhanced choriodal, retinal, and skin blood flow by 17 ± 4%, 26 ± 5% (P < 0·001), and 47 ± 19% (P = 0·03) from baseline, respectively. In contrast, a mere threefold increase of FFA by infusion of Intralipid® alone did not affect outcome parameters, despite the presence of plasma TG levels of 250,700 mg dL,1; similar to those obtained during combined Intralipid®/heparin infusion. Systemic haemodynamics were not affected by drug infusion. Conclusions, Present findings demonstrate a concentration-dependent increase in ocular and skin blood flow by FFA independently of elevated TG plasma concentrations. As vasodilation of resistance vessels occur rapidly, FFA may play a role in the development of continued regional hyperperfusion and deteriorate microvascular function. [source] Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skinEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2003R. G. IJzerman Abstract Background To investigate whether microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function, we investigated skin microvascular function in individuals with increased coronary heart disease (CHD) risk. Materials and methods Forty-six healthy White individuals aged 30,70 years were studied. Coronary heart disease risk was assessed with the use of the CHD risk score according to the Framingham Heart Study, which is based on the risk factors age, blood pressure, cigarette smoking, total cholesterol, HDL cholesterol and diabetes. Endothelium-dependent and -independent vasodilation in skin were evaluated with laser Doppler after iontophoresis of acetylcholine and sodium nitroprusside. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion. Results Coronary heart disease risk score (i.e. the 10-year probability of CHD) varied from 1,37%. Microvascular function decreased with increasing quartiles of CHD risk (for acetylcholine-mediated vasodilation: 687, 585, 420 and 326%, P = 0·002; for nitroprusside-mediated vasodilation: 776, 582, 513 and 366%, P = 0·02; for capillary recruitment: 49·9, 44·6, 27·2 and 26·7%, P = 0·001). These trends were similar in men and women (P for interaction > 0·2) and independent of body mass index. Conclusions Increased CHD risk is associated with an impaired endothelium-dependent vasodilatation and capillary recruitment in skin, suggesting that microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function. [source] Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signalingJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010Claudia Kusmic Abstract Previous studies related impaired myocardial microcirculation in diabetes to oxidative stress and endothelial dysfunction. Thus, this study was aimed to determine the effect of up-regulating pAMPK-pAKT signaling on coronary microvascular reactivity in the isolated heart of diabetic mice. We measured coronary resistance in wild-type and streptozotocin (STZ)-treated mice, during perfusion pressure changes. Glucose, insulin, and adiponectin levels in plasma and superoxide formation, NOx levels and heme oxygenase (HO) activity in myocardial tissue were determined. In addition, the expression of HO-1, 3-nitrotyrosine, pLKB1, pAMPK, pAKT, and peNOS proteins in control and diabetic hearts were measured. Coronary response to changes in perfusion pressure diverged from control in a time-dependent manner following STZ administration. The responses observed at 28 weeks of diabetes (the maximum time examined) were mimicked by L-NAME administration to control animals and were associated with a decrease in serum adiponectin and myocardial pLKB1, pAMPK, pAKT, and pGSK-3 expression. Cobalt protoporphyrin treatment to induce HO-1 expression reversed the microvascular reactivity seen in diabetes towards that of controls. Up-regulation of HO-1 was associated with an increase in adiponectin, pLKB1, pAKT, pAMPK, pGSK-3, and peNOS levels and a decrease in myocardial superoxide and 3-nitrotyrosine levels. In the present study we describe the time course of microvascular functional changes during the development of diabetes and the existence of a unique relationship between the levels of serum adiponectin, pLKB1, pAKT, and pAMPK activation in diabetic hearts. The restoration of microvascular function suggests a new therapeutic approach to even advanced cardiac microvascular derangement in diabetes. J. Cell. Biochem. 109: 1033,1044, 2010. © 2010 Wiley-Liss, Inc. [source] Molecular Diversity of VEGF-A as a Regulator of Its Biological ActivityMICROCIRCULATION, Issue 7 2009Jeanette Woolard ABSTRACT The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF-A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5,7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice-site selection in exon 8 generates proangiogenic, termed VEGFxxx, or antiangiogenic proteins, termed VEGFxxxb. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF-A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF-A as a regulator of its biological activity and compare the role of the pro- and antiangiogenic VEGF-A splice isoforms in both normal and pathophysiological processes. [source] Influence of Glucose Control and Improvement of Insulin Resistance on Microvascular Blood Flow and Endothelial Function in Patients with Diabetes Mellitus Type 2MICROCIRCULATION, Issue 7 2005THOMAS FORST ABSTRACT Objective: The study was performed to investigate the effect of improving metabolic control with pioglitazone in comparison to glimepiride on microvascular function in patients with diabetes mellitus type 2. Methods: A total of 179 patients were recruited and randomly assigned to one treatment group. Metabolic control (HbA1c), insulin resistance (HOMA index), and microvascular function (laser Doppler fluxmetry) were observed at baseline and after 3 and 6 months. Results: HbA1c improved in both treatment arms (pioglitazone: 7.52 ± 0.85% to 6.71 ± 0.89%, p < .0001; glimepiride: 7.44 ± 0.89% to 6.83 ± 0.85%, p < .0001). Insulin-resistance decreased significantly in the pioglitazone group (6.15 ± 4.05 to 3.85 ± 1.92, p < .0001) and remained unchanged in the glimepiride group. The microvascular response to heat significantly improved in both treatment groups (pioglitazone 48.5 [15.2; 91.8] to 88.8 [57.6; 124.1] arbitrary units [AU], p < .0001; glimepiride 53.7 [14.1; 91.9] to 87.9 [52.9, 131.0] AU, p < .0001, median [lower and upper quartile]). Endothelial function as measured with the acetylcholine response improved in the pioglitazone group (38.5 [22.2; 68.0] to 60.2 [36.9; 82.8], p = .0427) and remained unchanged in the glimepiride group. Conclusions: Improving metabolic control has beneficial effects in microvascular function in type 2 diabetic patients. Treatment of type 2 diabetic patients with pioglitazone exerts additional effects on endothelial function beyond metabolic control. [source] Intravital intestinal videomicroscopy: Techniques and experiencesMICROSURGERY, Issue 4 2005Paul J. Matheson Ph.D. Intravital videomicroscopy (IVM) of the gastrointestinal (GI) tract is a sophisticated and powerful technique to directly observe the neurologically intact microvasculature of rats in naive and pathological conditions. We combine IVM with other techniques (i.e., vascular ring tension analysis and colorimetric microsphere determination of whole organ blood flow) to develop a strategy for the systematic analysis of the regulation of GI blood flow in healthy animals and in models of systemic sepsis and resuscitated hemorrhagic shock. We also study the molecular biology of the GI tract (enzyme- or radio-linked immunosorbent assays, fluorescent Greiss assay, and immunoblots) to correlate expression and levels of vascular mediators in tissue and arterial, venous, and portal blood with functional activity of the GI microvascular tree. When combined, these techniques develop a picture of gut pathophysiology at the level of the endothelium, vascular smooth muscle cells, and blood cells in the microcirculation. Our work led us to the general hypothesis that altered microcirculatory function in disease states lies primarily at the level of the interface between vascular and tissue physiology, i.e., the endothelial cell. This review focuses on methods and techniques for studying microvascular function, and concludes with focused reviews of pertinent findings. © 2005 Wiley-Liss, Inc. Microsurgery 25:247,257, 2005. [source] Effect of HTK on the microcirculation in the rat cremaster muscle during warm ischemia and reperfusionMICROSURGERY, Issue 2 2005Jacqueline Bastiaanse M.D. Histidine-tryptophan-ketoglutarate (HTK) preserves rat muscle function during cold storage. We examined the effect of HTK perfusion on preservation of microvascular function during 4 h of warm ischemia and subsequent reperfusion (I/R) in the rat cremaster muscle. Leukocyte-endothelium interactions, capillary perfusion, and arteriole diameters were quantified prior to HTK-perfusion and/or ischemia, and at 0, 1, and 2 h after restoration of blood flow. In all groups, the number of rolling leukocytes increased with time, whereas I/R induced a slight increase in leukocyte adhesion. After ischemia, capillary perfusion rapidly recovered to about 50% and returned to near normal (90%) after 2 h. HTK at 22°C did not affect the assessed microcirculation variables, whereas HTK at 4°C reduced leukocyte rolling, but not adhesion. Therefore, microvascular function of HTK-perfused muscles was not better preserved during warm I/R than that of nonperfused muscles. Contrary to other preservation solutions, HTK perfusion in itself was not detrimental to the microcirculation. © 2005 Wiley-Liss, Inc. Microsurgery 25:174,180, 2005. [source] Impairment of Coronary Microvascular Function in Patients with Neurally Mediated SyncopePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 2p1 2003JAW-WEN CHEN CHEN, J.-W., et al.: Impairment of Coronary Microvascular Function in Patients with Neurally Mediated Syncope.Recent evidence suggests that myocardial ischemia may occur in patients with neurally mediated syncope and normal coronary angiograms. This study was conducted to evaluate if coronary microvascular function is impaired in such patients. Coronary hemodynamic studies and head-up tilt table tests (HUTs) were performed on 30 consecutive patients with normal coronary angiograms and recurrent syncope. Another ten subjects with atypical chest pain and no evidence of myocardial ischemia or syncope served as a control. Great cardiac vein flow (GCVF) and coronary sinus flow (CSF) were measured by the thermodilution method at baseline and after dipyridamole infusion (0.56 mg/kg IV for 4 minutes). Coronary flow reserve (CFR), derived from CSF and GCVF, was significantly lower in the 15 patients with positive HUT than in the other 15 patients with negative HUT (1.75 ± 0.48vs2.64 ± 0.8, P < 0.01and2.29 ± 0.45vs3.07 ± 0.63, P < 0.01, respectively). Ischemic-like ECG was noted during treadmill exercise test in 40% of the former and in 7% of the latter group(P = 0.01). There was no significant difference in CFR between patients with negative HUT and control subjects. Coronary microvascular function was impaired in syncopal patients with positive HUT and relatively preserved in those with negative HUT, suggesting the possible linkage between coronary microvascular dysfunction and the development of neurally mediated syncope. (PACE 2003; 26[Pt. I]:605,612) [source] Altered coronary vasomotor function in young patients with systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 6 2007Kumiko Hirata Objective Accelerated atherosclerosis is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Altered coronary microvascular function may act as a marker of changes that predispose to the development of significant coronary vascular disease. The purpose of this study was to compare coronary flow reserve (CFR) in a group of premenopausal women with SLE and a group of age-, sex-, and race-matched healthy control subjects. Methods Coronary flow velocity in 18 premenopausal women with SLE (mean ± SD age 29.4 ± 5.9 years) and 19 matched healthy controls (mean ± SD age 28.2 ± 4.3 years) was assessed by transthoracic Doppler echocardiography after an overnight fast. The CFR was calculated as the ratio of hyperemic to baseline coronary blood flow velocity in the left anterior descending coronary artery. Hyperemia was induced by intravenous administration of adenosine triphosphate. Results The mean ± SD duration of SLE was 8.2 ± 7.2 years (range 0.25,25 years), and the mean ± SD score on the Systemic Lupus Erythematosus Disease Activity Index was 11.0 ± 5.3 (range 4.0,21.0). Adequate recordings of flow velocity in the left anterior descending artery under both conditions were obtained using an ultrasound procedure in all study subjects. CFR was significantly lower in SLE patients as compared with control subjects (mean ± SD 3.4 ± 0.8 versus 4.5 ± 0.5; P < 0.0001). Conclusion These findings provide evidence that coronary vasomotor function is impaired in patients with SLE and support the notion that many of these young patients have subclinical coronary artery disease. [source] Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: Implications for vascular dysfunction and progression of diseaseARTHRITIS & RHEUMATISM, Issue 7 2003Sanjay Rajagopalan Objective To compare microvascular and macrovascular functions in a cohort of patients with primary and secondary Raynaud's phenomenon (RP) who were matched for demographic, risk factor, and severity profiles. Methods Forty patients with primary or secondary RP matched for vascular risk factors and severity scores underwent testing of endothelial function and cold pressor responsiveness of the brachial artery. Microvascular perfusion of the digital vasculature was assessed using laser Doppler fluxmetry in response to reactive hyperemia. Plasma was assayed for endothelin 1 (ET-1), asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1). Results Patients with RP had abnormal vasoconstrictor responses to cold pressor tests (CPT) that were similar in primary and secondary RP. There were no differences in median flow-mediated and nitroglycerin-mediated dilation or CPT of the brachial artery in the 2 populations. Patients with secondary RP were characterized by abnormalities in microvascular responses to reactive hyperemia, with a reduction in area under the curve adjusted for baseline perfusion, but not in time to peak response or peak perfusion ratio. Plasma ET-1, ADMA, VCAM-1, and MCP-1 levels were significantly elevated in secondary RP compared with primary RP. There was a significant negative correlation between ET-1 and ADMA values and measures of microvascular perfusion but not macrovascular endothelial function. Conclusion Secondary RP is characterized by elevations in plasma ET-1 and ADMA levels that may contribute to alterations in cutaneous microvascular function. [source] Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endotheliumBIOFACTORS, Issue 1 2009John X. Wilson Abstract Circulating levels of vitamin C (ascorbate) are low in patients with sepsis. Parenteral administration of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of sepsis, intravenous ascorbate injection increases survival and protects several microvascular functions, namely, capillary blood flow, microvascular permeability barrier, and arteriolar responsiveness to vasoconstrictors and vasodilators. The effects of parenteral ascorbate on microvascular function are both rapid and persistent. Ascorbate quickly accumulates in microvascular endothelial cells, scavenges reactive oxygen species, and acts through tetrahydrobiopterin to stimulate nitric oxide production by endothelial nitric oxide synthase. A major reason for the long duration of the improvement in microvascular function is that cells retain high levels of ascorbate, which alter redox-sensitive signaling pathways to diminish septic induction of NADPH oxidase and inducible nitric oxide synthase. These observations are consistent with the hypothesis that microvascular function in sepsis may be improved by parenteral administration of ascorbate as an adjuvant therapy. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] The Pancreas as a Source of Cardiovascular Cell Activating FactorsMICROCIRCULATION, Issue 3 2000ERIK B. KISTLER ABSTRACT Objective: Physiological shock leads to elevated levels of plasma factors that activate circulating leukocytes and endothelial cells, thereby compromising microvascular functions. The nature and source of these plasma-derived activators are unknown. To examine the possible origin of these factors, we homogenized rat internal organs and measured their activity on cardiovascular cells in vivo and in vitro. Methods: Fresh tissue samples from small intestine, spleen, heart, liver, kidney, adrenals, and pancreas were homogenized. Their ability to induce leukocyte pseudopod formation and nitroblue tetrazolium (NBT) reduction was tested and their impact in vivo on blood pressure, survival, and microvascular cell injury was examined. Results: A dramatic increase (p < 0.001) in leukocyte activation compared to controls was observed with pancreas homogenate but not with homogenates from the other organs. Leukocyte activation was induced by homogenates of other tissues only after prior incubation with substimulatory concentrations of pancreatic homogenate. Pancreatic serine proteases, trypsin and chymotrypsin, which did not stimulate leukocytes, also generated activity from other tissues. Leukocyte pseudopod formation could be significantly inhibited by adding the serine protease inhibitor 6-amidino-2-naphthyl p -guanidinobenzoate dimethanesulfonate (ANGD) during tissue homogenization (p < 0.001). Injection of pancreatic homogenate into rats led to increased plasma hydrogen peroxide levels and an instantaneous drop in mean arterial pressure that was often lethal. These responses were prevented by prior infusion of ANGD (p < 0.001). Intravital microscopy of the rat mesentery confirmed that superfusion of filtered pancreatic homogenate leads to significant increases in cell death (p < 0.05), as detected by propidium iodide, and hydrogen peroxide formation (p < 0.05), as determined by dichlorofluorescein diacetate (DCFH) fluorescence. Conclusion: These results suggest that pancreatic enzymes attack tissue and generate cellular activators that are associated with organ dysfunction in shock. [source] Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endotheliumBIOFACTORS, Issue 1 2009John X. Wilson Abstract Circulating levels of vitamin C (ascorbate) are low in patients with sepsis. Parenteral administration of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of sepsis, intravenous ascorbate injection increases survival and protects several microvascular functions, namely, capillary blood flow, microvascular permeability barrier, and arteriolar responsiveness to vasoconstrictors and vasodilators. The effects of parenteral ascorbate on microvascular function are both rapid and persistent. Ascorbate quickly accumulates in microvascular endothelial cells, scavenges reactive oxygen species, and acts through tetrahydrobiopterin to stimulate nitric oxide production by endothelial nitric oxide synthase. A major reason for the long duration of the improvement in microvascular function is that cells retain high levels of ascorbate, which alter redox-sensitive signaling pathways to diminish septic induction of NADPH oxidase and inducible nitric oxide synthase. These observations are consistent with the hypothesis that microvascular function in sepsis may be improved by parenteral administration of ascorbate as an adjuvant therapy. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] | |||||||||||||||||||||||||