(Circulation. 2001;103:1618.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Ascorbate Restores Endothelium-Dependent Vasodilation Impaired by Acute Hyperglycemia in Humans
From the Cardiovascular Division (J.A.B., M.B.G., M.A.C.), Brigham and Women’s Hospital, and the Division of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School (A.B.G.), Boston, Mass.
Correspondence to Mark A. Creager, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mcreager{at}rics.bwh.harvard.edu
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Abstract |
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Background—Endothelium-dependent vasodilation is impaired in patients with insulin-dependent and non–insulin-dependent diabetes mellitus and restored by vitamin C administration, implicating a causative role for oxidant stress. Hyperglycemia per se attenuates endothelium-dependent vasodilation in healthy subjects. Accordingly, this study investigated whether impaired endothelium-dependent vasodilation caused by hyperglycemia in nondiabetic humans is restored by administration of the antioxidant vitamin C.
Methods and Results—Endothelium-dependent vasodilation was measured by incremental brachial artery administration of methacholine chloride (0.3 to 10 µg/min) during euglycemia, after 6 hours of hyperglycemia (300 mg/dL) created by dextrose (50%) intra-arterial infusion, and with coadministration of vitamin C (24 mg/min) during hyperglycemia. Endothelium-dependent vasodilation was significantly diminished by hyperglycemia (P=0.02 by ANOVA) and restored by vitamin C (P=0.04). In contrast, endothelium-dependent vasodilation was not affected by equimolar infusions of mannitol, with and without vitamin C coinfusion (P=NS). Endothelium-independent vasodilation was measured by incremental infusion of verapamil chloride (10 to 300 µg/min) without and with coadministration of NG-monomethyl-L-arginine (L-NMMA). In the absence of L-NMMA, endothelium-independent vasodilation was not significantly altered during hyperglycemia (P=NS) but was augmented by vitamin C (P=0.04). The coadministration of L-NMMA eliminated the vitamin C–related augmentation in verapamil-mediated vasodilation.
Conclusions—Vitamin C administration restores endothelium-dependent vasodilation impaired by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia may contribute in part to impaired vascular function through production of superoxide anion.
Key Words: nitric oxide • diabetes mellitus • antioxidants • glucose
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Introduction |
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Atherosclerosis is the leading cause of morbidity and mortality in patients with diabetes mellitus. One putative cause of atherosclerosis in diabetes mellitus is impaired endothelial function stemming from reduced bioavailability of nitric oxide. Endothelium-derived nitric oxide regulates vasomotor tone and performs many important vasoprotective functions such as inhibiting platelet aggregation and preventing adhesion of inflammatory cells (leukocytes) to the endothelial surface.1 Endothelium-dependent vasodilation is impaired in animal models and humans with type 1 and type 2 diabetes mellitus.2 3 4 Administration of vitamin C, an antioxidant, improves endothelium-dependent vasodilation in patients with either type of diabetes mellitus,3 4 thus implicating inactivation of nitric oxide by oxygen-derived free radicals as a mechanism of endothelial dysfunction in both forms of diabetes.5 6
Hyperglycemia may be a fundamental abnormality underlying the mechanism that causes endothelial dysfunction in diabetes. Indeed, endothelium-dependent relaxation of aortic rings from healthy rabbits are impaired when incubated in a hyperglycemic milieu.7 Our laboratory and others have demonstrated that endothelium-dependent vasodilation is impaired in healthy subjects after 6 hours of a hyperglycemic clamp.8 9 Moreover, increases in blood glucose further depress endothelium-dependent vasodilation in subjects with type 2 diabetes mellitus.10 Taken together, these findings raise the possibility that endothelial dysfunction in diabetes may occur as a result of oxidant stress induced by hyperglycemia. Hyperglycemia may promote superoxide production as a consequence of glucose auto-oxidation, the formation of advanced glycation end products, abnormal arachidonic acid metabolism and its coupling to cyclo-oxygenase catalysis, by activating protein kinase C, by depleting tetrahydrobiopterin, and by increasing the activity of nitric oxide synthase.11 12 13 14 15 16 17
Therefore, the purpose of this study was to test the hypothesis that hyperglycemia per se impairs endothelium-dependent vasodilation in humans by inducing the formation of superoxide anion and reducing the bioavailability of endothelium-derived nitric oxide. To test this hypothesis, we sought to determine whether administration of the antioxidant vitamin C would improve the impaired endothelium-dependent vasodilation caused by experimental hyperglycemia in vivo in healthy, nondiabetic humans.
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Methods |
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The protocol was approved by the Human Research Committee of Brigham and Women’s Hospital. Twenty-eight healthy volunteers were recruited by newspaper advertisement and provided written informed consent. All subjects underwent screening history, physical examination, and laboratory analysis, including complete blood count, serum electrolytes, fasting glucose, blood urea nitrogen, creatinine, transaminases, alkaline phosphatase, and a lipid profile. Subjects with hypertension, history of tobacco use, LDL cholesterol or total cholesterol greater than the 75th percentile for age and sex, cardiovascular disease, or other disease were excluded.
Subjects were studied in the morning in the postabsorptive state, fasting after the previous midnight. Cyclo-oxygenase inhibitors, alcohol, and caffeine were prohibited for 12 hours before study initiation. With the use of subcutaneous lidocaine anesthesia and sterile conditions, a 20-gauge Teflon catheter was inserted into the brachial artery of the nondominant forearm for drug infusion and blood pressure measurement. Intravenous cannulas were inserted into antecubital veins of each arm. The vascular research laboratory was quiet, dimly lit, and temperature controlled at 23°C. Subjects rested for a minimum of 30 minutes after insertion of the catheters before baseline hemodynamic data were acquired.
Forearm Hyperglycemic Clamp Method
A forearm hyperglycemic clamp was used to raise and
maintain forearm glucose concentration at 300 mg/dL (16.7 mmol/L) as
previously described.8 A 50%
dextrose solution was infused into the forearm through the brachial
artery catheter. Fifteen minutes after the infusion was started,
ipsilateral antecubital venous blood was obtained, the blood glucose
level was determined, and the infusion rate was adjusted. The infusion
rate was adjusted every 10 to 15 minutes for the duration of the study
to maintain the hyperglycemic clamp at 300 mg/dL. In addition, the
somatostatin analog octreotide was infused at 30 ng ·
kg-1 ·
min-1 to suppress pancreatic insulin
because insulin is a known
vasodilator18 19
whose vascular effects are mediated at least in part by
endothelium-derived nitric oxide. The octreotide infusion was initiated
30 minutes before the first hemodynamic measurement and maintained
throughout each protocol. No vasoactive effects have been identified in
studies that used the same doses of
octreotide.20 Systemic
glucose and insulin samples were obtained at baseline, 3 hours into the
clamp, and after 6 hours of hyperglycemic clamp from the contralateral
antecubital vein.
Hemodynamic Measurements
Bilateral forearm blood flow was measured by
venous-occlusion, mercury-in-silastic, strain-gauge plethysmography, by
established methods.21
During data acquisition, wrist cuffs were inflated to 200 mm Hg to
exclude the hand circulation. A venous occlusion pressure of 40 mm Hg
was generated by cuffs placed on each arm above the elbow for each
measurement of blood flow, which is reported as mL/100 mL of tissue per
minute. Arterial blood pressure was measured by the brachial artery
cannula. The cannula was attached to a pressure transducer contiguous
with an amplifier on a Gould physiological recorder. Heart rate was
determined by the R-R interval of a continuous ECG
monitor.
Laboratory Analyses
Whole-blood glucose concentration was measured at the
bedside by means of the glucose oxidase method, with a glucose
reflectometer. Reported values represent analyses performed
subsequently on plasma with a Glucose Analyzer II (Beckman Instruments
Inc). Insulin was measured with a radioimmunoassay. Osmolality was
determined by freezing point depression. All sample measurements were
performed in duplicate.
Experimental Protocols
The effects of 6 hours of hyperglycemia and the acute
administration of vitamin C on endothelium-dependent vasodilation were
investigated in 18 healthy subjects. First, during fasting euglycemia,
basal forearm blood flow and the blood flow response to 4-minute
intra-arterial infusions of incremental doses of methacholine chloride
(0.3, 1.0, 3.0, and 10.0 µg/min) were assessed to determine
vasodilation in response to endothelium-derived nitric oxide. Forearm
glucose concentration was then clamped at 300 mg/dL (16.7 mmol/L) by
intra-arterial infusion of 50% dextrose for 6 hours, as described
above. After 6 hours of hyperglycemic clamp, a time frame based on our
previous experience,8 basal
forearm blood flow, and the blood flow responses to methacholine were
measured. After discontinuation of methacholine and reestablishment of
basal flow, vitamin C was infused intra-arterially at a dose of 24
mg/min in conjunction with the hyperglycemic clamp. Ten minutes
thereafter, basal forearm blood flow and methacholine-induced increases
in forearm blood flow were measured again.
As a time and osmolality control, the protocol was repeated in 10 subjects in whom dextrose was replaced with an equimolar 25% mannitol infusion to maintain a hyperosmolar clamp. All of these subjects previously participated in a hyperglycemic clamp. The dextrose infusion rates in the first study were used as a guide for mannitol infusion rates. Venous samples from the study arm were obtained to record the osmolality attained. Methacholine dose-response curves were measured before and after 6 hours of the hyperosmolar clamp. The dose response to methacholine during the hyperosmolar clamp was then measured during coinfusion of vitamin C as described above. Mannitol has modest antioxidant properties as a hydroxyl radical scavenger but does not scavenge other oxidants including superoxide anion and lipid peroxides.22
To ascertain whether the vascular effects of hyperglycemia and vitamin C were limited to the endothelium, a subset of 9 subjects was studied on a separate occasion with the calcium channel blocker verapamil at doses of 10, 30, 100, and 300 µg/min. Forearm blood blow measurements were made under basal conditions and with verapamil infusions during euglycemia, after 6 hours of hyperglycemic clamp, and during hyperglycemic clamp along with vitamin C administration. Verapamil causes vasorelaxation by a direct action on vascular smooth muscle. However, the resultant increase in blood flow may induce release of nitric oxide from nitric oxide synthase.23 24 25 26 To eliminate the contribution of nitric oxide synthase from the vasodilator effect of verapamil, NG-monomethyl-L-arginine (L-NMMA) was coinfused at 2 mg/min with verapamil in 6 additional subjects during the hyperglycemic clamp. Forearm blood flow responses to verapamil were made in the subjects before and after vitamin C administration.
Statistical Analyses
Values are reported as mean±SEM. Basal forearm blood
flow, osmolality, glucose concentration, and insulin concentration were
compared by paired 2-tailed t
tests. Statistical analyses of the dose-response curves for each drug
(methacholine and verapamil) were conducted by the absolute increase in
blood flow from the resting flow rate. Two-way repeated-measures ANOVA
was performed to compare the dose-response curves during euglycemic
conditions and after 6 hours of hyperglycemic clamp and the
dose-response curves during the hyperglycemic clamp before and after
the coinfusion of vitamin C. Statistical significance was accepted at
the 95% confidence level
(P
0.05).
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Results |
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Baseline Characteristics
Twenty-eight healthy subjects, including 10 men and 18 women (age, 26.6±4 years), participated in the protocols. Mean blood pressure was 116/66±13/7 mm Hg, fasting glucose was 71±11 mg/dL, baseline insulin level was 1.1±0.5 mU/mL, and total cholesterol concentration was 166±30 mg/dL. Serum cholesterol, insulin, glucose, and mean arterial pressure were within normal limits in all subjects.
Effect of Hyperglycemia, Hyperosmolality, and
Vitamin C on Basal Forearm Blood Flow
Basal, that is, resting, forearm blood flow was
measured in all conditions
(Table 1
). Resting forearm blood flow in the
experimental forearm increased from 2.3±0.2 mL/100 mL per minute
during euglycemia to 3.3±0.4 mL/100 mL per minute during hyperglycemia
(P<0.01) and increased further
to 4.7±0.7 after vitamin C administration
(P<0.01). Resting forearm
blood flow increased also during the hyperosmolar clamp from 1.9±0.1
to 3.5±0.4 mL/100 mL per minute during
(P<0.01) and then to 4.7±0.4
mL/100 mL per minute (P<0.01)
with vitamin C administration
(Table 1). The pattern of increase to hyperglycemia and
subsequently with vitamin C was also observed in the verapamil
experiments.
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Effect of Hyperglycemia and Vitamin C on
Response to Methacholine
During euglycemia, the ipsilateral forearm venous
glucose concentration was 71±11 mg/dL. Forearm glucose averaged
379±100 mg/dL over the 6 hours of hyperglycemic clamp, whereas the
systemic (contralateral venous) concentration averaged 121±32 mg/dL.
Systemic insulin levels increased only slightly, from 1.06±0.5 to
2.82±1.1 µU/mL (P<0.01).
Incremental doses of methacholine increased forearm blood flow during
both euglycemia and hyperglycemia. However, compared with euglycemia,
the forearm blood flow response to intra-arterial methacholine was
reduced significantly after the 6-hour hyperglycemic clamp.
(Figure 1, P=0.02).
Thereafter, the administration of vitamin C significantly increased the
forearm blood flow response to methacholine compared with that during
hyperglycemia alone
(Figure 1, P=0.04),
achieving a response similar to that observed during euglycemia. Heart
rate, mean arterial pressure, and the contralateral forearm blood flow
were not significantly affected by methacholine infusion,
hyperglycemia, or vitamin C administration.
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Effect of Hyperosmolality and Vitamin C on
Response to Methacholine
Forearm osmolality was clamped at 300±8 mOsm/kg during
the 6-hour hyperosmolar clamp. Baseline and 6-hour glucose and
osmolality are reported in
Table 2. Incremental infusions of methacholine increased
forearm blood flow in a dose-dependent manner during normal and
hyperosmolar conditions. In contrast to the hyperglycemic clamp, the
forearm blood flow response to methacholine did not change
significantly after 6 hours of hyperosmolality
(Figure 2). Moreover, the administration of vitamin C during
the hyperosmolar clamp did not alter the blood flow response to
methacholine
(Figure 2). Neither serum glucose nor insulin levels were
affected by the mannitol infusion.
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Effect of Hyperglycemia and Vitamin C on
Response to Verapamil
The response to verapamil was assessed before and after
forearm glucose was clamped at 353±74 mg/dL over 6 hours. The infusion
of verapamil increased forearm blood flow in a dose-dependent manner
during euglycemia and hyperglycemia, and the dose response was not
significantly different between euglycemic and hyperglycemic
conditions. The infusion of vitamin C, however, did enhance the forearm
blood flow response to verapamil
(P=0.04)
(Figure 3a). Six subjects underwent the second verapamil
protocol, in which measurements were made during coinfusion of L-NMMA.
In these subjects, administration of vitamin C did not change the
forearm blood flow response to verapamil
(Figure 3b).
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Discussion |
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The important and novel finding of this study is that vitamin C improved the abnormality in endothelium-dependent vasodilation that was caused by experimental hyperglycemia in healthy, nondiabetic human subjects in vivo. This observation suggests that hyperglycemia, by increasing the production of oxygen-derived free radicals, decreases the bioavailability of nitric oxide. Oxygen-derived free radicals rapidly combine with nitric oxide, decrease its bioavailability, and thereby impair normal endothelial function.5 6
Impaired endothelium-dependent vasodilation and, by extension, decreased bioavailability of endothelium-derived nitric oxide, has been widely demonstrated in animal models of diabetes mellitus and in patients with both type 1 and type 2 diabetes.2 21 27 28 29 Augmented generation of oxygen-derived free radicals as a cause of this endothelial dysfunction has been implicated by studies in humans with type 1 and type 2 diabetes mellitus in whom infusions of the antioxidant vitamin C restores endothelium-dependent vasodilation toward normal.3 4 One feature common to the in vitro, animal, and human models of diabetes is hyperglycemia. Hyperglycemia per se has been shown to attenuate endothelium-dependent vasodilation in healthy, nondiabetic animal and human arteries.8 30 31
Hyperglycemia and Oxidant Stress
Elevations of F2-isoprostane, a
marker of oxidant stress, have been found in subjects with both types
of diabetes.32 Improved
glycemic control decreases the level of
F2-isoprostane, suggesting a causal relation
between blood glucose levels and oxidant
stress.32 There are several
mechanisms by which hyperglycemia may increase oxidant
stress,33 including
condensation of excess glucose with plasma proteins to form advanced
glycation end products and superoxide anion; glucose auto-oxidation;
abnormal arachidonic acid metabolism; activation of protein kinase C;
depletion of a cofactor for nitric oxide synthase, tetrahydrobiopterin;
and activation of the aldose reductase
pathway.11 12 13 14 15 16
Recent work has suggested that nitric oxide synthase may be an important source for superoxide in hyperglycemia.17 Cosentino and colleagues17 examined the effect of exposing endothelial cells in vitro to 22 mmol/L glucose. Production of nitric oxide and superoxide was compared between human endothelial cell cultures exposed to 5 mmol/L glucose and 22 mmol/L glucose. The group demonstrated that endothelial exposure to hyperglycemia caused nitric oxide synthase to modestly increase its production of nitric oxide by 40% and markedly increase its production of superoxide anion by 300%.
Our findings support an important role for superoxide anion as a cause of abnormal endothelium-dependent vasodilation caused by hyperglycemia. Indeed, the reduction in forearm blood flow response to hyperglycemia was reversed when vitamin C was infused during the hyperglycemic clamp. These findings cannot be attributed to the hyperosmolar effects of hyperglycemia because the forearm dose response to methacholine was not affected by hyperosmolality alone or with concurrent vitamin C.
Hyperglycemia did not change the forearm blood flow response to verapamil, confirming previous observations8 ; however, the blood flow response to verapamil was increased during hyperglycemia when vitamin C was administered. L-NMMA eliminated the increase in flow seen during coinfusion of vitamin C with verapamil. There are two potential explanations for these observations. First, the verapamil infusion caused release of nitric oxide as a consequence of the increase in flow and resultant greater bioavailability of nitric oxide. L-NMMA eliminated this potential endothelium-dependent component of verapamil-mediated vasodilation; therefore, the scavenging of superoxide anion by vitamin C did not augment flow.
Alternatively, hyperglycemia may act independent of flow to alter the function of nitric oxide synthase, augmenting production of both superoxide anion and nitric oxide but preferentially producing a greater proportion of superoxide anion.17 Hyperglycemia has been demonstrated to affect the activity of nitric oxide synthase by depleting its cofactor, tetrahydrobiopterin, and by activating protein kinase C.12 14 16 34 If this were the case, vitamin C would reveal increased ambient nitric oxide by scavenging the increased superoxide and augment vasodilation, as was observed in this study when vitamin C was coinfused with verapamil. Indeed, this reasoning is supported by our experiments with L-NMMA, which inhibits the production of nitric oxide by endothelial nitric oxide synthase.35 36 Thus, L-NMMA, by inhibiting the hyperglycemia-mediated increased production of nitric oxide by nitric oxide synthase, abrogated the improvement in blood flow that occurred when vitamin C was coinfused with verapamil.
Effect of Hyperglycemia on Basal Forearm
Blood Flow
Even though hyperglycemia decreased
endothelium-dependent vasorelaxation, basal forearm blood flow
increased after the 6-hour hyperglycemic clamp. It is likely that the
increase in basal flow was largely an effect of osmolality because
basal forearm flow also increased during the hyperosmolar clamp. The
increase in basal forearm blood flow that accompanied the vitamin C
infusion occurred in both settings, hyperglycemia and hyperosmolality,
suggesting that this was either a time-dependent phenomenon or a
consequence of decreased inactivation of ambient nitric
oxide.
Antioxidant Properties of Vitamin C
In these experiments, vitamin C, a water-soluble
antioxidant, was used to test the primary hypothesis that hyperglycemia
impairs endothelium-dependent vasodilation in humans through production
of superoxide anion and consequent inactivation of nitric oxide.
Vitamin C may act extracellularly as a superoxide anion scavenger and
intracellularly by affecting the redox state. The infusion of 24 mg/min
of vitamin C for 10 minutes yields a local forearm concentration of 1
to 10 mmol/L. Jackson et
al37 demonstrated in vitro
that this concentration of vitamin C competes effectively with
endogenous antioxidants for superoxide anion. Reduced vitamin C also
may increase nitric oxide by increasing the activity of nitric oxide
synthase directly; however, Heller et
al38 demonstrated in vitro
that intracellular ascorbic acid transport was time dependent and did
not affect nitric oxide synthase activity at 1 hour. Thus, it is likely
that the short-duration, high-dose infusion of vitamin C used in this
study acted by scavenging extracellular oxygen-derived free
radicals.
Both reduced and oxidized vitamin C inhibit intracellular transport of glucose through the GLUT 1 transporter39 and conceivably might prevent glucose from impairing endothelium-dependent vasodilation by this mechanism. However, the hyperglycemic clamp had been maintained for 6 hours before vitamin C administration, and there is evidence that the effects of prolonged hyperglycemia remain hours after restitution of normal extracellular glucose concentration.40
Conclusions
The results of this investigation indicate that in
healthy humans, vitamin C reverses the impairment of
endothelium-dependent vasodilation caused by acute hyperglycemia. This
observation is consistent with the postulate that vitamin C increases
the bioavailability of nitric oxide by scavenging excess oxygen-derived
free radicals produced by hyperglycemia. We speculate that an important
mechanism whereby hyperglycemia induces oxidant stress is through the
stimulation of nitric oxide synthase, preferentially increasing the
synthesis of superoxide anion over nitric oxide. Taken together, the
findings of this study support a fundamental role of hyperglycemia per
se in mediating endothelial dysfunction in patients with diabetes
mellitus.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (HL-56607, HL-48743). Dr Beckman is the recipient of an American College of Cardiology/Merck Award.
Received November 9, 2000; revision received December 8, 2000; accepted December 14, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Vane JR, Nygard EE, Botting RM. Regulatory function in the vascular endothelium. N Engl J Med. 1990;323:27–36.[Medline] [Order article via Infotrieve]
2.
Pieper GM, Gross
GJ. Oxygen free radicals abolish endothelium-dependent relaxation in
diabetic rat aorta. Am J
Physiol. 1988;255:H825-H833.
3.
Timimi FK, Ting HH,
Haley EA, et al. Vitamin C improves endothelium-dependent vasodilation
in patients with insulin-dependent diabetes mellitus.
J Am Coll Cardiol. 1998;31:552–557.
4. Ting HH, Timimi FK, Boles KS, et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1996;97:22–28.[Medline] [Order article via Infotrieve]
5. Rubanyi GM, Vanhoutte PM. Oxygen-derived free radicals, endothelium, and responsiveness of vascular smooth muscle. Am J Physiol. 1986;250:H815-H821.
6.
Beckman JS, Beckman
TW, Chen J, et al. Apparent hydroxyl radical production by
peroxynitrite: implications for endothelial injury from nitric oxide
and superoxide. Proc Natl Acad Sci
U S A. 1990;87:1620–1624.
7. Tesfamariam B, Brown ML, Deykin D, et al. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest. 1990;85:929–932.
8.
Williams SB,
Goldfine AB, Timimi FK, et al. Acute hyperglycemia attenuates
endothelium-dependent vasodilation in humans in vivo.
Circulation. 1998;97:1695–1701.
9. Akbari CM, Saouaf R, Barnhill DF, et al. Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia. J Vasc Surg. 1998;28:687–694.[Medline] [Order article via Infotrieve]
10.
Kawano H,
Motoyama T, Hirashima O, et al. Hyperglycemia rapidly suppresses
flow-mediated endothelium-dependent vasodilation of brachial artery.
J Am Coll Cardiol. 1999;34:146–154.
11. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med. 1994;16:383–392.[Medline] [Order article via Infotrieve]
12.
Ohara Y, Sayegh
HS, Yamin JJ, et al. Regulation of endothelial constitutive nitric
oxide synthase by protein kinase C.
Hypertension. 1995;25:415–420.
13. Nishio E, Watanabe Y. Glucose-induced down-regulation of NO production and inducible NOS expression in cultured rat aortic vascular smooth muscle cells: role of protein kinase C. Biochem Biophys Res Commun. 1996;229:857–863.[Medline] [Order article via Infotrieve]
14. Pieper GM. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol. 1997;29:8–15.[Medline] [Order article via Infotrieve]
15. Shimizu S, Ishii M, Momose K, et al. Role of tetrahydrobiopterin in the function of nitric oxide synthase, and its cytoprotective effect (review). Int J Mol Med. 1998;2:533–540.[Medline] [Order article via Infotrieve]
16. Shinozaki K, Kashiwagi A, Nishio Y, et al. Abnormal biopterin metabolism is a major cause of impaired endothelium- dependent relaxation through nitric oxide/O2 imbalance in insulin- resistant rat aorta. Diabetes. 1999;48:2437–2445.[Abstract]
17.
Cosentino F,
Hishikawa K, Katusic ZS, et al. High glucose increases nitric oxide
synthase expression and superoxide anion generation in human aortic
endothelial cells. Circulation. 1997;96:25–28.
18. Scherrer U, Randin D, Vollenweider P, et al. Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest. 1994;94:2511–2515.
19. Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994;94:1172–1179.
20. Moller N, Bagger JP, Schmitz O, et al. Somatostatin enhances insulin-stimulated glucose uptake in the perfused human forearm. J Clin Endocrinol Metab. 1995;80:1789–1793.[Abstract]
21. Williams SB, Cusco JA, Roddy M-A, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996;27:567–574.[Abstract]
22. Bagchi D, Garg A, Krohn RL, et al. Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol. 1997;95:179–189.[Medline] [Order article via Infotrieve]
23.
Liao JC, Kuo L.
Interaction between adenosine and flow-induced dilation in coronary
microvascular network. Am J
Physiol. 1997;272:H1571–H1581.
24.
Koller A, Kaley
G. Endothelial regulation of wall shear stress and blood flow in
skeletal muscle microcirculation. Am
J Physiol. 1991;260:H862–H868.
25.
Ohno M, Gibbons
GH, Dzau VJ, et al. Shear stress elevates endothelial cGMP: role of a
potassium channel and G protein coupling.
Circulation. 1993;88:193–197.
26.
Rizzo V, McIntosh
DP, Oh P, et al. In situ flow activates endothelial nitric oxide
synthase in luminal caveolae of endothelium with rapid caveolin
dissociation and calmodulin association.
J Biol Chem. 1998;273:34724–34729.
27. Meraji S, Jayakody L, Senaratne MP, et al. Endothelium-dependent relaxation in aorta of BB rat. Diabetes. 1987;36:978–981.[Abstract]
28.
Johnstone MT,
Creager SJ, Scales KM, et al. Impaired endothelium-dependent
vasodilation in patients with insulin- dependent diabetes mellitus.
Circulation. 1993;88:2510–2516.
29. McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1992;35:771–776.[Medline] [Order article via Infotrieve]
30.
Bohlen HG, Lash
JM. Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation
of normal rat arterioles. Am J
Physiol. 1993;265:H219-H225.
31. Tesfamariam B, Brown ML, Cohen RA. Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest. 1991;87:1643–1648.
32.
Davi G,
Ciabattoni G, Consoli A, et al. In vivo formation of
8-iso-prostaglandin F2-
and platelet activation in diabetes
mellitus: effects of improved metabolic control and vitamin E
supplementation. Circulation. 1999;99:224–229.
33.
Keaney JF Jr,
Loscalzo J, Diabetes, oxidative stress, and platelet activation.
Circulation. 1999;99:189–191.
34.
Hirata K-I,
Kuroda R, Sakoda T, et al. Inhibition of endothelial nitric oxide
synthase activity by protein kinase C.
Hypertension. 1995;25:180–185.
35.
Pritchard KAJ,
Groszek L, Smalley DM, et al. Native low-density lipoprotein increases
endothelial cell nitric oxide synthase generation of superoxide anion.
Circ Res. 1995;77:510–518.
36.
Pou S, Pou WS,
Bredt DS, et al. Generation of superoxide by purified brain nitric
oxide synthase. J Biol
Chem. 1992;267:24173–24176.
37.
Jackson TS, Xu A,
Vita JA, et al. Ascorbate prevents the interaction of superoxide and
nitric oxide only at very high physiological concentrations.
Circ Res. 1998;83:916–922.
38.
Heller R,
Munscher-Paulig F, Grabner R, et al. L-ascorbic acid potentiates nitric
oxide synthesis in endothelial cells.
J Biol Chem. 1999;274:8254–8260.
39. Loewen PC, Richter HE. Inhibition of sugar uptake by ascorbic acid in Escherichia coli. Arch Biochem Biophys. 1983;226:657–665.[Medline] [Order article via Infotrieve]
40. Vinals F, Gross A, Testar X, et al. High glucose concentrations inhibit glucose phosphorylation, but not glucose transport, in human endothelial cells. Biochim Biophys Acta. 1999;1450:119–129. [Medline] [Order article via Infotrieve]
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 A. Ceriello, K. Esposito, L. Piconi, M. A. Ihnat, J. E. Thorpe, R. Testa, M. Boemi, and D. Giugliano Oscillating Glucose Is More Deleterious to Endothelial Function and Oxidative Stress Than Mean Glucose in Normal and Type 2 Diabetic Patients Diabetes, May 1, 2008; 57(5): 1349 - 1354. [Abstract] [Full Text] [PDF]
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L. Xiang, J. Dearman, S. R. Abram, C. Carter, and R. L. Hester Insulin resistance and impaired functional vasodilation in obese Zucker rats Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1658 - H1666. [Abstract] [Full Text] [PDF]
|
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|
|
|
E. Toth, A. Racz, J. Toth, P. M. Kaminski, M. S. Wolin, Z. Bagi, and A. Koller Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH2/TXA2 mediation Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3096 - H3104. [Abstract] [Full Text] [PDF]
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 |
|
 H. Zheng, M. Patel, R. Cable, L. Young, and S. D. Katz Insulin Sensitivity, Vascular Function, and Iron Stores in Voluntary Blood Donors Diabetes Care, October 1, 2007; 30(10): 2685 - 2689. [Abstract] [Full Text] [PDF]
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|
 R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]
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|
 R. Hovorka, J. Kremen, J. Blaha, M. Matias, K. Anderlova, L. Bosanska, T. Roubicek, M. E. Wilinska, L. J. Chassin, S. Svacina, et al. Blood Glucose Control by a Model Predictive Control Algorithm with Variable Sampling Rate Versus a Routine Glucose Management Protocol in Cardiac Surgery Patients: A Randomized Controlled Trial J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2960 - 2964. [Abstract] [Full Text] [PDF]
|
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P. H. McNulty, M. A. Tulli, B. J. Robertson, V. Lendel, L. A. Harach, S. Scott, and J. P. Boehmer Effect of simulated postprandial hyperglycemia on coronary blood flow in cardiac transplant recipients Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H103 - H108. [Abstract] [Full Text] [PDF]
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Y.-S. Kim, R. Krogh-Madsen, P. Rasmussen, P. Plomgaard, S. Ogoh, N. H. Secher, and J. J. van Lieshout Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H467 - H473. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, A. Dunaif, M. Gerhard-Herman, and M. A. Creager Endothelial Function Varies According to Insulin Resistance Disease Type Diabetes Care, May 1, 2007; 30(5): 1226 - 1232. [Abstract] [Full Text] [PDF]
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|
 V. O. Palmieri, I. Grattagliano, P. Portincasa, and G. Palasciano Systemic Oxidative Alterations Are Associated with Visceral Adiposity and Liver Steatosis in Patients with Metabolic Syndrome J. Nutr., December 1, 2006; 136(12): 3022 - 3026. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 H. E. Tawfik, A. B. El-Remessy, S. Matragoon, G. Ma, R. B. Caldwell, and R. W. Caldwell Simvastatin Improves Diabetes-Induced Coronary Endothelial Dysfunction J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 386 - 395. [Abstract] [Full Text] [PDF]
|
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 |
|
 I. J. Goldberg and H. M. Dansky Diabetic Vascular Disease: An Experimental Objective Arterioscler Thromb Vasc Biol, August 1, 2006; 26(8): 1693 - 1701. [Abstract] [Full Text] [PDF]
|
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|
|
|
D. D. Heistad Oxidative Stress and Vascular Disease: 2005 Duff Lecture Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 689 - 695. [Abstract] [Full Text] [PDF]
|
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M. Ayaz and B. Turan Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1071 - H1080. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 C. Vecchione, A. Aretini, G. Marino, U. Bettarini, R. Poulet, A. Maffei, M. Sbroggio, L. Pastore, M. T. Gentile, A. Notte, et al. Selective Rac-1 Inhibition Protects From Diabetes-Induced Vascular Injury Circ. Res., February 3, 2006; 98(2): 218 - 225. [Abstract] [Full Text] [PDF]
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|
H. Chen, R. J. Karne, G. Hall, U. Campia, J. A. Panza, R. O. Cannon III, Y. Wang, A. Katz, M. Levine, and M. J. Quon High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H137 - H145. [Abstract] [Full Text] [PDF]
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J.-Z. Sheng, D. Wang, and A. P. Braun DAF-FM (4-Amino-5-methylamino-2',7'-difluorofluorescein) Diacetate Detects Impairment of Agonist-Stimulated Nitric Oxide Synthesis by Elevated Glucose in Human Vascular Endothelial Cells: Reversal by Vitamin C and L-Sepiapterin J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 931 - 940. [Abstract] [Full Text] [PDF]
|
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|
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B. Capaldo, M. Galderisi, A. A. Turco, A. D'Errico, S. Turco, A. A. Rivellese, G. de Simone, O. de Divitiis, and G. Riccardi Acute Hyperglycemia Does Not Affect the Reactivity of Coronary Microcirculation in Humans J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 3871 - 3876. [Abstract] [Full Text] [PDF]
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J. Molnar, S. Yu, N. Mzhavia, C. Pau, I. Chereshnev, and H. M. Dansky Diabetes Induces Endothelial Dysfunction but Does Not Increase Neointimal Formation in High-Fat Diet Fed C57BL/6J Mice Circ. Res., June 10, 2005; 96(11): 1178 - 1184. [Abstract] [Full Text] [PDF]
|
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|
 A. L. Moens, I. Goovaerts, M. J. Claeys, and C. J. Vrints Flow-Mediated Vasodilation: A Diagnostic Instrument, or an Experimental Tool? Chest, June 1, 2005; 127(6): 2254 - 2263. [Abstract] [Full Text] [PDF]
|
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|
 A. Ceriello Acute hyperglycaemia: a 'new' risk factor during myocardial infarction Eur. Heart J., February 2, 2005; 26(4): 328 - 331. [Abstract] [Full Text] [PDF]
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A. Ceriello Postprandial Hyperglycemia and Diabetes Complications: Is It Time to Treat? Diabetes, January 1, 2005; 54(1): 1 - 7. [Abstract] [Full Text] [PDF]
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N. R. Madamanchi, A. Vendrov, and M. S. Runge Oxidative Stress and Vascular Disease Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 29 - 38. [Abstract] [Full Text] [PDF]
|
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B. A. Mullan, C. N. Ennis, H. J. P. Fee, I. S. Young, and D. R. McCance Protective effects of ascorbic acid on arterial hemodynamics during acute hyperglycemia Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1262 - H1268. [Abstract] [Full Text] [PDF]
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Z. Bagi, E. Toth, A. Koller, and G. Kaley Microvascular dysfunction after transient high glucose is caused by superoxide-dependent reduction in the bioavailability of NO and BH4 Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H626 - H633. [Abstract] [Full Text] [PDF]
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S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]
|
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|
|
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|
 A. S. Reed, N. Charkoudian, A. Vella, P. Shah, R. A. Rizza, and M. J. Joyner Forearm vascular control during acute hyperglycemia in healthy humans Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E472 - E480. [Abstract] [Full Text]
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V. Fonseca, C. Desouza, S. Asnani, and I. Jialal Nontraditional Risk Factors for Cardiovascular Disease in Diabetes Endocr. Rev., February 1, 2004; 25(1): 153 - 175. [Abstract] [Full Text] [PDF]
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S. Clement, S. S. Braithwaite, M. F. Magee, A. Ahmann, E. P. Smith, R. G. Schafer, and I. B. Hirsch Management of Diabetes and Hyperglycemia in Hospitals Diabetes Care, February 1, 2004; 27(2): 553 - 591. [Full Text] [PDF]
|
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|
|
|
|
M. Raitakari, T. Ilvonen, M. Ahotupa, T. Lehtimaki, A. Harmoinen, P. Suominen, J. Elo, J. Hartiala, and O. T. Raitakari Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 124 - 128. [Abstract] [Full Text] [PDF]
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|
 E. R. Werner, A. C.F. Gorren, R. Heller, G. Werner-Felmayer, and B. Mayer Tetrahydrobiopterin and Nitric Oxide: Mechanistic and Pharmacological Aspects Experimental Biology and Medicine, December 1, 2003; 228(11): 1291 - 1302. [Abstract] [Full Text] [PDF]
|
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|
|
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|
D. Tousoulis, C. Antoniades, C. Tountas, E. Bosinakou, M. Kotsopoulou, P. Toutouzas, and C. Stefanadis Vitamin C Affects Thrombosis/ Fibrinolysis System and Reactive Hyperemia in Patients With Type 2 Diabetes and Coronary Artery Disease Diabetes Care, October 1, 2003; 26(10): 2749 - 2753. [Abstract] [Full Text] [PDF]
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|
|
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|
 M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I Circulation, September 23, 2003; 108(12): 1527 - 1532. [Full Text] [PDF]
|
|
|
|
 |
|
 J. G Regensteiner, S. Popylisen, T. A Bauer, J. Lindenfeld, E. Gill, S. Smith, C. K Oliver-Pickett, J. E. Reusch, and J. V Weil Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes Vascular Medicine, August 1, 2003; 8(3): 169 - 175. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Kuroki, K. Isshiki, and G. L. King Oxidative Stress: The Lead or Supporting Actor in the Pathogenesis of Diabetic Complications J. Am. Soc. Nephrol., August 1, 2003; 14(90003): S216 - 220. [Full Text] [PDF]
|
|
|
|
|
|
N. Ihlemann, C. Rask-Madsen, A. Perner, H. Dominguez, T. Hermann, L. Kober, and C. Torp-Pedersen Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H875 - H882. [Abstract] [Full Text] [PDF]
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|
 |
|
 J. E. Gerich Clinical Significance, Pathogenesis, and Management of Postprandial Hyperglycemia Arch Intern Med, June 9, 2003; 163(11): 1306 - 1316. [Abstract] [Full Text] [PDF]
|
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|
|
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A. Ceriello New Insights on Oxidative Stress and Diabetic Complications May Lead to a "Causal" Antioxidant Therapy Diabetes Care, May 1, 2003; 26(5): 1589 - 1596. [Abstract] [Full Text] [PDF]
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|
|
E. R. Gross, J. F. LaDisa Jr., D. Weihrauch, L. E. Olson, T. T. Kress, D. A. Hettrick, P. S. Pagel, D. C. Warltier, and J. R. Kersten Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1552 - H1559. [Abstract] [Full Text] [PDF]
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|
|
 |
|
 G. E. Drossos, I. K. Toumpoulis, D. G. Katritsis, J. P. A. Ioannidis, P. Kontogiorgi, E. Svarna, and C. E. Anagnostopoulos Is vitamin C superior to diltiazem for radial artery vasodilation in patients awaiting coronary artery bypass grafting? J. Thorac. Cardiovasc. Surg., February 1, 2003; 125(2): 330 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Padayatty, A. Katz, Y. Wang, P. Eck, O. Kwon, J.-H. Lee, S. Chen, C. Corpe, A. Dutta, S. K Dutta, et al. Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention J. Am. Coll. Nutr., February 1, 2003; 22(1): 18 - 35. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 T. Pawelczyk, M. Podgorska, and M. Sakowicz The Effect of Insulin on Expression Level of Nucleoside Transporters in Diabetic Rats Mol. Pharmacol., January 1, 2003; 63(1): 81 - 88. [Abstract] [Full Text] [PDF]
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|
 |
|
 A. N. Friedman, C. Ritter, J. C. F. Moreira, F. Dal-Pizzol, M. G. Ziegler, X. Bao, R. Matz, Y. Higashi, K. Chayama, and M. Yoshizumi Renovascular Hypertension, Endothelial Function, and Oxidative Stress N. Engl. J. Med., November 7, 2002; 347(19): 1528 - 1530. [Full Text] [PDF]
|
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|
|
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G. Fuchsjager-Mayrl, J. Pleiner, G. F. Wiesinger, A. E. Sieder, M. Quittan, M. J. Nuhr, C. Francesconi, H.-P. Seit, M. Francesconi, L. Schmetterer, et al. Exercise Training Improves Vascular Endothelial Function in Patients with Type 1 Diabetes Diabetes Care, October 1, 2002; 25(10): 1795 - 1801. [Abstract] [Full Text] [PDF]
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J. Pleiner, G. Schaller, F. Mittermayer, M. Bayerle-Eder, M. Roden, and M. Wolzt FFA-Induced Endothelial Dysfunction Can Be Corrected by Vitamin C J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2913 - 2917. [Abstract] [Full Text] [PDF]
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C. Rask-Madsen, N. Ihlemann, T. Krarup, E. Christiansen, L. Kober, C. Nervil Kistorp, and C. Torp-Pedersen Insulin Therapy Improves Insulin-Stimulated Endothelial Function in Patients With Type 2 Diabetes and Ischemic Heart Disease Diabetes, November 1, 2001; 50(11): 2611 - 2618. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, and M. A. Creager Inhibition of Protein Kinase C{beta} Prevents Impaired Endothelium-Dependent Vasodilation Caused by Hyperglycemia in Humans Circ. Res., January 11, 2002; 90(1): 107 - 111. [Abstract] [Full Text] [PDF]
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