AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H103-H108, 2007. First published March 16, 2007; doi:10.1152/ajpheart.00779.2006
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/H103    most recent
00779.2006v2
00779.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McNulty, P. H.
Right arrow Articles by Boehmer, J. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McNulty, P. H.
Right arrow Articles by Boehmer, J. P.

Effect of simulated postprandial hyperglycemia on coronary blood flow in cardiac transplant recipients

Patrick H. McNulty, Mark A. Tulli, Bryan J. Robertson, Vasili Lendel, Lisa A. Harach, Sofia Scott, and John P. Boehmer

Division of Cardiology, Penn State College of Medicine, Hershey, Pennsylvania

Submitted 20 July 2006 ; accepted in final form 8 March 2007


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Patients with diabetes mellitus exhibit postprandial hyperglycemia, systemic oxidative stress, impaired endothelium-dependent, nitric oxide (NO)-mediated coronary artery dilatation, and an increased incidence of coronary events. Whether hyperglycemia causally mediates these associations is unknown. To test the hypothesis that postprandial hyperglycemia acutely impairs coronary endothelial function in humans, we compared the ability of the endothelium-dependent vasodilator acetylcholine to increase conduit coronary diameter (the macrovascular response) and coronary blood flow velocity (the microvascular response) in 12 cardiac transplant recipients without diabetes before and after blood glucose was raised from 6.7 ± 1.3 mmol/l (121 ± 24 mg/dl) to 17.8 ± 1.5 mmol/l (321 ± 27 mg/dl) for 1 h. Hyperglycemia acutely doubled circulating levels of the oxidation product malondialdehyde, indicating systemic oxidative stress, but did not affect the ability of acetylcholine to dilate conduit coronary segments or accelerate coronary blood flow. We conclude that the oxidative stress associated with a single acute episode of hyperglycemia affects neither acetylcholine-mediated coronary endothelial NO release nor the subsequent bioavailability, metabolism, or action of NO within the coronary circulation of cardiac transplant recipients. These observations imply that the relationship among hyperglycemia, oxidative stress, and coronary endothelial dysfunction is presumably mediated by mechanisms operating over longer periods of time.

diabetes mellitus; coronary artery; coronary endothelial dysfunction

ONE OF THE EARLIEST ABNORMALITIES identified in both animal models of diabetes mellitus (29, 34) and humans with the disease (31, 32, 37) is impairment in the ability of the coronary endothelium to effect nitric oxide (NO)-mediated arterial dilatation. Several lines of evidence suggest this may be mediated by hyperglycemia. Hyperglycemia is the hallmark of diabetes and one of its earliest features. In vitro, hyperglycemia accelerates glucose consumption by endothelial cells resulting in cytosolic accumulation of diacylglycerol, activation of protein kinase C, and inhibition of endothelial NO synthase (eNOS) (12, 43). Hyperglycemia also fuels the formation of reactive oxygen species (ROS) and of advanced glycosylation end products of endovascular proteins, both of which quench NO in vitro (5, 26). Perfusing the isolated rat heart with hyperglycemic solution for 1 h accelerates venous washout of nitrotyrosine (a byproduct of the reaction of ROS with NO) and increases coronary vascular resistance (9). Hyperglycemia may also stimulate the elaboration of substances [e.g., endothelin-1 (24, 35), tumor necrosis factor-{alpha} (11, 30)], which indirectly oppose endothelium-dependent vasodilation (46).

Both high dietary glucose consumption (25) and postprandial hyperglycemia (7, 8, 17) are recognized to increase the risk of adverse clinical coronary events. Whether hyperglycemia itself mediates this risk, by episodically impairing endothelium-dependent coronary dilatation and thereby interfering with minute-to-minute control of coronary tone, is a question of considerable clinical importance. We used selective coronary angiography and intracoronary Doppler ultrasonography to test the hypothesis that acutely raising circulating glucose concentration from a fasting to a supraphysiological level acutely reduces the capacity for endothelium-dependent coronary arterial dilatation in human subjects.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Study subjects. The study was approved by the Institutional Review Board of The Pennsylvania State University College of Medicine, and all subjects gave written consent. Experiments were performed in cardiac transplant patients undergoing annual coronary angiography to screen for graft coronary artery disease. Transplant patients are frequently glucose intolerant, and they develop an accelerated form of coronary atherosclerosis of which the pathogenesis is incompletely understood. However, because they usually carry the hearts of healthy young organ donors, transplant patients typically exhibit robust endothelium-dependent coronary responses, especially early after transplantation (18, 23). They are consequently a uniquely convenient population in which to test the study hypothesis.

Twelve heart transplant patients with no history of diabetes were studied in the morning after an overnight fast. All subjects were being treated with cyclosporine or tacrilomus and a statin drug, but none were receiving corticosteroids. Clinical and demographic characteristics are listed in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1. Demographic and clinical descriptors of study subjects

 
Study protocol. Transfemoral right and left heart catheterization and selective coronary angiography were performed in standard fashion using a low-osmolality radiocontrast agent. After we waited 15 min for radiocontrast to clear the coronary circulation, heparin sodium was administered by intravenous bolus in a dose of 60 U/kg body mass to prevent coronary thrombosis during the research protocol. Blood-activated coagulation time (ACT) was measured at intervals during each study and was maintained >200 s by administration of additional heparin if needed. A size 6-Fr guiding catheter was positioned in the left main coronary artery and used to introduce a 0.014-in. diameter Doppler flow wire (FloMap system, Jomed, Rancho Cordova, CA) into the proximal left anterior descending (LAD) coronary artery. This device incorporates a 20-MHz Doppler transducer, which generates a continuous, high-fidelity recording of the velocity of red blood cells traversing a 0.5-cm3 volume immediately distal to the wire tip within the coronary artery lumen. The wire's position was adjusted to give an optimal Doppler spectral signal, and this position was recorded by digital angiography to allow conformation of stable wire position throughout each study.

After a sample of femoral arterial blood was removed for chemical analyses, LAD coronary vasodilator reserve was measured as previously reported (28). Briefly, endothelium-dependent microvascular dilatation was measured by recording the coronary flow velocity response to sequential 3-min infusions of a 20 µg/ml solution of the endothelium-dependent dilator acetylcholine (Clinalfa) administered through the coronary guiding catheter at rates of 0.5 and 1.0 ml/min (10 and 20 µg/in) calculated to achieve estimated concentrations in coronary capillary blood of 100 and 200 µg/l (0.7 and 1.4 x 10–6 M), respectively. At the end of the 20 µg/min infusion, selective left coronary angiography was repeated, and endothelium-dependent macrovascular dilatation was calculated as the change in diameter of the LAD coronary segment containing the Doppler wire in response to acetylcholine. After 3 min was allowed for the acetylcholine effect to dissipate, endothelium-independent vasodilatation was determined by measuring the LAD coronary flow velocity response to a 40-µg intracoronary injection of adenosine (Fujisawa) calculated to achieve an estimated concentration in coronary capillary blood of 400 µg/l (1.5 x 10–6 M). Subjects then received a primed (12.5 g over 1 min), continuous (0.8 g/min) 60-min intravenous infusion of glucose, and measurements were repeated in the hyperglycemic state.

Chemical analyses. Glucose concentration was measured in whole blood using an automated glucose oxidase analyzer (Analox Instruments). Insulin concentration was measured in plasma by radioimmunoassay. Plasma free fatty acids (FFA) were measured using a colorimetric assay kit (Fisher Scientific). Oxidative stress is known to form malondialdehyde as a product of the reaction of excess ROS with fatty acids in low-density lipoproteins. Circulating concentrations of malondiadehyde [detectable in plasma as a thiobarbituric acid-reactive substance (TBARS)] are reported to be elevated in patients with diabetes mellitus (15–16, 33), suggesting that diabetes is a condition of systemic oxidative stress (14). To determine whether hyperglycemic infusion constituted an oxidative stress in these experiments, TBARS concentration was measured in basal and hyperglycemic serum using a microfluorometric assay kit (Oxitek assay, Zeptometrix, Buffalo, NY).

LAD coronary blood flow velocity. LAD coronary flow velocity was recorded continuously throughout each study using the Doppler wire, as previously reported (28). By convention, velocity is reported as the instantaneous peak diastolic velocity observed during each cardiac cycle. The analog signal generated by the Doppler wire was digitally converted and stored on an Apple PowerMac laptop computer using PowerLab software (ADI). To smooth recorded signals for beat-to-beat variations due to the respiratory cycle, coronary velocity responses to acetylcholine and adenosine were measured during midcycle breath holding. To allow detection of trends during glucose infusion, the continuous digital recording was scanned off-line and average LAD flow velocity was calculated for each 10-min segment of the 60-min infusion. Heart rate and mean arterial pressure were recorded basally and during the final 5 min of each hyperglycemic infusion by an electronic transducer connected to the femoral arterial sheath.

LAD coronary diameter. The segment of each LAD coronary artery holding the Doppler wire was imaged by digital cineangiography at 30 frames/s using a Siemens Coroskop C-arm image intensifier system positioned at an optimal projection angle. Identical projection angles and imaging techniques were used to record LAD diameter three times: at the beginning of each study, immediately after the 20 µg/min intracoronary acetylcholine infusion in the basal state, and immediately after the same acetylcholine infusion in the hyperglycemic state. Digital cineangiogram loops were reviewed by an experienced reader blinded to the treatment protocol, and a single representative image frame from each loop was chosen for analysis. On this image, the diameter of the LAD coronary at the level of the Doppler wire's tip was measured by electronic calipers (Heartlab, Westerly, RI) using the known diameter of the coronary guiding catheter as an internal reference.

LAD coronary blood flow. To calculate a surrogate of actual volumetric LAD coronary blood flow (cm3/s) under each of the experimental conditions examined, measured peak diastolic blood flow velocity (cm/s) was multiplied by the calculated cross-sectional area (cm2 = {pi} x coronary radius2) of the coronary artery segment containing the tip of the Doppler. For this analysis it was assumed that the LAD coronary has a circular cross section. It is recognized that the quantity so calculated will be an overestimation of true LAD coronary blood flow volume, the calculation of which would require multiplying LAD cross-sectional area by a factor integrating instantaneous blood flow velocity during systole and diastole throughout each cardiac cycle.

Calculations. Continuous variables were compared between basal and hyperglycemic conditions using analysis of variance. Average flow velocities during each 10-min interval were compared using repeated measures analysis of variance with the Bonferroni test for repeated measures. Differences are considered significant if P < 0.05.


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Angiographic and hemodynamic measurements. Demographic and metabolic data are shown in Table 1 and hemodynamic data are shown in Table 2. No subject's coronary angiogram demonstrated significant arteriopathy. Baseline systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures were within normal limits in all subjects, and glucose infusion affected neither systemic arterial blood pressure nor heart rate.


View this table:
[in this window]
[in a new window]

  		Table 2. Hemodynamic descriptors of study subjects

 
Metabolic parameters. Individual metabolic data are shown in Fig. 1. Blood glucose concentration averaged 6.7 ± 1.3 mmol/l (121 ± 24 mg/dl) in the basal fasting state (normal range: 4.0–6.5 mmol/l) and rose to 17.8 ± 1.5 mmol/l (321 ± 27 mg/dl) during the 60-min glucose infusion (Fig. 2). This was accompanied by a rise in plasma insulin concentration from 151 ± 100 pmol/l (19 ± 12 µU/ml) to 520 ± 200 pmol/l (65 ± 25 µU/ml) and a corresponding fall in plasma FFA concentration from 0.91 ± 0.18 to 0.42 ± 0.13 mmol/l. Serum TBARS concentration rose more than twofold during glucose infusion from 0.44 ± 0.10 to 1.12 ± 0.13 nmol/l.


Figure 1
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 1. Whole blood glucose (A), plasma insulin (B), plasma free fatty acid (FFA) (C), and serum malondialdehyde (MDA) concentrations (D) in the basal fasting state (BASAL) and again during the last 5 min of a 60-min hyperglycemic glucose infusion (HYPERGLYCEMIA). Closed circles are individual values in 12 subjects; open circles are means ± SD.

 

Figure 2
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 2. Whole blood glucose concentration during a primed (12.5 g) continuous (0.8 g/min) intravenous infusion of glucose. Data represent means ± SD for 12 subjects.

 
Coronary flow velocity. LAD coronary flow velocity averaged 27 ± 6 cm/s in the fasting state (Fig. 3). Average flow velocity did not change significantly during the first 40 min of glucose infusion, but the 50-min value exceeded the basal value for LAD flow velocity in 10 of 12 subjects (30 ± 6 vs. 27 ± 6 cm/s, P = 0.25) suggesting a possible mild coronary vasodilator effect of hyperglycemia and/or hyperinsulinemia.


Figure 3
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 3. Coronary flow velocity measured by Doppler ultrasonography in the left anterior descending (LAD) coronary artery during hyperglycemic glucose infusion. Data represent means ± SD in 12 subjects. *P < 0.05 vs. basal.

 
Endothelium-independent and -dependent microvascular coronary dilatation. In the basal state, intracoronary acetylcholine infusion was associated with a 44 ± 17% increase in LAD coronary flow velocity at the 10 µg/min dose and a 100 ± 28% increase at the 20 µg/min dose, whereas infusion of adenosine was associated with a 288 ± 23% increase. When subjects were separated into two groups on the basis of time elapsed since transplantation, the more recently transplanted group (n = 6, elapsed time = 2 ± 1 y) had a greater (P < 0.05) average acetylcholine-mediated flow velocity response (140 ± 24% increase at the 20 µg/min dose) than the more remotely transplanted group (n = 6, elapsed time = 4 ± 2 y, 60 ± 15% increase at the 20 µg/min dose). Time elapsed since transplantation had no effect on the coronary flow response to adenosine. Coronary flow responses to acetylcholine and adenosine in the hyperglycemic state were nearly identical to those observed in the basal state for the 12 subjects, whether considered together (Fig. 4) or analyzed on the basis of time elapsed since transplantation (data not shown).


Figure 4
View larger version (8K):
[in this window]
[in a new window]

  		Fig. 4. Effect of acetylcholine [10 µg/min (ACh-10) or 20 µg/min (ACh-20) coronary infusion] or adenosine (40 µg coronary bolus) on LAD coronary flow velocity (A) and LAD coronary blood flow (B). Open circles are observations made in the basal state at blood glucose = 6.7 ± 1.3 mmol/l ; closed circles are observations made during the final 5 min of a 60-min hyperglycemic glucose infusion, at blood glucose = 17.8 ± 1.5 mmol/l. *P < 0.05 vs. value at basal glucose level.

 
Endothelium-dependent macrovascular coronary dilatation. In the basal state, the 20 µg/min acetylcholine infusion increased LAD coronary diameter by 6 ± 4% from 3.3 ± 0.3 to 3.5 ± 0.4 mm (P < 0.01), whereas in the hyperglycemic state LAD diameter was 3.3 + 0.4 mm before and 3.5 + 0.3 mm after acetylcholine (P = 0.01) (P = not significant vs. basal postacetlycholine diameter).


   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Hyperglycemic patients with diabetes mellitus exhibit impaired endothelium-dependent vasodilatation in both the peripheral (21, 44) and coronary (20, 37, 43) circulation. Longitudinal studies have demonstrated this impairment to be associated with a substantially increased risk of adverse coronary events (2). Previous studies testing whether hyperglycemia per se confers this impairment have been limited to the limb circulation and have yielded mixed results. Thus, whereas some investigators have reported that hyperglycemic exposures ranging in duration from 1 to 6 h impair endothelium-dependent vasodilatation in the forearm circulation of healthy subjects (1, 4, 22, 42, 45), others have observed no such impairment (19, 38) even after hyperglycemic exposure for 24 h (19).

In the present study, which we believe is the first to examine this question directly in the human coronary circulation, we sought to mimic the physiological state produced by ingestion of a high-glucose meal by glucose-intolerant patients (i.e., temporary systemic hyperglycemia, endogenous insulin secretion, fall in circulating FFA levels) and measured both macrovascular and microvascular responses to the potent endothelium-dependent vasodilator acetylcholine. Study subjects exhibited moderate fasting elevations in blood levels of glucose and insulin, consistent with systemic metabolic insulin resistance. Despite the known association of insulin resistance with impaired endothelium-dependent vasodilation (29, 31–32, 34, 37), they nevertheless demonstrated robust basal coronary vasodilator responses to acetylcholine. This is consistent with previous observations that cardiac grafts obtained from healthy young donors retain relatively normal coronary endothelial function for several years after transplantation, even in middle-aged recipients who exhibit conditions (e.g., systemic insulin resistance) normally associated with vascular endothelial dysfunction and who demonstrate endothelial dysfunction in noncoronary vascular beds (18, 23). We note that some observers have described substantial coronary endothelial dysfunction, associated with elevated circulating levels of oxidized low-density lipoprotein cholesterol, in cardiac transplant recipients examined early after transplantation (13). The more normal endothelium-dependent coronary responses we observed may reflect the universal use of statins by our subjects (40) and the more complete recovery of their cardiac grafts from perioperative ischemic injury (36).

In our subjects, hyperglycemic glucose infusion more than doubled serum concentrations of TBARS, suggesting increased vascular ROS formation (14) but did not acutely impair the ability of acetylcholine to dilate either capacitance coronary arteries or the coronary microcirculation. This implies that, in nondiabetic subjects, a single episode of acute hyperglycemia affects neither acetylcholine-mediated coronary endothelial NO release nor the subsequent bioavailability, metabolism, or action of endothelium-derived NO within the coronary circulation.

Insulin, like acetylcholine, has been reported to stimulate endothelial NO secretion and produce endothelium-dependent vasodilatation in several tissues, including the heart (3, 27, 41). We previously observed that physiological hyperinsulinemia modestly increased coronary blood flow in subjects without diabetes (43), but that this effect was absent in patients with Type 2 diabetes who were studied under hyperglycemic conditions (20). In the present study, a 1-h glucose infusion induced endogenous insulin secretion. Coincident with this, we observed a modest increase in LAD coronary flow velocity in 10 of 12 subjects (Fig. 3), despite the concomitant presence of hyperglycemia. This suggests that the impairment in coronary vasodilator response to insulin we previously observed in hyperglycemic patients with diabetes (20) likewise cannot be entirely attributed to hyperglycemia.

FFA have been hypothesized to affect both endothelium-dependent and endothelium-independent vasodilator responses by reducing eNOS activity (12) and increasing blood viscosity (39) respectively. Whereas little information is available about the influence of blood FFA concentration on coronary blood flow in vivo in humans, this hypothesis has potentially important clinical implications. For example, it would predict that the diurnal variation in FFA levels associated with normal feeding and fasting cycles might produce a corresponding diurnal variation in coronary vasodilator reserve. Our failure to observe an amplification of the coronary flow velocity response to acetylcholine or adenosine associated with the fall in plasma FFA level from 0.9 to 0.4 mmol/l in our experiment suggests that changes in circulating FFA level within the physiological range probably do not exert a clinically significant influence on coronary vasodilator reserve in humans.

Several limitations must be acknowledged. Safety considerations related to performing invasive studies within the coronary circulation of volunteer subjects limited the duration of the experiments to about 1 h. The possibility that longer duration exposure to hyperglycemia, or repetitive exposure, might impair acetylcholine-mediated coronary dilatation cannot be excluded. Likewise, we cannot exclude that hyperglycemia might have impaired the coronary dilator response to endothelial stimulants (e.g., shear stress) other than acetylcholine. Whereas the choice of cardiac transplant recipients as study subjects ensured a robust basal endothelium-dependent coronary flow response against which to measure potential effects of hyperglycemia, we acknowledge that because the transplanted heart is de-enervated, our study could not have detected neurally mediated effects of hyperglycemia on coronary flow. Our subjects had no evidence of coronary artery disease as judged by selective coronary angiography. We acknowledge that they may nevertheless have had subclinical coronary atherosclerosis and that this could have affected their responsiveness to vasoactive stimuli. Likewise, we studied subjects at only one point in time along the continuum of coronary endothelial dysfunction and cannot exclude that abnormal coronary responses to hyperglycemia might be present at earlier or later time points.

In contrast to the present observations in nondiabetic subjects, studies in the peripheral circulation have suggested that hyperglycemia may impair endothelium-dependent vasodilatation in patients with diabetes (6, 10). If this suggestion is correct, the negative findings of the present study would logically suggest that one or more diabetes-specific factors may play a permissive role in mediating the effects of hyperglycemia on the coronary endothelium. Additional studies testing the effect of hyperglycemia on endothelium-dependent coronary vasodilatation in patients with diabetes will be necessary to test this hypothesis.


   GRANTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by a grant from the American Heart Association National Center (0350681N), State of Pennsylvania Tobacco Settlement funds, The National Heart, Lung, Blood Institute Grant R01 HL-70222, and the General Clinical Research Center of the Penn State Milton S. Hershey Medical Center (MO1 RR10732 and C06 RR016499).


   ACKNOWLEDGMENTS
 
The authors thank the staff of the Penn State Cardiovascular Center cardiac catheterization laboratories for help in the performance of these studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. H. McNulty, Div. of Cardiology, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326 (e-mail: patrick.mcnulty{at}bassett.org)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Akbari CM, Saouaf R, Barnhill DF, Newman PA, LoGerfo FW, Veves A. Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia. J Vasc Surg 29: 942–943, 1998.
  2. Al Suwaidi J, Hamasaki S, Higano S, Nishamura R, Holmes D, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101: 948–954, 2000.[Abstract/Free Full Text]
  3. Baron AD, Steinberg H, Chaker H, Leaming R, Johnson A, Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J Clin Invest 96: 786–792, 1995.[Web of Science][Medline]
  4. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103: 1618–1623, 2001.[Abstract/Free Full Text]
  5. Bucala R, Tracey K, Cerami A. Advanced glycosylation end products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest 87: 432–438, 1991.[Web of Science][Medline]
  6. Caballero AE, Arora S, Saouaf R, Lim SC, Smakowsk P, Park JY, King GL, LoGerfo FW, Horton ES, Veves A. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 48: 1856–1862, 1999.[Abstract]
  7. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systemic overview. Lancet 355: 773–778, 2000.[CrossRef][Web of Science][Medline]
  8. Ceriello A. The emerging role of post-prandial hyperglycemic spikes in the pathogenesis of diabetic complications. Diabetes Metab 15: 188–193, 1998.
  9. Ceriello A, Quagliaro L, D'Amico M, Di Filippo C, Marfella R, Nappo F, Berrino L, Rossi F, Giugliano D. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes 51: 1076–1082, 2002.[Abstract/Free Full Text]
  10. Clarkson P, Celermajor DS, Donald AE, Sampson M, Sorenson KE, Adams M, Yue DK, Bettreridge DJ, Deanfield JE. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol 28: 573–579, 1996.[Abstract]
  11. Couglan MT, Oliva K, Georgiou HM, Permezel JM, Rice GE. Glucose-induced release of tumor necrosis factor-alpha from human placental and adipose tissues in gestational diabetes mellitus. Diabetes Metab 18: 921–927, 2001.
  12. Davda RK, Stepniakowski KT, Lu G, Ullian ME, Goodfriend TL, Egan BM. Oleic acid inhibits endothelial nitric oxide synthase by a protein kinase C-independent mechanism. Hypertension 26: 764–770, 1995.[Abstract/Free Full Text]
  13. Fang JC, Kinlay S, Behrendt D, Hikita H, Witztum JL, Selwyn AP, Ganz P. Circulating antibodies to oxidized LDL correlate with impaired coronary endothelial function after cardiac transplantation. Arterioscler Thromb Vasc Biol 22: 2044–2048, 2002.[Abstract/Free Full Text]
  14. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114: 1752–1761, 2004.[CrossRef][Web of Science][Medline]
  15. Gallou G, Ruelland A, Legras B, Maugendre D, Allannic H, Cloarec L. Plasma malondialdehyde in type 1 and type 2 diabetic patients. Clin Chem Acta 214: 227–234, 1993.[CrossRef][Web of Science][Medline]
  16. Griesmacher A, Kindhauser M, Andert SE, Schreiner W, Toma C, Knobel P, Pietschmann P, Prager R, Schnack C, Schernthaner G. Enhanced serum levels of thiobarbituric-acid-reactive substances in diabetes mellitus. Am J Med 98: 469–475, 1995.[CrossRef][Web of Science][Medline]
  17. Haffner SM. The importance of hyperglycemia in the non-fasting state to the development of cardiovascular disease. Endocr Rev 19: 583–592, 1998.[Abstract/Free Full Text]
  18. Hollenberg S, Klein L, Parillo J, Scherer M, Burns D, Tamburro P, Oberoi M, Johnson M, Costanzo M. Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death. Circulation 104: 3091–3096, 2001.[Abstract/Free Full Text]
  19. Houben AJ, Schaper NC, de Haan CH, Huvers FC, Slaaf DW, de Leeuw PW, Nieuwnehuijzen KC. Local 24-h hyperglycemia does not affect endothelium-dependent or -independent vasoreactivity in humans. Am J Physiol Heart Circ Physiol 270: H2014–H2020, 1996.[Abstract/Free Full Text]
  20. Jagasia D, Whiting JM, Pfau S, McNulty PH. Effect of non-insulin-dependent diabetes mellitus on myocardial insulin responsiveness in patients with ischemic heart disease. Circulation 103: 1734–1739, 2001.[Abstract/Free Full Text]
  21. Johnstone M, Creager S, Scales K, Cusco J, Lee B, Creager M. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 88: 2510–2516, 1993.[Abstract/Free Full Text]
  22. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 34: 146–154, 1999.[Abstract/Free Full Text]
  23. Klauss V, Spes CH, Rieber J, Siebert U, Werner F, Stempfle HU, Uberfuhr P, Theisen K, Angermann CE, Reichart B, Mudra H. Predictors of reduced coronary flow reserve in heart transplant recipients without angiographically significant coronary artery disease. Transplantation 68: 1477–81, 1999.[CrossRef][Web of Science][Medline]
  24. Lerman A, Holmes D, Bell M, Garratt K, Nishimura R, Burnett J. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 92: 2426–2431, 1995.[Abstract/Free Full Text]
  25. Liu S, Willett WC. Dietary glycemic load and atherothrombotic risk. Curr Atheroscler Rep 4: 454–461, 2002.[Medline]
  26. Marfella R, Quagliaro L, Nappo F, Ceriello A, Giugliano D. Acute hyperglycemia induces an oxidative stress in healthy subjects. J Clin Invest 108: 635–636, 2001.[CrossRef][Web of Science][Medline]
  27. McNulty PH, Pfau S, Deckelbaum LI. Effect of plasma insulin level on myocardial blood flow and its mechanism of action. Am J Cardiol 85: 123–126, 2000.
  28. McNulty PH, King N, Scott S, Hartman G, McCann J, Kozak M, Chambers CE, Demers LM, Sinoway LI. Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization. Am J Physiol Heart Circ Physiol 288: H1057–H1062, 2005.[Abstract/Free Full Text]
  29. Meriaji S, Jayakody L, Senaratne M, Thompson A, Kappagoda T. Endothelium-dependent relaxation in aorta of BB rat. Diabetes 36: 978–981, 1987.[Abstract]
  30. Nappo F, Esposito K, Cioffi M, Giugliano G, Molinari A, Paolisso G, Marfella R, Giugliano D. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol 39: 1145–1150, 2002.[Abstract/Free Full Text]
  31. Nitenberg A, Valensi R, Sachs M, Dali E, Aptecar E, Attali J. Impairment of coronary vascular reserve and Ach-induced coronary vasodilatation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function. Diabetes 42: 1017–1025, 1993.[Abstract]
  32. Nitenberg A, Ledoux S, Valensi P, Sachs R, Attali J, Anthony I. Impairment of coronary microvascular dilatation in response to cold pressor-induced sympathatic stimulation in type-2 diabetic patients with abnormal stress thallium imaging. Diabetes 50: 1180–1185, 2001.[Abstract/Free Full Text]
  33. Noberasco G, Odetti P, Boeri D, Maiello M, Adezati L. Malondialdehyde (MDA) level in diabetic subjects. Relationship with blood glucose and glycosylated hemoglobin. Biomed Pharmacother 45: 193–196, 1991.[CrossRef][Medline]
  34. Oyama Y, Kawasaki H, Hattori Y, Kanno M. Attenuation of endothelium-dependent relaxation in aorta from diabetic rats. Eur J Pharmacol 132: 75–78, 1986.[CrossRef][Web of Science][Medline]
  35. Park LY, Takahara N, Gabriele A, Chou E, Naruse K, Suzuma K, Yamauchi T, Ha SW, Meier M, Rhodes CJ, King GL. Induction of endothelin-1 expression by glucose. An effect of protein kinase C activation. Diabetes 49: 1239–1248, 2000.[Abstract]
  36. Preumont N, Berkenboom G, Vachiery J, Jansens J, Antoine M, Wikler D, Damhaut P, Degre S, Lenaers A, Goldman S. Early alterations of myocardial blood flow reserve in heart transplant recipients with angiographically normal coronary arteries. J Heart Lung Transplant 19: 538–545, 2000.[CrossRef][Web of Science][Medline]
  37. Reddy K, Nair R, Sheehan H, Hodgson J. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 23: 833–843, 1994.[Abstract]
  38. Reed AS, Charkoudian N, Vella A, Shah P, Rizza RA, Joyner MJ. Forearm vascular control during acute hyperglycemia in healthy humans. Am J Physiol Endocrinol Metab 286: E472–E480, 2004.[Abstract/Free Full Text]
  39. Rim S, Leong-Poi H, Linder J, Wei K, Fisher N, Kaul S. Decrease in coronary blood flow reserve during hyperlipidemia is secondary to an increase in blood viscosity. Circulation 104: 2704–2709, 2001.[Abstract/Free Full Text]
  40. See VY, DeNofrio D, Goldberg L, Chang G, Sasseen B, Kolansky DM, Pickering F, Kao A, Loh E, Wilensky RL. Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction. Am J Cardiol 92: 11–15, 2003.[CrossRef][Web of Science][Medline]
  41. Steinberg H, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilatation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 94: 1172–1179, 1994.[Web of Science][Medline]
  42. Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol 36: 2185–2191, 2000.[Abstract/Free Full Text]
  43. Way KJ, Katai N, King GL. Protein kinase C and the development of diabetic vascular complications. Diabet Med 18: 945–956, 2001.[CrossRef][Web of Science][Medline]
  44. Williams S, Cusco J, Roddy M, Johnstone M, Creager M. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27: 567–574, 1996.[Abstract]
  45. Williams S, Goldfine A, Timini F, Ting H, Roddy MA, Simonson D, Creager M. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 97: 1695–1701, 1998.[Abstract/Free Full Text]
  46. Youd JM, Rattigan S, Clark MG. Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. Diabetes 49: 1904–1909, 2000.[Abstract]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/H103    most recent
00779.2006v2
00779.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McNulty, P. H.
Right arrow Articles by Boehmer, J. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McNulty, P. H.
Right arrow Articles by Boehmer, J. P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.