(Circulation. 1996;93:1331-1333.)
© 1996 American Heart Association, Inc.
Articles |
Endothelial Nitric Oxide Production and Insulin Sensitivity
A Physiological Link With Implications for Pathogenesis of Cardiovascular Disease
From the Department of Medicine and Therapeutics, University of Glasgow, and the Department of Medicine (D.J.W.), Western General Hospital, University of Edinburgh, United Kingdom.
Correspondence to Dr John R. Petrie, Department of Medicine and Therapeutics, University of Glasgow G11 6NT, United Kingdom. E-mail jrp1s@clinmed.gla.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background Insulin sensitivity varies up to threefold in apparently healthy individuals, but the mechanism for this is unknown. We have examined the hypothesis that vascular endothelial nitric oxide production and insulin sensitivity are directly related in humans.
Methods and Results Nineteen healthy male subjects were studied on 3 separate days 1 week apart during which time they underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (soluble insulin 1.5 mU·kg-1·min-1) and measurement of in vivo basal and stimulated endothelial nitric oxide production by forearm venous occlusion plethysmography. There was a correlation between insulin sensitivity and forearm vasoconstrictor responses to NG-monomethyl-L-arginine, the substrate inhibitor of nitric oxide synthase (r=.52, P<.05). No correlations were observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium nitroprusside responses.
Conclusions Endothelial nitric oxide synthesis and insulin sensitivity are positively related in healthy humans, which suggests a direct physiological link.
Key Words: diabetes mellitus • insulin • hypertension • endothelium-derived factors • blood flow
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The association between hyperinsulinemia and essential hypertension has been recognized for over 30 years.1 The elevation in circulating insulin levels appears to occur as a pancreatic ß-cell compensatory response to decreased sensitivity to insulin-stimulated glucose uptake in peripheral tissues, particularly skeletal muscle,2 but the mechanisms that underlie the development of insulin resistance in hypertension and other common conditions such as obesity and non–insulin-dependent diabetes mellitus remain unknown.
The elucidation of these mechanisms has been complicated by the threefold variation in insulin sensitivity observed within groups of apparently healthy nonobese individuals.3 Insulin is an arterial vasodilator in skeletal-muscle vascular beds, and there is evidence that insulin-mediated vasodilation is reduced in states of insulin resistance.4 It has been suggested recently that the vascular effects of insulin may be dependent on endothelial nitric oxide synthesis/release,5 and decreased basal endothelial nitric oxide synthesis has been reported in essential hypertension.6
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Nineteen healthy, normotensive, male volunteers aged 21 to 35 years with normal glucose tolerance participated in these studies with the approval of the West Ethical Committee of the West Glasgow Hospitals University NHS Trust. No subjects were taking medication, and all subjects abstained from alcohol and tobacco for 24 hours and from food and caffeine-containing drinks overnight before study days. At a screening visit, physical health was confirmed by history and physical examination, supine blood pressure was measured in triplicate (Dinamap Critikon, Johnson and Johnson Professional Products Ltd), and a self-reported index of moderate and vigorous physical activity level was determined.7 Characteristics (mean±SD) of the subjects were body mass index (BMI) 24.6±3.0 kg/m2, fasting glucose level 5.1±0.3 mmol/L, fasting cholesterol level 4.40±0.74 mmol/L, and blood pressure 130±10/69±7 mm Hg. Mean (±SD) age was 27.1±5.3 years; three subjects were smokers; six had a family history of cardiovascular disease or diabetes; and median alcohol consumption was 16 U (interquartile range, 6 to 20 U).
Hyperinsulinemic Euglycemic
Clamp
On the first study day, subjects underwent assessment of
sensitivity to insulin-mediated glucose uptake by use of a 3-hour
primed infusion of 1.5
mU·kg-1·min-1
soluble insulin (Human Actrapid, NovoNordisk A/S) along with a
variable-rate infusion of 20% dextrose (Baxter Healthcare)
adjusted to achieve euglycemia at 5.2 mmol/L on the basis of
arterialized samples withdrawn every 5 minutes from an
ipsilateral right dorsal hand vein (heated-air box at 55°C,
University of Nottingham Department of Physiology and Pharmacology).
Whole-body insulin sensitivity (M) was calculated from the glucose
infusion rate during the final 40 minutes.8
Forearm Venous Occlusion Plethysmography
On 2 additional study days, measurements of basal and stimulated
endothelial nitric oxide production were
obtained from the subjects. Forearm blood flow was measured by use of
venous occlusion plethysmography with mercury-in–silicone
elastomer (Silastic) strain gauges that had been electrically
calibrated (Hokanson set, PMS instruments).9 A 27-gauge
unmounted steel needle (Cooper's Needleworks) was inserted under local
anesthesia into the brachial artery of the nondominant arm
for drug infusion. Temperature was maintained at 24°C to 26°C.
Local incremental doses of drugs (see "Results") were dissolved
in 0.9% saline and infused intra-arterially at a
constant rate of 1 mL/min. A 30-minute washout period was allowed
between drug infusions. On day 1, subjects received acetylcholine
(Miochol, Cibavision), an endothelium-dependent
stimulator of nitric oxide synthase, and sodium nitroprusside (Roche),
an endothelium-independent donor of nitric oxide.
On day 2, subjects received ascending doses of
noradrenaline (Levophed, Sanofi-Winthrop), a control
vasoconstrictor, and
NG-monomethyl-L-arginine
(L-NMMA; Clinalfa AG), a substrate inhibitor of nitric
oxide synthase. Blood flow was measured in both forearms, and each
value was the mean of five sequential measurements. Percent change from
basal values in the ratio of blood flow between infused and noninfused
arms was calculated with blood flow in the noninfused arm as a
concurrent control.9 Because serial measurements were
made, each subject's mean response to all administered doses of each
drug was calculated as a summary measure.10
Statistical Evaluation
Data were initially examined by use of simple regression
(Pearson); a multiple regression analysis was performed to
examine potential confounders (Minitab statistical package, Minitab
Inc).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Insulin sensitivity (M) ranged from 6.2 to 11.6 mg·kg-1·min-1. All 19 subjects completed acetylcholine and sodium nitroprusside infusions; 15 completed noradrenaline and L-NMMA infusions (arterial cannulation could not be repeated in 2 subjects, and 2 withdrew for personal reasons). Grouped (mean±SE) vasodilator responses to ascending doses of acetylcholine (20, 40, 80, and 160 pmol/min) were 131±32%, 224±54%, 329±71%, and 426±61%, respectively; for sodium nitroprusside (3, 10, and 30 pmol/min), these responses were 118±11%, 232±24%, and 527±99%, respectively. Grouped (mean±SE) vasoconstrictor responses to ascending doses (15, 30, 150, and 300 pmol/min) of noradrenaline were 9±1%, 14±2%, 29±4%, and 38±4%, respectively; and for L-NMMA (1, 2, and 4 µmol/min), responses were 13±2%, 22±2%, and 30±3%, respectively. For each individual across all doses, mean vasodilator responses (percent change in forearm blood-flow ratio) ranged from 52% to 669% for acetylcholine and from 102% to 754% for sodium nitroprusside. For each individual, mean vasoconstrictor responses ranged between 8% and 41% for noradrenaline and between 11% and 29% for L-NMMA. Individual measurements of insulin sensitivity (M) were positively related to the mean L-NMMA responses (r=.52, P<.05; Fig). However, no relationships were observed between M values and noradrenaline responses (r=.14, P=NS; Fig), acetylcholine responses (r=.15, P=NS), or sodium nitroprusside responses (r=.31, P=NS). Similar results were obtained when the area under the curve was used as an alternative summary measure of drug response.10 The results of a multiple regression analysis, in which one subject identified by the statistical package as an unusual observation was excluded and which took into account age, BMI, mean arterial pressure, plasma glucose level, serum cholesterol level, alcohol intake, family history, and physical activity level, are shown in the Table
.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Our results in healthy young men demonstrate, for the first time, a positive relationship between basal vascular endothelial nitric oxide production and insulin sensitivity. Under physiological circumstances, insulin causes arterial vasodilation in skeletal-muscle vascular beds. By increasing its own delivery and that of glucose to insulin-sensitive tissues, it may amplify its own action in promoting glucose uptake, and it has been reported previously4 that insulin-mediated vasodilation is impaired in insulin-resistant states. Our data, along with recent evidence that endothelial nitric oxide may mediate the vascular effects of insulin,5 suggest a direct physiological link between vascular endothelial function and insulin sensitivity, ie, individuals who are relatively insensitive to insulin-mediated glucose uptake also appear to have a corresponding decrease in basal endothelial nitric oxide production.
We observed no relationship between noradrenaline responses and insulin sensitivity and suggest that this argues against a nonspecific decrease in vascular reactivity in subjects who are less sensitive to insulin-mediated glucose uptake. Furthermore, the absence of relationships with either the acetylcholine or sodium nitroprusside responses suggests that decreased insulin sensitivity is not associated with a reduced ability of the vascular endothelium to synthesize nitric oxide when stimulated or with a reduction in the sensitivity of vascular smooth muscle to nitric oxide released from the endothelium.
Insulin sensitivity has been shown to be related to age, BMI, and maximal aerobic capacity in normal subjects but may vary up to threefold in subjects who are apparently similar in these respects.3 The present study group was as homogeneous as possible for these variables, with only a twofold variation in insulin sensitivity. The relationship between the L-NMMA response and the measured insulin sensitivity was stronger than the relationships between all of the other variables and insulin sensitivity, accounting for 43% of the variance, and was not explained by a known confounding variable such as obesity. The relationship identified in the present study is compatible with three hypotheses: (1) decreased basal endothelial nitric oxide production results in decreased insulin sensitivity, possibly due to reduced insulin-mediated vasodilation in skeletal muscle; (2) decreased insulin sensitivity results in decreased basal production of nitric oxide by the vascular endothelium; and (3) decreased basal endothelial nitric oxide production and impaired insulin sensitivity are manifestations of a common genetic or environmental antecedent. The present data do not allow us to decide between these possibilities. Further study is required to determine whether a similar relationship is observed between endothelial function and insulin sensitivity in pathophysiological states such as essential hypertension and to determine the mechanistic explanation for the observed relationship.
|
|
Acknowledgments |
|---|
This study was supported by a BHF junior research fellowship awarded to Dr Petrie.
Received December 12, 1995; revision received January 24, 1996; accepted January 29, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Reaven G. Role of insulin in human disease. Diabetes. 1988;37:1595-1607. [Abstract]
2. Ferrannini E, Buzzicoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilqacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-357. [Abstract]
3.
Hollenbeck C, Reaven GM. Variations in
insulin-stimulated glucose uptake in healthy individuals with
normal glucose tolerance. J Clin Endocrinol
Metab. 1987;64:1169-1173.
4. Baron AD. Cardiovascular actions of insulin in humans: implications for insulin sensitivity and vascular tone. Baillieres Clin Endocrinol Metab. 1993;7:961-987. [Medline] [Order article via Infotrieve]
5. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide accounts for insulin's vascular effects in humans. J Clin Invest. 1994;94:2511-2515.
6. Calver A, Collier J, Moncada S, Vallance P. Effect of intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension: the nitric oxide dilator system appears abnormal. J Hypertens. 1992;10:1025-1031. [Medline] [Order article via Infotrieve]
7.
Sallis JF, Haskell WL, Wood PD, Fortmann SP, Rogers T,
Blair S, Paffenbarger RS. Physical activity assessment
methodology in the five-city project. Am J
Epidemiol. 1985;121:91-106.
8.
DeFronzo RA, Tobin J, Andres R. Glucose clamp
technique: a method for quantifying insulin secretion and
resistance. Am J Physiol. 1979;237:E214-E223.
9.
Benjamin N, Calver A, Collier J, Robinson B, Vallance
P, Webb D. Measuring forearm blood-flow and interpreting the
responses to drugs and mediators.
Hypertension. 1995;25:918-923.
10. Matthews JNS, Altman DG, Campbell MJ, Royston P. Analysis of serial measures in medical research. Br Med J. 1990;300:230-235.
This article has been cited by other articles:
 |
|
 |
|
  D. Shi, M. K. Dyck, R. R. E. Uwiera, J. C. Russell, S. D. Proctor, and D. F. Vine A Unique Rodent Model of Cardiometabolic Risk Associated with the Metabolic Syndrome and Polycystic Ovary Syndrome Endocrinology, September 1, 2009; 150(9): 4425 - 4436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steinberger, S. R. Daniels, R. H. Eckel, L. Hayman, R. H. Lustig, B. McCrindle, and M. L. Mietus-Snyder Progress and Challenges in Metabolic Syndrome in Children and Adolescents: A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism Circulation, February 3, 2009; 119(4): 628 - 647. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Blouet, F. Mariotti, V. Mathe, D. Tome, and J.-F. Huneau Nitric Oxide Bioavailability and Not Production Is First Altered During the Onset of Insulin Resistance in Sucrose-Fed Rats Experimental Biology and Medicine, December 1, 2007; 232(11): 1458 - 1464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sierra-Johnson, A. Romero-Corral, V. K. Somers, F. Lopez-Jimenez, G. Walldius, A. Hamsten, M.-L. Hellenius, and R. M. Fisher ApoB/apoA-I ratio: an independent predictor of insulin resistance in US non-diabetic subjects Eur. Heart J., November 1, 2007; 28(21): 2637 - 2643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Tessari, A. Coracina, L. Puricelli, M. Vettore, A. Cosma, R. Millioni, D. Cecchet, A. Avogaro, A. Tiengo, and E. Kiwanuka Acute effect of insulin on nitric oxide synthesis in humans: a precursor-product isotopic study Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E776 - E782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J Hamilton, G. T Chew, and G. F Watts Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 89 - 102. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Melancon, H. Bachelard, M. Badeau, F. Bourgoin, M. Pitre, R. Lariviere, and A. Nadeau Effects of high-sucrose feeding on insulin resistance and hemodynamic responses to insulin in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2571 - H2581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Watanabe, T. Tagawa, K. Yamakawa, M. Shimabukuro, and S. Ueda Inhibition of the Renin-Angiotensin System Prevents Free Fatty Acid-Induced Acute Endothelial Dysfunction in Humans Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2376 - 2380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mather and S. Verma Function determines structure in the vasculature: lessons from insulin resistance Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R305 - R306. [Full Text] [PDF]
|
|
|
|
|
|
A.A. Lteif, K. Han, and K.J. Mather Obesity, Insulin Resistance, and the Metabolic Syndrome: Determinants of Endothelial Dysfunction in Whites and Blacks Circulation, July 5, 2005; 112(1): 32 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Diamanti-Kandarakis, K Alexandraki, A Protogerou, C Piperi, C Papamichael, A Aessopos, J Lekakis, and M Mavrikakis Metformin administration improves endothelial function in women with polycystic ovary syndrome Eur. J. Endocrinol., May 1, 2005; 152(5): 749 - 756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Cariou, J.-C. Fruchart, and B. Staels Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists The British Journal of Diabetes & Vascular Disease, May 1, 2005; 5(3): 126 - 132. [Abstract] [PDF]
|
|
|
|
 |
|
 C. K. Roberts and R. J. Barnard Effects of exercise and diet on chronic disease J Appl Physiol, January 1, 2005; 98(1): 3 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Jadhav, J Petrie, W Ferrell, S Cobbe, and N Sattar Insulin resistance as a contributor to myocardial ischaemia independent of obstructive coronary atheroma: a role for insulin sensitisation? Heart, December 1, 2004; 90(12): 1379 - 1383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nielsen, J. R. Halliwill, M. J. Joyner, and M. D. Jensen Vascular Response to Angiotensin II in Upper Body Obesity Hypertension, October 1, 2004; 44(4): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Prasad and A. A. Quyyumi Renin-Angiotensin System and Angiotensin Receptor Blockers in the Metabolic Syndrome Circulation, September 14, 2004; 110(11): 1507 - 1512. [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Perry, A. Spiers, S. J. Cleland, G. D. O. Lowe, J. R. Petrie, and J. M. C. Connell Glucocorticoids and Insulin Sensitivity: Dissociation of Insulin's Metabolic and Vascular Actions J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6008 - 6014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kawano, H. Yasue, A. Kitagawa, N. Hirai, T. Yoshida, H. Soejima, S. Miyamoto, M. Nakano, and H. Ogawa Dehydroepiandrosterone Supplementation Improves Endothelial Function and Insulin Sensitivity in Men J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3190 - 3195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimabukuro, N. Higa, T. Asahi, Y. Oshiro, N. Takasu, T. Tagawa, S. Ueda, I. Shimomura, T. Funahashi, and Y. Matsuzawa Hypoadiponectinemia Is Closely Linked to Endothelial Dysfunction in Man J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3236 - 3240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. P. Salt, V. A. Morrow, F. M. Brandie, J. M. C. Connell, and J. R. Petrie High Glucose Inhibits Insulin-stimulated Nitric Oxide Production without Reducing Endothelial Nitric-oxide Synthase Ser1177 Phosphorylation in Human Aortic Endothelial Cells J. Biol. Chem., May 23, 2003; 278(21): 18791 - 18797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. N. Kernan, S. E. Inzucchi, C. M. Viscoli, L. M. Brass, D. M. Bravata, G. I. Shulman, J. C. McVeety, and R. I. Horwitz Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke Neurology, May 13, 2003; 60(9): 1447 - 1451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Paradisi, H. O. Steinberg, M. K. Shepard, G. Hook, and A. D. Baron Troglitazone Therapy Improves Endothelial Function to Near Normal Levels in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 576 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. K. Roberts, N. D. Vaziri, and R. J. Barnard Effect of Diet and Exercise Intervention on Blood Pressure, Insulin, Oxidative Stress, and Nitric Oxide Availability Circulation, November 12, 2002; 106(20): 2530 - 2532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. V. van Venrooij, M. A. van de Ree, M. L. Bots, R. P. Stolk, M. V. Huisman, and J. D. Banga Aggressive Lipid Lowering Does Not Improve Endothelial Function in Type 2 Diabetes: The Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial Diabetes Care, July 1, 2002; 25(7): 1211 - 1216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Stuhlinger, F. Abbasi, J. W. Chu, C. Lamendola, T. L. McLaughlin, J. P. Cooke, G. M. Reaven, and P. S. Tsao Relationship Between Insulin Resistance and an Endogenous Nitric Oxide Synthase Inhibitor JAMA, March 20, 2002; 287(11): 1420 - 1426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. G. Kelly, A. Speirs, G. W. Gould, J. R. Petrie, H. Lyall, and J. M. C. Connell Altered Vascular Function in Young Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 742 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I.J.A.M Jonkers, M.A van de Ree, A.H.M Smelt, F.H.A.F de Man, H Jansen, A.E Meinders, A van der Laarse, and G.J Blauw Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia Cardiovasc Res, February 1, 2002; 53(2): 496 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. B. Wilkinson, I. R. Hall, H. MacCallum, I. S. Mackenzie, C. M. McEniery, B. J. van der Arend, Y.-E. Shu, L. S. MacKay, D. J. Webb, and J. R. Cockcroft Pulse-Wave Analysis: Clinical Evaluation of a Noninvasive, Widely Applicable Method for Assessing Endothelial Function Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 147 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.J Irving, B.R Walker, J.P Noon, G.C.M Watt, D.J Webb, and A.C Shore Microvascular correlates of blood pressure, plasma glucose, and insulin resistance in health Cardiovasc Res, January 1, 2002; 53(1): 271 - 276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
A. M Storey, C. J Perry, and J. R Petrie Review: Endothelial dysfunction in type 2 diabetes The British Journal of Diabetes & Vascular Disease, August 1, 2001; 1(1): 22 - 27. [Abstract] [PDF]
|
|
|
|
|
|
P. Piatti, L. D. Monti, G. Valsecchi, F. Magni, E. Setola, F. Marchesi, M. Galli-Kienle, G. Pozza, and K. G. M.M. Alberti Long-Term Oral L-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients Diabetes Care, May 1, 2001; 24(5): 875 - 880. [Abstract] [Full Text]
|
|
|
|
|
|
P. FORTE and N. BENJAMIN Does an impaired flow mediated vasodilatation predict hypertension in offspring hypertensive parents? Heart, February 1, 2001; 85(2): 131 - 132. [Full Text]
|
|
|
|
|
|
F. Perticone, R. Ceravolo, S. Iacopino, C. Cloro, G. Ventura, R. Maio, E. Gulletta, N. Perrotti, and P. L. Mattioli Relationship between Angiotensin-Converting Enzyme Gene Polymorphism and Insulin Resistance in Never-Treated Hypertensive Patients J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 172 - 178. [Abstract] [Full Text]
|
|
|
|
|
|
F. Perticone, R. Ceravolo, M. Candigliota, G. Ventura, S. Iacopino, F. Sinopoli, and P. L. Mattioli Obesity and Body Fat Distribution Induce Endothelial Dysfunction by Oxidative Stress: Protective Effect of Vitamin C Diabetes, January 1, 2001; 50(1): 159 - 165. [Abstract] [Full Text]
|
|
|
|
|
|
K. J. Mather, E. G. Norman, J. C. Prior, and T. G. Elliott Preserved Forearm Endothelial Responses with Acute Exposure to Progesterone: A Randomized Cross-Over Trial of 17-{beta} Estradiol, Progesterone, and 17-{beta} Estradiol with Progesterone in Healthy Menopausal Women J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4644 - 4649. [Abstract] [Full Text]
|
|
|
|
|
|
A. Natali, A. M. Sironi, E. Toschi, S. Camastra, G. Sanna, A. Perissinotto, S. Taddei, and E. Ferrannini Effect of Vitamin C on Forearm Blood Flow and Glucose Metabolism in Essential Hypertension Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2401 - 2406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hirai, H. Kawano, O. Hirashima, T. Motoyama, Y. Moriyama, T. Sakamoto, K. Kugiyama, H. Ogawa, K. Nakao, and H. Yasue Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1172 - H1178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.W. Laight, M.J. Carrier, and E.E. Anggard Antioxidants, diabetes and endothelial dysfunction Cardiovasc Res, August 18, 2000; 47(3): 457 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tomiyama, Y. Kimura, R. Okazaki, T. Kushiro, M. Abe, Y. Kuwabara, H. Yoshida, S. Kuwata, T. Kinouchi, and N. Doba Close Relationship of Abnormal Glucose Tolerance With Endothelial Dysfunction in Hypertension Hypertension, August 1, 2000; 36(2): 245 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. PIATTI, L. D. MONTI, I. ZAVARONI, G. VALSECCHI, C. VAN PHAN, S. COSTA, M. CONTI, E. P. SANDOLI, B. SOLERTE, G. POZZA, et al. Alterations in Nitric Oxide/Cyclic-GMP Pathway in Nondiabetic Siblings of Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2416 - 2420. [Abstract] [Full Text]
|
|
|
|
|
|
H. O. Steinberg, G. Paradisi, J. Cronin, K. Crowde, A. Hempfling, G. Hook, and A. D. Baron Type II Diabetes Abrogates Sex Differences in Endothelial Function in Premenopausal Women Circulation, May 2, 2000; 101(17): 2040 - 2046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Mather, S. Verma, B. Corenblum, and T. J. Anderson Normal Endothelial Function Despite Insulin Resistance in Healthy Women with the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1851 - 1856. [Abstract] [Full Text]
|
|
|
|
|
|
M. Evans, R. A. Anderson, J. Graham, G. R. Ellis, K. Morris, S. Davies, S. K. Jackson, M. J. Lewis, M. P. Frenneaux, and A. Rees Ciprofibrate Therapy Improves Endothelial Function and Reduces Postprandial Lipemia and Oxidative Stress in Type 2 Diabetes Mellitus Circulation, April 18, 2000; 101(15): 1773 - 1779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Balletshofer, K. Rittig, M. D. Enderle, A. Volk, E. Maerker, S. Jacob, S. Matthaei, K. Rett, and H. U. Haring Endothelial Dysfunction Is Detectable in Young Normotensive First-Degree Relatives of Subjects With Type 2 Diabetes in Association With Insulin Resistance Circulation, April 18, 2000; 101(15): 1780 - 1784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Cleland, J. R. Petrie, M. Small, H. L. Elliott, and J. M. C. Connell Insulin Action Is Associated With Endothelial Function in Hypertension and Type 2 Diabetes Hypertension, January 1, 2000; 35(1): 507 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sartori, L. Trueb, P. Nicod, and U. Scherrer Effects of Sympathectomy and Nitric Oxide Synthase Inhibition on Vascular Actions of Insulin in Humans Hypertension, October 1, 1999; 34(4): 586 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-L. Liao, K. Saku, J. Ou, S. Jimi, B. Zhang, K. Shirai, and K. Arakawa A Missense Mutation of the Nitric Oxide Synthase (eNOS) Gene (Glu298Asp) in Five Patients with Coronary Artery Disease: Case Reports Angiology, August 1, 1999; 50(8): 671 - 676. [Abstract] [PDF]
|
|
|
|
|
|
B. H. Sung, J. L. Izzo Jr, P. Dandona, and M. F. Wilson Vasodilatory Effects of Troglitazone Improve Blood Pressure at Rest and During Mental Stress in Type 2 Diabetes Mellitus Hypertension, July 1, 1999; 34(1): 83 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T Gerber, K. Holemans, I. O'Brien-Coker, A. I Mallet, R. van Bree, F A. Van Assche, and L. Poston Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat J. Physiol., June 1, 1999; 517(2): 607 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. H. Serne, C. D. A. Stehouwer, J. C. ter Maaten, P. M. ter Wee, J. A. Rauwerda, A. J. M. Donker, and R. O. B. Gans Microvascular Function Relates to Insulin Sensitivity and Blood Pressure in Normal Subjects Circulation, February 23, 1999; 99(7): 896 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Cleland, J. R. Petrie, S. Ueda, H. L. Elliott, and J. M. C. Connell Insulin-Mediated Vasodilation and Glucose Uptake Are Functionally Linked in Humans Hypertension, January 1, 1999; 33(1): 554 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. V. G. Katakam, M. R. Ujhelyi, M. E. Hoenig, and A. W. Miller Endothelial dysfunction precedes hypertension in diet-induced insulin resistance Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1998; 275(3): R788 - R792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nitenberg, F. Paycha, S. Ledoux, R. Sachs, J.-R. Attali, and P. Valensi Coronary Artery Responses to Physiological Stimuli Are Improved by Deferoxamine but not by L-Arginine in Non–Insulin-Dependent Diabetic Patients With Angiographically Normal Coronary Arteries and No Other Risk Factors Circulation, March 3, 1998; 97(8): 736 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Natali, A. Q. Galvan, N. Pecori, G. Sanna, E. Toschi, and E. Ferrannini Vasodilation With Sodium Nitroprusside Does Not Improve Insulin Action in Essential Hypertension Hypertension, February 1, 1998; 31(2): 632 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. O. Steinberg, B. Bayazeed, G. Hook, A. Johnson, J. Cronin, and A. D. Baron Endothelial Dysfunction Is Associated With Cholesterol Levels in the High Normal Range in Humans Circulation, November 18, 1997; 96(10): 3287 - 3293. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Higashi, T. Oshima, N. Sasaki, N. Ishioka, Y. Nakano, R. Ozono, M. Yoshimura, K. Ishibashi, H. Matsuura, and G. Kajiyama Relationship Between Insulin Resistance and Endothelium-Dependent Vascular Relaxation in Patients With Essential Hypertension Hypertension, January 1, 1997; 29(1): 280 - 285. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||