Vascular Effects of Acute Hyperglycemia in Humans Are Reversed by l-Arginine: Evidence for Reduced Availability of Nitric Oxide During Hyperglycemia
Abstract
BACKGROUND: Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical-mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide. METHODS AND RESULTS: Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases (P < .05) starting after 30 minutes of hyperglycemia; leg blood flow decreased significantly (15%; P < .05) at 60 and 90 minutes. Platelet aggregation to ADP and blood viscosity also showed significant increments (P < .05). The infusion of L-arginine (n = 7, 1 g/min) but not D-arginine (n = 5, 1 g/min) or L-lysine (n = 5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of NG-monomethyl-L-arginine (L-NMMA; 2 mg/min) to inhibit endogenous nitric oxide synthesis in 8 normal subjects produced vascular effects qualitatively similar to those of hyperglycemia but quantitatively higher (P < .05); however, heart rate and plasma catecholamine levels decreased during L-NMMA infusion, presumably as a consequence of baroreflex activation. Infusion of L-NMMA during hyperglycemia produced changes not different from those obtained during infusion of L-NMMA alone. CONCLUSIONS: The results show that acute hyperglycemia in normal subjects causes significant hemodynamic and rheological changes that are reversed by L-arginine. Moreover, the effects of hyperglycemia are mimicked to a large extent, but not entirely, by infusion of L-NMMA. This suggests that hyperglycemia may reduce nitric oxide availability in humans.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The postprandial inflammatory response appears to play a more crucial role in insulin resistance, metabolic syndrome, and atherosclerosis than previously thought.
“The pathophysiological significance of a postprandial inflammatory response in causing insulin resistance, the metabolic syndrome and atherosclerosis is currently under investigation, and this response appears to play a much more crucial role than previously thought (162) .”
From Dietary factors and low-grade inflammation in relation to overweight and obesity (2011) · cites this paper as [162]
Cites
(1993) · New England Journal of Medicine · doi:10.1056/nejm199309303291401 · Cited by 24,667 · see citing works
The L-Arginine-Nitric Oxide Pathway
Epstein, F. H., Moncada, S., & Higgs, A. (1993) · New England Journal of Medicine · doi:10.1056/nejm199312303292706 · Cited by 6,678 · see citing works
Vascular endothelial cells synthesize nitric oxide from L-arginine
Palmer, R. M. J., Ashton, D., & Moncada, S. (1988) · Nature · doi:10.1038/333664a0 · Cited by 4,745 · see citing works
Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo
Rees, D. D., Palmer, R. M. J., Schulz, R., Hodson, H. F., & Moncada, S. (1990) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1990.tb14151.x · Cited by 1,856 · see citing works
Role of endothelium-derived nitric oxide in the regulation of blood pressure.
Rees, D. D., Palmer, R. M. J., & Moncada, S. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.9.3375 · Cited by 1,827 · see citing works
An L-arginine/nitric oxide pathway present in human platelets regulates aggregation.
Radomski, M. W., Palmer, R. M., & Moncada, S. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.13.5193 · Cited by 1,208 · see citing works
Bucala, R., Tracey, K. J., & Cerami, A. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115014 · Cited by 1,162 · see citing works
Parati, G., Casadei, R., Groppelli, A., Di Rienzo, M., & Mancia, G. (1989) · Hypertension · doi:10.1161/01.hyp.13.6.647 · Cited by 899 · see citing works
Hyperglycemie and Microvascular and Macrovascular Disease in Diabetes
Klein, R. (1995) · Diabetes Care · doi:10.2337/diacare.18.2.258 · Cited by 849 · see citing works
Acute Hyperglycemia Attenuates Endothelium-Dependent Vasodilation in Humans In Vivo
Williams, S. B., Goldfine, A. B., Timimi, F. K., Ting, H. H., Roddy, M.-A., Simonson, D. C., & Creager, M. A. (1998) · Circulation · doi:10.1161/01.cir.97.17.1695 · Cited by 793 · see citing works
Hemodynamic actions of insulin
Baron, A. (1994) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1994.267.2.e187 · Cited by 608 · see citing works
NIDDM and Its Metabolic Control Predict Coronary Heart Disease in Elderly Subjects
Kuusisto, J., Mykkänen, L. M., Pyörälà, K., & Laakso, M. (1994) · Diabetes · doi:10.2337/diab.43.8.960 · Cited by 588 · see citing works
Free radicals mediate endothelial cell dysfunction caused by elevated glucose
Tesfamariam, B., & Cohen, R. A. (1992) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1992.263.2.h321 · Cited by 558 · see citing works
Diabetes mellitus, hypertension, and cardiovascular disease: Which role for oxidative stress?
Giugliano, D., Ceriello, A., & Paolisso, G. (1995) · Metabolism · doi:10.1016/0026-0495(95)90167-1 · Cited by 369 · see citing works
Self-citationThe Prevalence and Incidence of Lower Extremity Amputation in a Diabetic Population
Moss, S. E. (1992) · Archives of Internal Medicine · doi:10.1001/archinte.1992.00400150120022 · Cited by 313 · see citing works
Singer, D. E., Nathan, D. M., Anderson, K. M., Wilson, P. W. F., & Evans, J. C. (1992) · Diabetes · doi:10.2337/diab.41.2.202 · Cited by 292 · see citing works
The transport of cationic amino acids across the plasma membrane of mammalian cells
White, M. F. (1985) · Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes · doi:10.1016/0304-4157(85)90015-2 · Cited by 289 · see citing works
DISFUNCTION OF VASCULAR ENDOTHELIUM IN DIABETES MELLITUS
Cohen, R. A. (1993) · Cited by 254 · see citing works
Bouloux, P. M., Perrett, D. I., & Besser, G. M. (1985) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456328502200217 · Cited by 155 · see citing works
l -Arginine Increases Exhaled Nitric Oxide in Normal Human Subjects
Kharitonov, S. A., Lübec, G., Lubec, B., et al. (1995) · Clinical Science · doi:10.1042/cs0880135 · Cited by 154 · see citing works
Cytoprotective effects of nitric oxide.
Cooke, J. P., & Tsao, P. S. (1993) · Circulation · doi:10.1161/01.cir.88.5.2451 · Cited by 151 · see citing works
Bode‐Böger, S. M., Böger, R. H., Creutzig, A., Tsikas, D., Gutzki, F. M., Alexander, K. G., & Frölich, J. C. (1994) · Clinical Science · doi:10.1042/cs0870303 · Cited by 148 · see citing works
Role of nitric oxide in neurally induced cerebroarterial relaxation.
Toda, N., & Okamura, T. (1991) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)20239-7 · Cited by 148 · see citing works
Topical hyperglycemia rapidly suppresses EDRF-mediated vasodilation of normal rat arterioles
Bohlen, H. G., & Lash, J. M. (1993) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1993.265.1.h219 · Cited by 145 · see citing works
Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects
Marfella, R., Verrazzo, G., Acampora, R., La Marca, C., Giunta, R., Lucarelli, C., Paolisso, G., Ceriello, A., & Giugliano, D. (1995) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1995.268.6.e1167 · Cited by 129 · see citing works
Self-citationIs nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans?
Hansen, J., Jacobsen, T. N., & Victor, R. G. (1994) · Hypertension · doi:10.1161/01.hyp.24.4.439 · Cited by 109 · see citing works
Vascular Thrombosis in Type II Diabetes Mellitus
Colwell, J. A. (1993) · Diabetes · doi:10.2337/diab.42.1.8 · Cited by 102 · see citing works
Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and non-insulin-dependent diabetics
Paolisso, G., di Maro, G., Pizza, G., D’Amore, A., Sgambato, S., Tesauro, P., Varricchio, M., & D'Onofrio, F. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.263.3.e435 · Cited by 97 · see citing works
Self-citationIn Vivo Spin Trapping of Glyceryl Trinitrate–Derived Nitric Oxide in Rabbit Blood Vessels and Organs
Mülsch, A., Mordvintcev, P. I., Bassenge, E., Jung, F., Clement, B., & Busse, R. (1995) · Circulation · doi:10.1161/01.cir.92.7.1876 · Cited by 76 · see citing works
Greater Effect of Glycemia on Incidence of Hypertension in Women Than in Men
Haffner, S. M., Valdez, R. A., Morales, P. A., Mitchell, B. D., Hazuda, H. P., & D, M. P. S. M. (1992) · Diabetes Care · doi:10.2337/diacare.15.10.1277 · Cited by 66 · see citing works
Smulders, R. A., Stehouwer, C. D. A., Olthof, C. G., van Kamp, G. J., Teerlink, T., VRIES, P. M. J. M. D., & Donker, A. J. M. (1994) · Clinical Science · doi:10.1042/cs0870037 · Cited by 64 · see citing works
Geographical variations in plasma viscosity and relation to coronary event rates
Köenig, W., Sund, M., Lowe, G. D. O., Lee, A. J., Tunstall‐Pedoe, H., Resch, K. L., Keil, U., & Ernst, E. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92207-1 · Cited by 50 · see citing works
Paolisso, G., Giugliano, D., Scheen, A., Franchimont, P., D'Onofrio, F., & Lefébvre, P. (1987) · Acta Endocrinologica · doi:10.1530/acta.0.1150161 · Cited by 45 · see citing works
Self-citationGiugliano, D., Marfella, R., Verrazzo, G., et al. (1995) · Annals of Internal Medicine · doi:10.7326/0003-4819-123-5-199509010-00003 · Cited by 33 · see citing works
Self-citationEFFECT OF GLUCOSE ON PLATELET THROMBOXANE BIOSYNTHESIS
Best, L. C., Jones, P. B. B., & Preston, F. E. (1979) · The Lancet · doi:10.1016/s0140-6736(79)92132-9 · Cited by 17 · see citing works
Stone, B. A., Heap, P. A., & Seamark, R. F. (1987) · Journal of Endocrinology · doi:10.1677/joe.0.1150161 · Cited by 16 · see citing works
Glutamic Acid Decarboxylase Antibodies and Diabetes Complications: Assay reliability and validity
Lernmark, Å. (1995) · Diabetes Care · doi:10.2337/diacare.18.2.269 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ceriello, A., & Motz, E. (2004) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000122852.22604.78 · Cited by 1,378 · see citing works
Ceriello, A., Esposito, K., Piconi, L., Ihnat, M. A., Thorpe, J. E., Testa, R., Boemi, M., & Giugliano, D. (2008) · Diabetes · doi:10.2337/db08-0063 · Cited by 1,310 · see citing works
Self-citationManagement of diabetes and hyperglycemia in hospitals.
Clement, S., Braithwaite, S. S., Magee, M. F., Ahmann, A., Smith, E. P., Schafer, R. G., Hirsch, I. B., & on behalf of the Diabetes in Hospitals Writing Committee (2004) · Diabetes Care · doi:10.2337/diacare.27.2.553 · Cited by 1,266 · see citing works
Dietary factors and low-grade inflammation in relation to overweight and obesity
Calder, P. C., Ahluwalia, N., Brouns, F., Buetler, T., Clement, K., Cunningham, K., Esposito, K., Jönsson, L. S., Kolb, H., Lansink, M., et al. (2011) · British Journal of Nutrition · doi:10.1017/s0007114511005460 · Cited by 1,098 · see citing works
Postprandial Hyperglycemia and Diabetes Complications
Ceriello, A. (2005) · Diabetes · doi:10.2337/diabetes.54.1.1 · Cited by 945 · see citing works
The Effects of Diet on Inflammation
Giugliano, D., Ceriello, A., & Esposito, K. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.03.052 · Cited by 842 · see citing works
Self-citationCeriello, A. (2003) · Diabetes Care · doi:10.2337/diacare.26.5.1589 · Cited by 734 · see citing works
Nappo, F., Esposito, K., Cioffi, M., Giugliano, G., Molinari, A. M., Paolisso, G., Marfella, R., & Giugliano, D. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(02)01741-2 · Cited by 555 · see citing works
Self-citationOxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia
Wright, E., Scism-Bacon, J. L., & Glass, L. C. (2006) · International Journal of Clinical Practice · doi:10.1111/j.1368-5031.2006.00825.x · Cited by 517 · see citing works
Esposito, K., Giugliano, D., Nappo, F., & Marfella, R. (2004) · Circulation · doi:10.1161/01.cir.0000134501.57864.66 · Cited by 440 · see citing works
Self-citationAcute hyperglycemia induces an oxidative stress in healthy subjects
Marfella, R., Quagliaro, L., Nappo, F., Ceriello, A., & Giugliano, D. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13727 · Cited by 242 · see citing works
Self-citationPlasma Glucose Levels Throughout the Day and HbA1c Interrelationships in Type 2 Diabetes
Bonora, E., Calcaterra, F., Lombardi, S., Bonfante, N., Formentini, G., Bonadonna, R. C., & Muggeo, M. (2001) · Diabetes Care · doi:10.2337/diacare.24.12.2023 · Cited by 235 · see citing works
The possible role of postprandial hyperglycaemia in the pathogenesis of diabetic complications
Ceriello, A. (2003) · Diabetologia · doi:10.1007/s00125-002-0931-5 · Cited by 181 · see citing works
Keating, F. K., Sobel, B. E., & Schneider, D. J. (2003) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2003.08.033 · Cited by 156 · see citing works
Postprandial Myocardial Perfusion in Healthy Subjects and in Type 2 Diabetic Patients
Scognamiglio, R., Negut, C., De Kreutzenberg, S. V., Tiengo, A., & Avogaro, A. (2005) · Circulation · doi:10.1161/circulationaha.104.495127 · Cited by 153 · see citing works
Bonora, E., Corrao, G., Bagnardi, V., Ceriello, A., Comaschi, M., Montanari, P., & Meigs, J. B. (2006) · Diabetologia · doi:10.1007/s00125-006-0203-x · Cited by 141 · see citing works
Esposito, K., Nappo, F., Giugliano, F., Giugliano, G., Marfella, R., & Giugliano, D. (2003) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/77.1.139 · Cited by 113 · see citing works
Self-citationKelly, A. S., Bergenstal, R. M., Gonzalez-Campoy, J., Katz, H., & Bank, A. J. (2012) · Cardiovascular Diabetology · doi:10.1186/1475-2840-11-64 · Cited by 98 · see citing works
Coppey, L. J., Gellett, J. S., Davidson, E. P., & Yorek, M. A. (2003) · Free Radical Research · doi:10.1080/1071576021000028442 · Cited by 82 · see citing works
ICU care for patients with diabetes
Umpierrez, G. E., & Kitabchi, A. E. (2004) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000129636.04145.84 · Cited by 35 · see citing works
- Authors
- Giugliano, D., Marfella, R., Coppola, L., Verrazzo, G., Acampora, R., Giunta, R., Nappo, F., Lucarelli, C., & D’Onofrio, F.
- Affiliations
- University of Campania "Luigi Vanvitelli" (IT)
- From the Department of Geriatrics and Metabolic Diseases (D.G., R.M., L.C., G.V., R.A., R.G., F.N., F.D.) and Institute of Pharmacology and Toxicology (C.L.), Second University of Naples, Italy.
- Venue
- Circulation
- Published
- 1997-04
- Volume
- 95
- Issue
- 7
- Pages
- 1783-1790
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1986579939
- Cited by
- 360
- References
- 37
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 11 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 8 · 2014: 14 · 2013: 17 · 2012: 19
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- acute hyperglycemia, L-arginine, nitric oxide bioavailability, vascular tone, blood pressure, leg blood flow, platelet aggregation, blood viscosity, L-NMMA, catecholamines, baroreflex, hemodynamics, rheology, glutathione, free radicals
- MeSH terms
- Acute Disease, Adult, Arginine, Blood Viscosity, Catecholamines, Female, Free Radicals, Glucose, Glutathione, Hemodynamics, Humans, Hyperglycemia, Insulin, Lysine, Male, Nitric Oxide, Platelet Aggregation, Vasoconstriction, omega-N-Methylarginine
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
