[Show abstract][Hide abstract] ABSTRACT: Isoprostanes (IPs) are a recently discovered complex group of stable prostaglandin-like molecules formed by the free radical-catalyzed
peroxidation of polyunsaturated fatty acids (1). F2-isoprostanes (F2-IPs) are formed by the oxidation of arachidonic acid and can be classified into four major regioisomeric groups, and characterized
by a cis-oriented side chain (2). Because the majority of arachidonic acid is currently esterified in phospholipids, F2-IPs are initially formed esterified and are subsequently released in the free form following cleavage by phospholipase A2 (3). The presence of F2-IPs in vivo was initially reported by Morrow et al. (1). The levels of one of the abundant isomers, 8-epi-PGF2α, was shown to increase by up to 200-fold in established animal models of oxidative injury (4). High levels of F2-IPs can disrupt the physicochemical integrity of cell membranes (3), but more importantly can exert significant pharmacological activity. 8-epi-PGF2α is a potent vasoconstrictor acting on the renal, pulmonary, and retinal vasculatures (1,5,6), modulates platelet aggregation (7), and is involved in the activation of intracellular signaling (8). Isoprostanes can also be formed enzymatically by the cyclooxygenase pathway in platelets, monocytes and vascular smooth
[Show abstract][Hide abstract] ABSTRACT: Nitrovasodilators produce characteristic changes in the shape of the peripheral pulse wave. Similar changes might also be caused by alteration of endogenous NO activity, which would allow such activity to be assessed in vivo.
We investigated whether manipulation of the NO pathway influences the pulse waveform, and the mechanisms involved. The pulse wave in the ear of normal rabbits was examined by reflectance photoplethysmography before and during infusion of vasoactive agents. Pulse wave velocity was assessed by using an additional sensor on the rear foot.
A diastolic peak was observed in the ear pulse; its timing was consistent with it being a reflection of the systolic peak from the lower body. The height of the dicrotic notch marking the start of this diastolic wave was decreased by acetylcholine or an NO donor, and further decreased by a phosphodiesterase type V inhibitor. The acetylcholine-induced decreases were blocked by inhibiting NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) but were unaffected by the inactive enantiomer D-NAME.
These data demonstrate that NO influences the height of the notch in the pulse wave. Heart rate and blood pressure were altered during acetylcholine or L-NAME infusion, but there were no changes in pulse wave amplitude or velocity, or in the timing of the diastolic peak or dicrotic notch. The slope of the pulse wave between the systolic peak and notch changed substantially. These effects are most convincingly explained by changes in wave reflection, not only from the lower body but also from more proximal sites.
British Journal of Pharmacology (2001) 133, 361–370; doi:10.1038/sj.bjp.0704084
British Journal of Pharmacology 07/2001; 133(3):361-70. DOI:10.1038/sj.bjp.0704084 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus.
Plasma total 8-epi-PGF2alpha, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography.
Plasma 8-epi-PGF2alpha increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF2alpha (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF2alpha was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001).
Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Oxidised LDL (oxLDL) is a key pathogenic mediator of atherogenesis, exhibiting many proatherogenic properties. We have examined the effect of oxLDL on monocyte adhesion in the endothelial cell line, EA.hy 926. This has included the role of endothelial cell adhesion molecule expression (ICAM-1 and VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and the transcription factor NFkappaB in this interaction. In response to oxLDL (10-100 microg/ml), monocyte adhesion to cells increased dose-dependently. Adhesion of oxLDL at 100 microg/ml was equivalent to that seen with TNFalpha (10 ng/ml). Unmodified LDL (nLDL, 100 microg/ml) had no effect. Both oxLDL and nLDL increased MCP-1 mRNA levels. Interestingly, oxLDL had no effect on the expression of ICAM-1 and VCAM-1. In addition NFkappaB was not activated as shown by western blots of IkappaB-alpha degradation and electrophoretic mobility shift assay. In summary these data show that increased monocyte adhesion to EA.hy 926 cells occurs independently of ICAM-1, VCAM-1, and NFkappaB activation and may involve novel adhesive mechanisms.
Biochemical and Biophysical Research Communications 07/2001; 284(1):239-44. DOI:10.1006/bbrc.2001.4955 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Because oxidative stress has been suggested to be a significant contributing factor in the development of endothelial dysfunction and insulin resistance, we investigated whether reactive oxygen species contribute to insulin resistance by impairing insulin uptake through an effect on endothelial insulin receptor function.
Following a 2-h pro-oxidant challenge with xanthine oxidase, we examined the temporal pattern of insulin processing in the human umbilical endothelial cell line Ea.Hy926 and bovine aortic endothelial cells equilibrated with [125I]-insulin. Insulin receptor mRNA concentrations were analysed by RT-PCR and insulin receptor tyrosine phosphorylation and protein concentrations were estimated by western blotting.
Xanthine oxidase exposure resulted in a major reduction in total insulin receptor-mediated [125I]-insulin internalization over a 1-h period in both Ea.Hy926 and bovine aortic endothelial cells. After 15 min, untreated bovine aortic endothelial cells internalized fivefold more cell-bound [125I]-insulin than pro-oxidant treated cells. The [125I]-insulin disappeared from the cell surface at a similar rate in both pro-oxidant and untreated cells, with relatively more [125I]-insulin being released into the medium in pro-oxidant treated cells. Although xanthine oxidase reduced insulin receptor mRNA and protein concentrations, cell surface insulin binding capacity was not affected. Following 5 min insulin exposure, insulin receptor auto-phosphorylation was considerably reduced in cells challenged with xanthine oxidase for 2 h, which could be important for insulin receptor activation and internalization.
Oxidative stress impairs insulin endocytosis in both arterial and venous endothelial cell lines. This was not a consequence of modified insulin binding capacity but could involve insufficient insulin receptor activation.
[Show abstract][Hide abstract] ABSTRACT: (a) We studied basal endothelial function in the insulin-resistant, obese Zucker rat, including the influence of superoxide anion on the regulation of contractile reactivity by nitric oxide (NO), following treatment in vivo with the antioxidant tiron or the pro-oxidant combination hydroquinone+buthionine sulfoximine. (b) The leftward shift in the contractile potency of phenylephrine due to NO synthase inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) was greater in the isolated aorta of the obese Zucker rat relative to its insulin-sensitive littermate, the lean Zucker rat. (c) Pretreatment with tiron depressed vasoconstriction to phenylephrine and comparably enhanced the L-NAME-mediated leftward shift in contractile reactivity in the obese and lean Zucker rats in hydroquinone+buthionine sulfoximine-sensitive manner. (d) Our data therefore indicate superior endothelial function in the obese relative to the lean Zucker rat, reflected by a greater regulation of vasoconstrictor reactivity by basal NO, while the regulation of NO bioavailability by superoxide anion is similar.
General Pharmacology 01/2001; 35(6):303-9. DOI:10.1016/S0306-3623(01)00120-3
[Show abstract][Hide abstract] ABSTRACT: While a damaged endothelium is recognised to be a key accessory to diabetic macroangiopathy, awareness is developing that impairments concerning endothelium- and nitric oxide (NO)-dependent microvascular function, may contribute to several other corollaries of diabetes, such as hypertension, dyslipidaemia and in vivo insulin resistance. There are now several reports describing elevations in specific oxidant stress markers in both insulin resistance syndrome (IRS) and diabetes, together with determinations of reduced total antioxidant defence and depletions in individual antioxidants. Such a pro-oxidant environment in diabetes may disrupt endothelial function through the inactivation of NO, resulting in the attenuation of a fundamental anti-atherogenic and euglycaemic vascular influence. Indeed, experimental and clinical data suggest that the supplementation of insulin resistant or diabetic states with antioxidants such as vitamin E, normalises oxidant stress and improves both endothelium-dependent vasodilation and insulin sensitivity. However, the promising potential efficacy of antioxidant therapy in cardiovascular disease and diabetes, in either a primary or secondary preventative role, awaits definitive clinical demonstration.
Cardiovascular Research 09/2000; 47(3):457-64. DOI:10.1016/S0008-6363(00)00054-7 · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: F2-isoprostanes (F2-IPs) are formed by the free radicalcatalysed oxidation of arachidonic acid. The measurement of F2-IPs, especially 8-epi- PGF(2α), is recognised as a reliable marker of lipid peroxidation and is currently used as a sensitive index of oxidative stress in vivo. The majority of 8-epi-PGF(2α) present in the circulation occurs in association with lipoproteins which are synthesised in the liver. Since lipoproteins are derived from dietary fatty acids and triglycerides, it is possible that 8- epiPGF(2α) generated in polyunsaturated fatty acid-rich food (during initial processing/packaging or during meal preparation) may become incorporated within these lipoproteins during synthesis. In view of the growing use of 8- epi-PGF(2α) as a marker of lipid peroxidation in vivo in nutritional or clinical studies, it is therefore important to investigate the possibility that the circulating levels measured could be confounded by the presence of 8-epi-PGF(2α) in food. In this study we evaluated the levels of 8-epi- PGF(2α) present in several popular fastfoods, using a combination of solid phase extraction and gas chromatography-mass spectrometry. Fastfoods were selected to represent meals prepared from vegetable-, chicken-, fish- and meat-derived ingredients. Total (free + esterified) 8-epi-PGF(2α) levels ranged from 0.09 to 0.73 pmol/g (122-644 pmol/mmol arachidonic acid), with the highest levels present in beef-derived meals. Further investigation of hamburgers and cheeseburgers revealed 8-epi-PGF(2α) levels of 1.83 ± 0.24 and 0.84 ± 0.03 nmol/mmol arachidonic acid, respectively. Lower concentrations of vitamin E were found in the hamburgers. The postprandial contribution to plasma 8-epi-PGF(2α) levels following ingestion of 100g portions of these fast-foods would therefore be expected to be no greater than the low picomole range, and would be unlikely to influence the normal endogenous levels of 8-epi-PGF(2α) and those produced during oxidative stress.
Free Radical Research 09/2000; 33(2):115-27. DOI:10.1080/10715760000300671 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have recently made the novel observation that a pro-oxidant challenge with hydroquinone in combination with buthionine sulfoximine (each at 50 mg/kg i.p. daily for 7 days) provokes the onset of type II diabetes mellitus in a model of insulin resistance, the obese Zucker rat. Since endothelial dysfunction in oxidant stress may aggravate in vivo insulin resistance, we have now investigated endothelium-dependent and nitric oxide (NO)-mediated vascular responses in the obese Zucker rat in vivo following this pro-oxidant insult. Pro-oxidant-treated animals exhibited defective vasodepression to the endothelium-dependent agent acetylcholine and to a lesser extent, the NO donor glyceryl trinitrate, together with a reduction in circulating levels of cGMP. Our data therefore suggest that the progression to type II diabetes mellitus in the obese Zucker rat mediated by a pro-oxidant insult is associated with impairments in agonist-stimulated, endothelium-dependent vasodilation and vascular NO signalling.
European Journal of Pharmacology 09/2000; 402(1-2):95-9. DOI:10.1016/S0014-2999(00)00451-9 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether raxofelast, a new water soluble antioxidant decreases oxidative stress and improves endothelial function in men with Type II (non-insulin dependent) diabetes mellitus.
We treated ten normotensive, normocholesterolaemic men with Type II diabetes and as controls ten healthy men matched with them for age with raxofelast (600 mg twice daily) for 1 week. Plasma 8-epi-PGF(2a), a non-enzymic oxidation product of arachidonic acid was measured by gas chromatography/mass spectrometry as an index of oxidative stress. Forearm vasodilator responses to brachial artery infusion of acetylcholine (7.5, 15 and 30 microg min(-1)) and of the nitric oxide donor nitroprusside (1, 3 and 10 microg min(-1)) were measured by strain gauge plethysmography.
Plasma concentrations of 8-epi-PGF(2a), were greater in diabetic than in control men (0.99 +/- 0.20 vs 0.18 +/- 0.01 nmol 1(-1), means +/- SEM, p < 0.001) and fell after raxofelast (from 0.99 +/- 0.20 to 0.47 +/- 0.07 nmol 1(-1), p < 0.05) in diabetic men but not in control men. Blood flow responses to acetylcholine were lower (p < 0.05) in diabetic than in control men (7.4 +/- 1.0 vs 12.9 +/- 2.3 ml min(-1) x 100 ml(-1) for the highest dose). In diabetic men, but not in control men, raxofelast increased (p < 0.05) blood flow responses to acetylcholine (from 7.4 +/- 1.0 m x min(-1) x 100 ml(-1) to 11.3 +/- 2.3 ml x min(-1) x 100 ml(-1) at highest dose). Blood flow responses to nitroprusside were similar in control and diabetic men and in both groups were similar before and after raxofelast.
Oral treatment with raxofelast for 1 week reduces oxidative stress and improves endothelial function in men with Type II diabetes.
[Show abstract][Hide abstract] ABSTRACT: The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration of L-[15N]2-arginine. The urinary excretion of the major urinary metabolite of 15-F2t-isoprostane (8-iso-prostaglandin-F2alpha), 2,3-dinor-5,6-dihydro-F2t-IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F2t-IsoP excretion between diabetic subjects and control subjects (44.8+/-7.8 vs. 41.4+/-10.0 ng/mmol creatinine, mean +/- 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species.
[Show abstract][Hide abstract] ABSTRACT: Measurement of the F(2)-isoprostane, 8-epi-PGF(2alpha) is increasingly used as a sensitive and reliable marker of lipid peroxidation in vivo. Because the majority of 8-epi-PGF(2alpha) in plasma is associated with lipoproteins, it is possible that 8-epi-PGF(2alpha) derived from polyunsaturated fatty acid-rich food may become incorporated within these lipoproteins during synthesis and could contribute to the levels detected in plasma. In this study, we evaluated the postprandial effect of a single fast-food meal (McDonald's Big Mac meal, McDonald's Corp., London, England) on plasma total 8-epi-PGF(2alpha) in nine healthy subjects. Blood was collected before and 2 h postprandially. 8-Epi-PGF(2alpha) was measured by immunoaffinity extraction and gas chromatography-mass spectrometry. Fasting plasma 8-epi-PGF(2alpha) (875 +/- 25 pM) increased postprandially (956 +/- 23 pM, p <.05), although no significant change was observed in the normalized concentrations (2. 78 +/- 0.1 vs. 2.95 +/- 0.3 nmol/mmol arachidonic acid). Plasma lipid hydroperoxides, fatty acids, vitamin E, total antioxidant status, cholesterol, and triglycerides were not altered. Plasma glucose increased postmeal (4.4 +/- 0.1 vs. 4.9 +/- 0.1 mM, p <.05). These results indicate that the overall contribution of this lipid-rich meal to plasma 8-epi-PGF(2alpha) and other lipid peroxidation markers was small.
Free Radical Biology and Medicine 03/2000; 28(5):806-14. DOI:10.1016/S0891-5849(00)00167-2 · 5.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to determine whether a simple index of pressure wave reflection may be derived from the digital volume pulse (DVP) and used to examine endothelium-dependent vasodilation in patients with type II diabetes mellitus.
The DVP exhibits a characteristic notch or inflection point that can be expressed as percent maximal DVP amplitude (IP(DVP)). Nitrates lower IP(DVP), possibly by reducing pressure wave reflection. Response of IP(DVP) to endothelium-dependent vasodilators may provide a measure of endothelial function.
The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl trinitrate (GTN) were administered locally by brachial artery infusion or systemically. Aortic pulse wave transit time from the root of the subclavian artery to aortic bifurcation (T(Ao)) was measured by simultaneous Doppler velocimetry.
Brachial artery infusion of drugs producing a greater than threefold increase in forearm blood flow within the infused limb was without effect on IP(DVP), whereas systemic administration of albuterol and GTN produced dose-dependent reductions in IP(DVP). The time between the first and second peak of the DVP correlated with T(Ao) (r = 0.75, n = 20, p < 0.0001). The effects of albuterol but not GTN on IP(DVP) were attenuated by N(G)-monomethyl-L-arginine. The IP(DVP) response to albuterol (400 microg by inhalation) was blunted in patients with type II diabetes mellitus as compared with control subjects (fall 5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 microg sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88).
The IP(DVP) is influenced by pressure wave reflection. The effects of albuterol on IP(DVP) are mediated in part through the nitric oxide pathway and are impaired in patients with type II diabetes.
Journal of the American College of Cardiology 01/2000; 34(7):2007-14. · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The obese Zucker rat, a popular model of insulin resistance allied with oxidant stress, is associated with either normal or paradoxically enhanced endothelial vasodilator function compared with its lean litter mate. We have investigated hindquarter endothelium-dependent vasodilation in the obese Zucker rat in-situ and have examined its relationship with oxidant stress. In perfused hindquarter preparations equivalently preconstricted with phenylephrine, vasodilator responses to the endothelium-dependent agent acetylcholine (0.03-1000 pmol) were greater in obese (pD2 = 11.03+/-0.19) compared with lean (pD2 = 10.53+/-0.13) animals (P < 0.01, two-way analysis of variance). In contrast, maximal vasodilation to the nitric oxide (NO) donor sodium nitroprusside (100 nmol) was similar in obese (59.6+/-19.8%) and lean (51.9+/-2.6%) preparations (P > 0.05). However, this exaggerated vasodilator reactivity to acetylcholine in obese animals was abolished following four-week dietary supplementation with the lipophilic antioxidant vitamin E (obese pD2 = 10.74+/-0.18; lean pD2 = 10.74+/-0.08). This antioxidant-mediated effect was associated with a reduction (P < 0.02, two-way analysis of variance) and an enhancement (P < 0.01, two-way analysis of variance) in endothelium-dependent vasodilator responses in obese and lean hindlimb preparations, respectively. Our data therefore now point to a differential modulation of hindquarter endothelium-dependent vasodilation in the obese and lean Zucker rat by the prevailing oxidant tone, resulting in an agonist-stimulated endothelial vasodilator hyperreactivity in obese animals.
Journal of Pharmacy and Pharmacology 01/2000; 52(1):83-6. DOI:10.1211/0022357001773544 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have characterized the in-vitro modulation of both nitric oxide (NO)-dependent vasodilator activity and anti-platelet function by the novel type-V phosphodiesterase inhibitor, ONO-1505 (4-[2-(2-hydroxyethoxy)ethylamino]-2-(1H-imidazol-1-yl)-6-methoxyquin azoline methanesulphonate). ONO-1505 elicited vasorelaxation in the rat isolated aorta. If the concentration of ONO-1505 was < or = 10 microM the vasorelaxation was abolished by N(G)-nitro-L-arginine methyl ester (L-NAME), by methylene blue, and by endothelial denudation. Furthermore, pretreatment of the rat isolated aorta for 10 min with ONO-1505 in the presence of L-NAME potentiated vasorelaxation to the NO-donor, sodium nitroprusside. Similarly, ONO-1505, although having no effect on adenosine diphosphate (ADP)-induced rat platelet aggregation in-vitro, augmented established anti-aggregatory effects of sodium nitroprusside. The data therefore show that the novel phosphodiesterase V inhibitor ONO-1505 augments endogenous and exogenous nitrovasodilator activity in-vitro; they also imply modulation of the NO pathway in the haemodynamic actions of this compound, previously reported in-vivo.
Journal of Pharmacy and Pharmacology 01/2000; 51(12):1429-33. DOI:10.1211/0022357991777074 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the ability of an acute pro-oxidant challenge in vivo to deteriorate glycaemic control and insulin action in the obese Zucker rat, a model of insulin resistance associated with oxidant stress. In obese animals, the daily administration for 1 week of hydroquinone (HQ) in combination with L-buthionine sulphoximine (BSO), elevated fasting plasma glycaemia and insulinaemia and markedly aggravated i.v. glucose-stimulated hyperinsulinaemia without significantly affecting i.v. glucose tolerance, suggesting exacerbated insulin resistance. Intermediate effects on hyperinsulinaemia in obese animals were determined with HQ treatment alone while BSO treatment alone had no effect. In contrast, none of the pro-oxidant treatments affected age-matched, insulin sensitive, lean Zucker rats. Our data therefore demonstrate for the first time, a vulnerability to deterioration in insulin action in an established insulin resistant state following an environmental pro-oxidative insult. This may have relevance in the conversion of insulin resistance syndrome (IRS) to non-insulin dependent diabetes mellitus (NIDDM).
British Journal of Pharmacology (1999) 128, 269–271; doi:10.1038/sj.bjp.0702801
British Journal of Pharmacology 10/1999; 128(2):269-71. DOI:10.1038/sj.bjp.0702801 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have concurrently investigated oxidant stress, glucose tolerance and glucose-stimulated insulin responses in the obese Zucker rat, a widely used model of insulin resistance. The plasma level of the lipid peroxidation product 8-epi-prostaglandin F2alpha, a sensitive in vivo marker of oxidant stress, was elevated approximately 5-fold in 13-week old obese relative to age-matched, insulin-sensitive lean Zucker rats. Supplementation of the diet with vitamin E (as (+)-alpha-tocopherol acetate, 0.5% w/w) for 4 weeks, reduced plasma 8-epi-prostaglandin F2alpha and concomitantly reversed glucose-stimulated hyperinsulinaemia in the obese Zucker rat without worsening glucose tolerance. We therefore provide evidence of oxidant stress, measured as elevated plasma 8-epi-prostaglandin F2alpha, for the first time in the obese Zucker rat which now provides a rationale for the beneficial effects of antioxidants on insulin action previously reported in this model of insulin resistance.
European Journal of Pharmacology 08/1999; 377(1):89-92. DOI:10.1016/S0014-2999(99)00407-0 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes mellitus (DM) represents a high risk condition for the development of atherosclerotic and thromboembolic macroangiopathy, which make major contributions to diabetic mortality and morbidity. While many cardiovascular risk factors are common to both atherosclerosis and Type 2 DM, the enhanced risk of diabetic macroangiopathy may be attributable to additional pro-atherogenic mediators associated with insulin resistance syndrome. Given the central pathogenic role of endotheliopathy in atherosclerosis, it is likely that this vascular monolayer is the ultimate target of injury in response to such mediators. Furthermore, a pro-oxidative, dysfunctional endothelium may actively contribute to the pro-atherogenic environment through an inappropriate regulation of vascular tone, permeability, coagulation, fibrinolysis, cell adhesion and proliferation. Such dysfunction may mediate hypertension, dyslipidaemia and altered haemostasis, in addition to aggravating in vivo insulin resistance.
Diabetes/Metabolism Research and Reviews 07/1999; 15(4):274-82. DOI:10.1002/(SICI)1520-7560(199907/08)15:43.3.CO;2-7 · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have developed a photometric microassay for the assessment of total antioxidant status in plasma at physiological pH and temperature and applied it to evaluate experimental oxidant stress in vivo associated with endothelial dysfunction in vitro. Rat plasma or l-ascorbic acid inhibited the peroxidase-mediated accumulation after 6 min at pH 7.4 and 37°C of ABTS(+) (2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radical), measured at 405 nm, in a concentration-dependent manner. Plasma total antioxidant status, expressed as the ascorbate equivalent antioxidant concentration, was subsequently found to be significantly reduced in rats treated daily for 7 days in vivo with the oxidant compounds hydroquinone (50 mg/kg i.p.) and triethylenetetramine (100 mg/kg i.p.), either alone or in combination with the glutathione-depleting agent l-buthionine sulfoximine (50 mg/kg i.p). Furthermore, basal endothelial function in isolated aorta was impaired after hydroquinone or triethylenetetramine in a manner aggravated by l-buthionine sulfoximine.