Impaired Insulin-Induced Attenuation of Noradrenaline-Mediated Vasoconstriction in Insulin-Resistant Obese Zucker Rats

Walker, Adrian B; Dores, Jorge; Buckingham, Robin E.; Savage, Matthew W.; Williams, Gareth

doi:10.1042/cs0930235

Cited by 47 publications

(50 citation statements)

References 36 publications

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“…31 In support of this hypothesis, several studies have suggested that insulin resistance and hyperinsulinemia play a pathogenic role in the development of high blood pressure hypertension. 32 This suggestion is supported by the observation that drugs that specifically counter insulin resistance (and attenuate hyperinsulinemia) also exhibit antihypertensive effects.…”

Section: Midaoui and De Champlainmentioning

confidence: 89%

Prevention of Hypertension, Insulin Resistance, and Oxidative Stress by α-Lipoic Acid

2002

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Abstract-The aim of the present study was to investigate whether a dietary supplementation of ␣-lipoic acid could prevent blood pressure elevation, insulin resistance, and the increase in aorta superoxide anion production in a new experimental model of hypertension associated with insulin resistance. Sprague-Dawley rats were given 10% D-glucose in their drinking water combined either with a normal chow diet or with an ␣-lipoic acid-supplemented diet and were compared with control rats during 3 weeks. Oxidative stress was evaluated by measuring the aortic superoxide anion production using the lucigenin chemiluminescence method. Increases in blood pressure, insulin resistance, and aorta superoxide production observed in glucose-fed rats were prevented by the supplementation of the diet with lipoic acid. Positive correlations were found between aortic superoxide production and blood pressure, between insulin resistance and blood pressure, or between superoxide production and insulin resistance. Moreover, a decrease in the activity of plasma glutathione peroxidase observed in the glucose-fed rats was prevented by lipoic acid treatment. These findings demonstrate that high-glucose feeding rapidly induced hypertension and insulin resistance in association with the induction of a vascular oxidative stress. The antihypertensive action and the prevention of insulin resistance by lipoic acid appears to be associated to its antioxidative properties because it prevented the increase in oxidative stress, as reflected by the normalization of superoxide anion production in aorta and the prevention of the fall in the activity of glutathione peroxidase in the glucose-fed rats. (Hypertension. 2002;39:303-307.)

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Section: Midaoui and De Champlainmentioning

confidence: 89%

Prevention of Hypertension, Insulin Resistance, and Oxidative Stress by α-Lipoic Acid

2002

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“…Endothelium-dependent vasorelaxation has been reported to be impaired in several models of obesity, including Zucker obese rats 31,32 and in vessels from rats with diet-induced obesity. 13,29 Interestingly, Auguet et al 33 found that the contractile response to PE of isolated aortic segments of Zucker obese rats was reduced only when the endothelium was denuded, and that this effect was no longer persistent in the intact vessel.…”

Section: Discussionmentioning

confidence: 99%

Enhanced vascular contractility and diminished coronary artery flow in rats made hypertensive from diet-induced obesity

et al. 2006

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Objective: To determine whether obesity-induced hypertension was associated with alterations in vascular contractility and/or cardiac function. Design: Male Sprague-Dawley rats were fed either a low fat (LF; 11% kcal as fat) or a moderately high fat (MHF; 32% kcal as fat) diet for 11 weeks. Measurements: Body weight; mean arterial pressure; angiotensin peptides; mesenteric contractile response to phenylephrine (PE), potassium chloride (KCl), serotonin, angiotensin II (AngII), calcium chloride; baseline and isoproterenol-induced cardiac contractility; baseline and isoproterenol-induced coronary artery blood flow. Results: Rats fed the MHF diet segregated into obesity-prone (OP) and obesity-resistant (OR) groups. OP rats exhibited elevations in mean arterial pressure (MAP) and elevations in systemic concentrations of angiotensin peptides. Mesenteric arteries from OP rats exhibited a greater contractile response to PE, KCl and serotonin (5-HT). Heightened responses to PE persisted in arteries from OP rats even after normalization of the response to KCl. In contrast, the response of permeabilized mesenteric arteries to a maximal concentration of calcium was similar in rats from each group. Isolated perfused hearts exhibited similar baseline and isoproterenol-induced contractility in rats from each group. However, isoproterenol was unable to increase coronary artery blood flow in hearts from OP rats. Conclusion: Enhanced vascular reactivity may contribute to obesity-induced hypertension, while reductions in coronary artery relaxation would impair the ability of the heart to respond to increased myocardial demand.

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“…To assess the effect of insulin on NO production, we compared the cumulative dose response to PE (1 nmol/l to 10 mol/l) before and after a 2-h incubation with insulin (100 mU/ml Actrapid; Novo Nordisk) (22,23). This dose of insulin was found to be optimal in preliminary experiments.…”

Section: Methodsmentioning

confidence: 99%

Preserved Glucoregulation but Attenuation of the Vascular Actions of Insulin in Mice Heterozygous for Knockout of the Insulin Receptor

Wheatcroft

Shah

et al. 2004

Diabetes

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Type 2 diabetes is preceded by years of insulin resistance and is characterized by reduced bioavailability of the antiatherosclerotic signaling molecule nitric oxide (NO) and premature atherosclerosis. The relationship between resistance to the glucoregulatory actions of insulin and its effects on the vasculature (in particular NO-dependent responses) is poorly characterized. We studied this relationship in mice heterozygous for knockout of the insulin receptor (IRKO), which have a mild perturbation of insulin signaling. Male heterozygous IRKO mice aged 8 -12 weeks were compared with age-and sex-matched littermates. IRKO mice had fasting blood glucose, insulin, free fatty acid, and triglyceride levels similar to those of wild-type mice. Intraperitoneal glucose and insulin tolerance tests were also similar in the two groups. Insulin levels in response to a glucose load were approximately twofold higher in IRKO compared with wild-type mice (1.08 ؎ 0.11 vs. 0.62 ؎ 0.13 ng/ml; P ‫؍‬ 0.004). Despite this mild metabolic phenotype, IRKO mice had increased systolic blood pressure (124 ؎ 4 vs. 110 ؎ 3 mmHg; P ‫؍‬ 0.01). Basal NO bioactivity, assessed from the increase in tension of phenylephrine preconstricted aortic rings in response to the NO synthase inhibitor N G -monomethyl-L-arginine, was reduced in IRKO (61 ؎ 14 vs. 152 ؎ 30%; P ‫؍‬ 0.005). Insulin-mediated NO release in aorta, assessed as the reduction in phenylephrine constrictor response after insulin preincubation, was lost in IRKO mice (5 ؎ 8% change vs. 66 ؎ 9% reduction in wild-type; P ‫؍‬ 0.03). Insulin-stimulated aortic endothelial NO synthase phosphorylation was also significantly blunted in IRKO mice (P < 0.05). These data demonstrate that insulin-stimulated NO responses in the vasculature are exquisitely sensitive to changes in insulin-signaling pathways in contrast to the glucoregulatory actions of insulin. These findings underscore the importance of early intervention in insulin-resistant states, where glucose homeostasis may be normal but substantial abnormalities of the vascular effects of insulin may already be present.

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Impaired Insulin-Induced Attenuation of Noradrenaline-Mediated Vasoconstriction in Insulin-Resistant Obese Zucker Rats

Cited by 47 publications

References 36 publications

Prevention of Hypertension, Insulin Resistance, and Oxidative Stress by α-Lipoic Acid

Prevention of Hypertension, Insulin Resistance, and Oxidative Stress by α-Lipoic Acid

Enhanced vascular contractility and diminished coronary artery flow in rats made hypertensive from diet-induced obesity

Preserved Glucoregulation but Attenuation of the Vascular Actions of Insulin in Mice Heterozygous for Knockout of the Insulin Receptor

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