Augmentation of nitric oxide is crucial for the time-dependent effects of rosiglitazone on blood pressure and baroreflex function in rats

Hsieh, Po‐Shiuan; Hong, Ling-Zong

doi:10.1097/hjh.0b013e3282f11934

Cited by 9 publications

(6 citation statements)

References 30 publications

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“…Tian et al demonstrated that rosiglitazone attenuated endothelin-1-induced vasoconstriction through the upregulation of endothelin B receptor and NO production in normal mouse aortas [15]. Hsieh and Hong reported that chronic rosiglitazone treatment augmented vascular responsiveness to acetylcholine and lowered blood pressure in normal male rats [39]. Walcher et al showed a rapid effect of single dose rosiglitazone treatment on flow-mediated endothelium-dependent vasodilatation in healthy men [12].…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone Restores Endothelial Dysfunction in a Rat Model of Metabolic Syndrome through PPARγ- and PPARδ-Dependent Phosphorylation of Akt and eNOS

et al. 2011

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Vascular endothelial dysfunction has been demonstrated in metabolic syndrome (MS). Chronic administration of rosiglitazone ameliorates endothelial dysfunction through PPARγ-mediated metabolic improvements. Recently, studies suggested that single dose of rosiglitazone also has direct vascular effects, but the mechanisms remain uncertain. Here we established a diet-induced rat model of MS. The impaired vasorelaxation in MS rats was improved by incubating arteries with rosiglitazone for one hour. Importantly, this effect was blocked by either inhibition of PPARγ or PPARδ. In cultured endothelial cells, acute treatment with rosiglitazone increased the phosphorylation of Akt and eNOS and the production of NO. These effects were also abolished by inhibition of PPARγ, PPARδ, or PI3K. In conclusion, rosiglitazone improved endothelial function through both PPARγ- and PPARδ-mediated phosphorylation of Akt and eNOS, which might help to reconsider the complex effects and clinical applications of rosiglitazone.

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Section: Discussionmentioning

confidence: 99%

Rosiglitazone Restores Endothelial Dysfunction in a Rat Model of Metabolic Syndrome through PPARγ- and PPARδ-Dependent Phosphorylation of Akt and eNOS

et al. 2011

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“…In addition to its use in clinical studies, the use of HOMA-IR in rodents to assess insulin sensitivity has been validated in a number of recent studies. 42,43…”

Section: Materials and Methods Experimental Modelmentioning

confidence: 99%

Insulin resistance and altered glucose transporter 4 expression in experimental uremia

Aksentijević

Bhandari

Seymour

2009

Kidney International

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Progressive ventricular hypertrophy can lead to the development of insulin resistance, a feature of both chronic kidney disease and heart failure. Here we induced uremia in adult male Sprague-Dawley rats using a remnant kidney model and studied the expression of glucose transporters. As expected, the reduction of nephron mass resulted in impaired renal function, cardiac hypertrophy, glucose intolerance, hyperinsulinemia, anemia, and hypertension. Insulin sensitivity was significantly reduced in the uremic animals as determined by oral glucose tolerance tests. After six weeks of uremia, at a point when cardiac hypertrophy had been established, left ventricle tissue had a marked increase in the expression of GLUT4 (insulin-dependent glucose transporter 4), consistent with hypertrophic remodeling, but not GLUT1 (insulin-independent glucose transporter 1). However, although uremic animals had systemic insulin resistance and glucose intolerance, there was no evidence of impaired GLUT4 translocation in the heart at 6 weeks of uremia, suggesting that other mechanisms may underpin insulin resistance in the uremic heart.

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“…Whether rosiglitazone acted in the brain or the efferent pathway was not investigated. However, this PPAR-␥ agonist probably did not impair the response of the heart to efferent autonomic nerves, because 4 to 8 weeks of treatment of rats fed a normal fat diet with a higher dose of rosiglitazone (8 mg/kg) failed to alter the HR responses to propranolol or atropine (Hsieh and Hong, 2008). Likewise, knockout of vascular PPAR-␥ attenuates vasoconstriction induced by ␣-adrenergic agonists (Halabi et al, 2008;Wang et al, 2009), suggesting that TZDs enhance, rather than inhibit, vascular responses to sympathetic activation.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet-Induced Obesity

Zhao

McCully²,

Brooks³

2012

The Journal of Pharmacology and Experimental Therapeutics

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Obesity decreases baroreflex gain (BRG); however, the mechanisms are unknown. We tested the hypothesis that impaired BRG is related to the concurrent insulin resistance, and, therefore, BRG would be improved after treatment with the insulinsensitizing drug rosiglitazone. Male rats fed a high-fat diet diverged into obesity-prone (OP) and obesity-resistant (OR) groups after 2 weeks. Then, OP and OR rats, as well as control (CON) rats fed a standard diet, were treated daily for 2 to 3 weeks with rosiglitazone (3 or 6 mg/kg) or its vehicle by gavage. Compared with OR and CON rats, conscious OP rats exhibited reductions in BRG (OP, 2.9 Ϯ 0.1 bpm/mm Hg; OR, 4.0 Ϯ 0.2 bpm/mm Hg; CON, 3.9 Ϯ 0.2 bpm/mm Hg; P Ͻ 0.05) and insulin sensitivity (hyperinsulinemic euglycemic clamp; OP, 6.8 Ϯ 0.9 mg/kg ⅐ min; OR, 22.2 Ϯ 1.2 mg/kg ⅐ min; CON, 17.7 Ϯ 0.8 mg/kg ⅐ min; P Ͻ 0.05), which were well correlated (r 2 ϭ 0.49; P Ͻ 0.01). In OP rats, rosiglitazone dose-dependently improved (P Ͻ 0.05) insulin sensitivity (12.8 Ϯ 0.6 mg/kg ⅐ min at 3 mg/kg; 16.0 Ϯ 1.5 mg/kg ⅐ min at 6 mg/kg) and BRG (3.8 Ϯ 0.4 bpm/mm Hg at 3 mg/kg; 5.3 Ϯ 0.7 bpm/mm Hg at 6 mg/kg). However, 6 mg/kg rosiglitazone also increased BRG in OR rats without increasing insulin sensitivity, disrupted the correlation between BRG and insulin sensitivity (r 2 ϭ 0.08), and, in OP and OR rats, elevated BRG relative to insulin sensitivity (analysis of covariance; P Ͻ 0.05). Moreover, in OP rats, stimulation of the aortic depressor nerve, to activate central baroreflex pathways, elicited markedly reduced decreases in heart rate and arterial pressure, but these responses were not improved by rosiglitazone. In conclusion, diet-induced obesity impairs BRG via a central mechanism that is related to the concurrent insulin resistance. Rosiglitazone normalizes BRG, but not by improving brain baroreflex processing or insulin sensitivity.

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Augmentation of nitric oxide is crucial for the time-dependent effects of rosiglitazone on blood pressure and baroreflex function in rats

Abstract: These data suggest that RSG-induced NO production is important for the time-dependent effects of RSG on MAP and BRS in rats.

Cited by 9 publications

References 30 publications

Rosiglitazone Restores Endothelial Dysfunction in a Rat Model of Metabolic Syndrome through PPARγ- and PPARδ-Dependent Phosphorylation of Akt and eNOS

Rosiglitazone Restores Endothelial Dysfunction in a Rat Model of Metabolic Syndrome through PPARγ- and PPARδ-Dependent Phosphorylation of Akt and eNOS

Insulin resistance and altered glucose transporter 4 expression in experimental uremia

Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet-Induced Obesity

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