Abstract
Several pathological conditions predict the use of glucocorticoids for the management of the inflammatory response; however, chronic or high dose glucocorticoid treatment is associated with hyperglycemia, hyperlipidemia, and insulin resistance and can be considered a risk factor for cardiovascular disease. Therefore, we investigated the mechanisms involved in the vascular responsiveness and inflammatory profile of mesenteric arteries of rats treated with high doses of glucocorticoids. Wistar rats were divided into a control (CO) group and a dexamethasone (DEX) group, that received dexamethasone for 7 days (2mg/kg/day, i.p.). Blood samples were used to assess the lipid profile and insulin tolerance. Vascular reactivity to Phenylephrine (Phe) and insulin, and O2•-production were evaluated. The intracellular insulin signaling pathway PI3K/AKT/eNOS and MAPK/ET-1 were investigated. Regarding the vascular inflammatory profile, TNF-α, IL-6, IL-1β and IL-18 were assessed. Dexamethasone-treated rats had decreased insulin tolerance test and endothelium-dependent vasodilation induced by insulin. eNOS inhibition caused vasoconstriction in the DEX group, which was abolished by the ET-A antagonist. Insulin-mediated relaxation in the DEX group was restored in the presence of the O2.- scavenger TIRON. Nevertheless, in the DEX group there was an increase in Phe-induced vasoconstriction. In addition, the intracellular insulin signaling pathway PI3K/AKT/eNOS was impaired, decreasing NO bioavailability. Regarding superoxide anion generation, there was an increase in the DEX group, and all measured proinflammatory cytokines were also augmented in the DEX group. In addition, the DEX-group presented an increase in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (TC) and reduced high-density lipoprotein cholesterol (HDL-c) levels. In summary, treatment with high doses of dexamethasone promoted changes in insulin-induced vasodilation, through the reduction of NO bioavailability and an increase in vasoconstriction via ET-1 associated with generation of O2•- and proinflammatory cytokines.
Highlights
Glucocorticoids (GC) have been widely used due to their antiallergic and anti-inflammatory properties; even a single dose can alter carbohydrate and lipid metabolism
Apart from its direct vasomotor activity, overproduction of ET-1 is associated with increased reactive oxygen species (ROS) production and inflammatory processes within the vascular wall, which are of importance in the atherosclerotic process, endothelial dysfunction and future cardiovascular events [14,15]
Concerning insulin sensitivity evaluated by Insulin Tolerance Test (ITT), there was elevated blood glucose at all time points (0, 30, 60 and 120 min, p
Summary
Glucocorticoids (GC) have been widely used due to their antiallergic and anti-inflammatory properties; even a single dose can alter carbohydrate and lipid metabolism. Chronic use may lead to various side effects such as changes in lipid, protein and carbohydrate metabolism, resulting in dyslipidemia, hyperglycemia, hyperlipidemia and insulin resistance [1,2]. This has been shown in clinical trials during mental stress and in patients with Cushing’s syndrome [3]. The insulin-signaling pathways regulate endothelial production of NO through binding to its receptor tyrosine kinase, resulting in the phosphorylation of the insulin receptor substrate (IRS-1), which binds and activates phosphatidylinositol 3-kinase (PI3K), stimulating Akt activity. The present study aimed to investigate the effects of high dose glucocorticoid treatment of rats on mechanisms of tone regulation and inflammatory profile in mesenteric arteries
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