Effects of high doses of glucocorticoids on insulin-mediated vasodilation in the mesenteric artery of rats

PLoS One. 2020 Mar 18;15(3):e0230514. doi: 10.1371/journal.pone.0230514. eCollection 2020.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / pharmacology*
  • Insulin / administration & dosage
  • Insulin / pharmacology*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Mesenteric Arteries / drug effects*
  • Mesenteric Arteries / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrogen Oxides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Vasodilation / drug effects*

Substances

  • Glucocorticoids
  • Insulin
  • Interleukin-18
  • Interleukin-1beta
  • Interleukin-6
  • Nitrogen Oxides
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • Nitric Oxide Synthase Type III

Grants and funding

This study was financed in part by the Conselho Conselho Nacional de Desenvolvimento Científico e Tecnológico – Brasil (CNPq), the Fundação de Apoio à Pesquisa e a Inovação Tecnológica do Estado de Sergipe (Fapitec/SE) - Brasil, the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES - Finance Code 001), and the Financiadora de Estudos e Projetos - Brasil (FINEP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.