Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide

Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):218-23. doi: 10.1073/pnas.0509779103. Epub 2005 Dec 22.

Abstract

Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, d-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor l-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine/xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe(3+). Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Aorta / anatomy & histology
  • Aorta / metabolism
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiopathology*
  • Enzyme Activation / drug effects
  • Hyperglycemia / drug therapy*
  • Hypertriglyceridemia / drug therapy*
  • Inositol Phosphates / pharmacology*
  • Inositol Phosphates / therapeutic use
  • Muscle Contraction / drug effects
  • Nitric Oxide / metabolism
  • Protein Kinase C / metabolism
  • Rabbits
  • Rats
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Inositol Phosphates
  • Reactive Oxygen Species
  • Nitric Oxide
  • Protein Kinase C