Open AccessInositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide
Author(s) -
Nilberto R.F. Nascimento,
Lucília Maria Abreu Lessa,
Marta Regina Kerntopf,
Clauber Mota De Sousa,
Renata de Sousa Alves,
Maria Goretti Rodrigues de Queiroz,
Jason P. Price,
Douglas Heimark,
Joseph Larner,
Xue Du,
Michael Brownlee,
Andrew J. Gow,
Cecilia Davis,
M. C. Fonteles
Publication year - 2005
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0509779103
Subject(s) - superoxide , medicine , endocrinology , xanthine oxidase , chemistry , glycation , endothelial dysfunction , reactive oxygen species , pharmacology , biochemistry , diabetes mellitus , enzyme
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 addedin vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositolsin vitro in rabbit penile corpus cavernosa. Inositolsin vitro restored impaired contraction by the eNOS inhibitorl -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 Fe3+ . 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.