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Moxonidine Reduce Blood Pressure and Activate the Insulin Signaling Cascade via the PKB/Akt‐eNOS Pathway
Author(s) -
BrownBryan TerryAnn,
Kennedy Wentsworth,
Gonzalez Ramon,
Edwards Lincoln
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a693-a
Subject(s) - moxonidine , protein kinase b , imidazoline receptor , insulin receptor , phosphorylation , endocrinology , medicine , insulin resistance , protein kinase a , signal transduction , chemistry , insulin , pharmacology , biology , receptor , biochemistry , agonist
Insulin resistance and hypertension are major disorders associated with Metabolic Syndrome X and type2 diabetes. Imidazoline compounds are potential single agent candidate drugs for the treatment of insulin resistance and hypertension. Our hypothesis is that imidazoline compounds lower blood pressure by central activation of I1‐imidazoline receptors and augment glucose metabolism by crosstalk with insulin receptor signaling pathways. Using the SHR rat model, we showed that moxonidine (10–50 nmoles) reduced blood pressure when injected into the medulla region of rat brain. We also treated both HEK293 and HepG2 cells with moxonidine (10‐10‐10‐5M) for various times. Western blot was used to determine proteins that were phosphorylated. We showed that moxonidine caused phosphorylation of several proteins in the insulin signaling pathway. There was a 5‐fold phosphorylation of protein kinase B (PKB/Akt), 3–5‐fold phosphorylation of protein dependent kinase 1 (PDK1), 2‐fold increase in the phosphorylation of IRS‐1/2, ERK1/2, the mitogen activated protein kinase (MAPK) protein showed a greater than 5‐fold increase in phosphorylation above control We also showed a 4–6 fold increase in the phosphorylation of endothelial nitric oxide synthase (eNOS) Furthermore, overexpression of the imidazoline receptor antisera‐selected protein (IRAS) in HEK293 kidney cells showed strong interaction with IRS‐4 protein. Moxonidine showed little or no effect on such protein‐protein interactions. Together, these results implicate the imidazoline agonists, moxonidine as a centrally acting antihypertensive agents and putative biochemical regulators of the insulin receptor signaling pathway.