Endothelin Stimulates Glucose Uptake via Activation of Endothelin-A Receptor in Neonatal Rat Cardiomyocytes

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Abstract
Summary: Endothelin-1 (ET-1) is a 21 amino acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have found that ET-1 stimulates glucose uptake in 3T3-L1 adipocytes. In this report, we extend the studies to neonatal rat cardiomyocytes. ET-1, but not angiotensin-II (A-II), stimulated glucose uptake in a dose-dependent manner with an EC50 value at ˜1 nM, and an approximately 2-fold stimulation at 100 nM. As a comparison, insulin stimulated glucose uptake in a dose-dependent manner with an EC50 value at 1 nM, and a 2.5-fold stimulation at 100 nM. Western blot analysis shows that ET-1 stimulated the translocation of insulin-responsive aminopeptidase (IRAP), an aminopeptidase in GLUT4 (glucose transporter)-con-taining vesicles, from the cytoplasm to the plasma membrane. The effect of ET-1 on glucose uptake was blocked by A-127722, an antagonist selective for the ETA-receptor. ET-1 treatment did not induce phosphorylation of insulin receptor-β (IRβ), insulin receptor substrate-1 (IRS-1) or Akt, but stimulated the phosphorylation of extracellular signal-regulated kinase (ERK1/2). The effect of ET-1 on glucose uptake was not inhibited by inhibitors for protein kinase C (PKC), protein kinase A (PKA) and phosphatidylino-sitol-3-kinase (P13'-kinase). Our results show that ET-1 stimulates glucose uptake in neonatal rat cardiomyocytes via activation of the ETA-receptor.

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