Rapid stimulation of L-arginine transport by D-glucose involves p42/44(mapk) and nitric oxide in human umbilical vein endothelium

Circ Res. 2003 Jan 10;92(1):64-72. doi: 10.1161/01.res.0000048197.78764.d6.

Abstract

D-glucose infusion and gestational diabetes induce vasodilatation in humans and increase L-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells. High D-glucose (25 mmol/L, 2 minutes) induced membrane hyperpolarization and an increase of L-arginine transport (V(max) 6.1+/-0.7 versus 4.4+/-0.1 pmol/ microg protein per minute) with no change in transport affinity (K(m) 105+/-9 versus 111+/-16 micromol/L). L-[3H]citrulline formation and intracellular cGMP, but not intracellular Ca2+, were increased by high D-glucose. The effects of D-glucose were mimicked by levcromakalim (ATP-sensitive K+ channel blocker), paralleled by p42/p44(mapk) and Ser(1177)-endothelial NO synthase phosphorylation, inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME; NO synthesis inhibitor), glibenclamide (ATP-sensitive K+ channel blocker), KT-5823 (protein kinase G inhibitor), PD-98059 (mitogen-activated protein kinase kinase 1/2 inhibitor), and wortmannin (phosphatidylinositol 3-kinase inhibitor), but they were unaffected by calphostin C (protein kinase C inhibitor). Elevated D-glucose did not alter superoxide dismutase activity. Our findings demonstrate that the human fetal endothelial L-arginine/NO signaling pathway is rapidly activated by elevated D-glucose via NO and p42/44(mapk). This could be determinant in pathologies in which rapid fluctuations of plasma D-glucose may occur and may underlie the reported vasodilatation in early stages of diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Basic
  • Arginine / metabolism*
  • Arginine / pharmacokinetics
  • Biological Transport / drug effects
  • Cationic Amino Acid Transporter 1 / genetics
  • Cationic Amino Acid Transporter 1 / metabolism
  • Cationic Amino Acid Transporter 2 / genetics
  • Cationic Amino Acid Transporter 2 / metabolism
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Glucose / pharmacology*
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nitric Oxide / metabolism*
  • Onium Compounds / pharmacokinetics
  • Organophosphorus Compounds / pharmacokinetics
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / pharmacology
  • Protein Kinase C / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Superoxide Dismutase / metabolism
  • Umbilical Veins / cytology
  • alpha-Tocopherol / pharmacology

Substances

  • Amino Acid Transport Systems, Basic
  • Cationic Amino Acid Transporter 1
  • Cationic Amino Acid Transporter 2
  • Enzyme Inhibitors
  • Onium Compounds
  • Organophosphorus Compounds
  • Potassium Channel Blockers
  • RNA, Messenger
  • SLC7A1 protein, human
  • SLC7A2 protein, human
  • Nitric Oxide
  • Arginine
  • Superoxide Dismutase
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • alpha-Tocopherol
  • Glucose
  • tetraphenylphosphonium