EMD638683, a novel SGK inhibitor with antihypertensive potency

Cell Physiol Biochem. 2011;28(1):137-46. doi: 10.1159/000331722. Epub 2011 Aug 16.

Abstract

The serum- and glucocorticoid-inducible kinase 1 (SGK1) is transcriptionally upregulated by mineralocorticoids and activated by insulin. The kinase enhances renal tubular Na(+)-reabsorption and accounts for blood pressure increase following high salt diet in mice made hyperinsulinemic by dietary fructose or fat. The present study describes the in vitro and in vivo efficacy of a novel SGK1 inhibitor (EMD638683). EMD638683 was tested in vitro by determination of SGK1-dependent phosphorylation of NDRG1 (N-Myc downstream-regulated gene 1) in human cervical carcinoma HeLa-cells. In vivo EMD638683 (4460 ppm in chow, i.e. approx. 600 mg/kg/day) was administered to mice drinking tap water or isotonic saline containing 10% fructose. Blood pressure was determined by the tail cuff method, and urinary electrolyte (flame photometry) concentrations determined in metabolic cages. In vitro testing disclosed EMD638683 as a SGK1 inhibitor with an IC50 of 3 μM. Within 24 hours in vivo EMD638683 treatment significantly decreased blood pressure in fructose/saline-treated mice but not in control animals or in SGK1 knockout mice. EMD638683 failed to alter the blood pressure in SGK1 knockout mice. Following chronic (4 weeks) fructose/high salt treatment, additional EMD638683 treatment again decreased blood pressure. EMD638683 thus abrogates the salt sensitivity of blood pressure in hyperinsulinism without appreciably affecting blood pressure in the absence of hyperinsulinism. EMD638683 tended to increase fluid intake and urinary excretion of Na(+), significantly increased urinary flow rate and significantly decreased body weight.

Conclusion: EMD638683 could serve as a template for drugs counteracting hypertension in individuals with type II diabetes and metabolic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology*
  • Antihypertensive Agents / therapeutic use
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism
  • Fructose / pharmacology
  • HeLa Cells
  • Humans
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Hydrazines / therapeutic use
  • Hypertension / drug therapy
  • Immediate-Early Proteins / antagonists & inhibitors*
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Sodium / urine
  • Sodium Chloride / pharmacology

Substances

  • Antihypertensive Agents
  • Benzamides
  • Cell Cycle Proteins
  • EMD 638683
  • Hydrazines
  • Immediate-Early Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein
  • Protein Kinase Inhibitors
  • Fructose
  • Sodium Chloride
  • Sodium
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase