Modification of the terminal residue of apelin-13 antagonizes its hypotensive action

Endocrinology. 2005 Jan;146(1):231-6. doi: 10.1210/en.2004-0359. Epub 2004 Oct 14.


The apelin peptide is the endogenous ligand for the apelin G protein-coupled receptor. The distribution of the apelin peptides and receptor are widespread in the central nervous system and periphery, with reported roles in the hypothalamic-pituitary-adrenal axis, blood pressure regulation and as one of the most potent positive inotropic substances yet identified. In this report, we show that in native tissues preproapelin exists as a dimer. Dimeric preproapelin was reduced to monomers by dithiothreitol treatment, indicating disulfide linkages. To evaluate the role of the carboxyl-terminal phenylalanine in the hypotensive action of apelin-13, analogs were generated and tested for their role on blood pressure regulation. Injections of apelin-13 and apelin-12 (15 microg/kg) into spontaneously hypertensive rats lowered systolic and diastolic blood pressure to result in decreases of approximately 60% and 15% in mean arterial blood pressure, respectively. Apelin-13(13[D-Phe]) treatment did not differ from apelin-13 in either efficacy or duration of effect, whereas apelin-13(F13A) revealed a loss of function. However, concomitant administration of apelin-13(F13A) (30 microg/kg) blocked hypotensive effects of apelin-13 (15 microg/kg), which revealed that apelin-13(F13A) behaved as an apelin-specific antagonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines
  • Amino Acid Sequence
  • Animals
  • Apelin
  • Blood Pressure / drug effects*
  • COS Cells
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / chemistry
  • Carrier Proteins / drug effects
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Dimerization
  • Dithiothreitol / pharmacology
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Mice, Transgenic
  • Phenylalanine
  • Rats
  • Rats, Inbred SHR
  • Rats, Wistar


  • Adipokines
  • Apelin
  • Apln protein, mouse
  • Apln protein, rat
  • Carrier Proteins
  • Intercellular Signaling Peptides and Proteins
  • apelin-12 peptide
  • apelin-13 peptide
  • Phenylalanine
  • Dithiothreitol