Modification of the terminal residue of apelin-13 antagonizes its hypotensive action.
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.
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Dennis K
DK
Lee
Victor R
VR
Saldivia
Tuan
T
Nguyen
Regina
R
Cheng
Susan R
SR
George
Brian F
BF
O'Dowd
D054392:Adipokines; D000595:Amino Acid Sequence; D000818:Animals; D000073861:Apelin; D001794:Blood Pressure / Q000187:drug effects*; D019556:COS Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D019281:Dimerization; D004229:Dithiothreitol / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D010649:Phenylalanine; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; C498579:Apln protein, rat; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; C495200:apelin-12 peptide; C495199:apelin-13 peptide; D010649:Phenylalanine; D004229:Dithiothreitol