Continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension.
Ghrelin is a hormone that mediates a variety of physiological roles, such as stimulating appetite, initiating food intake, and modulating energy metabolism. Although it has been reported that a bolus injection of ghrelin decreases blood pressure, the effect of continuous ghrelin administration on vasoregulation has yet to be determined. We examined the longitudinal effect of ghrelin on vasoregulation using Dahl-Iwai salt-sensitive rats. In this model, a high-salt diet induced high blood pressure and increased ghrelin levels but reduced food intake. In salt-sensitive hypertension, cumulative food intake decreased, while both ghrelin messenger RNA levels and plasma ghrelin content increased. Continuous administration of a ghrelin receptor agonist, growth hormone releasing peptide-6 (GHRP-6), for 2 weeks by mini-osmotic pump did not change blood pressure values although the cumulative food intake recovered. In contrast, continuous administration of a ghrelin receptor antagonist, [D-Lys³]-GHRP-6, induced early elevations in blood pressure without changes in heart rate. Quantitative RT-PCR revealed high expression levels of genes involved in the catecholamine biosynthetic pathway, tyrosine hydroxylase and dopamine-β-hydroxylase, after continuous [D-Lys³]-GHRP-6 administration. These results indicate that continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension in this animal model and suggests that increases in autonomic nervous activity induced by ghrelin receptor antagonism are responsible, as indicated by the high expression levels of genes in the catecholamine biosynthetic pathway.
Sato
Takahiro
T
Molecular Genetics, Institute of Life Science, Kurume University, Hyakunen-kouen 1-1, Kurume 839-0864, Japan.
Nakashima
Yoshiki
Y
Nakamura
Yuki
Y
Ida
Takanori
T
Kojima
Masayasu
M
D000818:Animals; D017776:Autonomic Pathways / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D054439:Ghrelin / Q000097:blood / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000139:chemically induced*; D009638:Norepinephrine / Q000097:blood; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
D054439:Ghrelin; D009842:Oligopeptides; D054440:Receptors, Ghrelin; D017673:Sodium Chloride, Dietary; C041048:growth hormone releasing hexapeptide; D009638:Norepinephrine; D004837:Epinephrine