[D-Lys3]-GHRP-6

(1) Growth hormone secretagogues (GHS) exhibit potent growth hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. (2) By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [D-Lys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. (3) Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca(2+)](i) increase, which was reversible and not blocked by nifedipine or removal of external Ca(2+). (4) Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle.

OBJECTIVES: ;Based on previous evidence showing that early weaning disturbs the ontogenesis of rat gastric glands, which are the major site of ghrelin synthesis, we investigated the distribution of ghrelin and its receptor (GHS-R) in the rat gastric epithelium during postnatal development and evaluated the effects of early weaning on their levels. Additionally, we studied the contribution of ghrelin to gastric growth during the abrupt nutrient transition.;METHODS: ;Wistar rats were submitted to early weaning at 15 d and suckling counterparts were taken as controls.;RESULTS: ;By running quantitative reverse transcription polymerase chain reaction, immunoblots, and immunohistochemistry, we detected a variation of ghrelin levels and an increase of expression and number of immunolabeled cells, 3 d after treatment (P < 0.05). Through confocal microscopy, we identified GHS-R in the neck region of the gland and did not observe changes in protein levels. Growth was evaluated after ghrelin antagonist ([D-Lys-3]-GHRP-6) administration, which reduced DNA synthesis index in early-weaned rats (P < 0.05) as determined by bromodeoxyuridine incorporation.;CONCLUSION: ;The present study demonstrated that ghrelin and GHS-R are distributed in gastric mucosa during the postnatal development, indicating that they can signal and function in epithelial cells.

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.