Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats

https://doi.org/10.1016/j.bbrc.2003.09.085Get rights and content

Abstract

Ghrelin is a novel growth hormone (GH)-releasing peptide which was isolated from the stomach. We have reported that ghrelin causes vasorelaxation in rats through GH-independent mechanisms. We investigated whether ghrelin improves endothelial dysfunction. Ghrelin was subcutaneously administered to GH-deficient rats for three weeks. After isolation of the thoracic aorta, aortic ring tension was measured to evaluate vasorelaxation. Acetylcholine-induced vasorelaxation was impaired in GH-deficient rats given placebo compared to that in normal rats given placebo. GH-deficient rats treated with ghrelin, however, showed a significant increase in the maximal relaxation as compared with those given placebo. This improvement by ghrelin was inhibited by NG-nitro-l-arginine methyl ester, a nonselective nitric oxide synthase (NOS) inhibitor. Western blot analysis demonstrated that treatment with ghrelin increased endothelial NOS (eNOS) expression in the aorta of GH-deficient rats. These results suggest that administration of ghrelin improves endothelial dysfunction and increases eNOS expression in rats through GH-independent mechanisms.

Section snippets

Methods

Experimental animals. Male spontaneous dwarf rats (GH-deficient rats) and male Sprague–Dawley (SD) rats were used in this study. All experimental protocols for animal research were approved by the local authorities of Hiroshima, Japan. At the age of 10 weeks, GH-deficient rats were randomized to receive administration of ghrelin (n=7) or saline (n=7) for three weeks. Similarly, normal rats (SD rats) received placebo for three weeks (n=7). Changes in body weight by treatment with ghrelin or

Effects of ghrelin on body weight, heart rate, and blood pressure

Baseline body weight in GH-deficient rats was significantly lower than that in normal rats (Table 1). GH-deficient rats given placebo showed an impaired increase in body weight compared with normal rats. However, GH-deficient rats treated with ghrelin showed a significantly greater increase in body weight than those given placebo. Heart rate and blood pressure tended to decrease in GH-deficient rats treated with ghrelin, although these changes did not reach statistical significance.

Effect of ghrelin on aortic vasorelaxation

After

Discussion

This is the first study to demonstrate beneficial effects of ghrelin on endothelial function in rats. In the present study, we demonstrated that (1) three-week administration of ghrelin improved impaired endothelium-dependent vasorelaxation in GH-deficient rats, (2) ACh-induced vasorelaxation was inhibited by l-NAME, but not by indomethacin, and (3) ghrelin increased expression of eNOS protein in the aorta of GH-deficient rats.

GHS-R, a specific receptor for ghrelin, exists not only in the

Acknowledgements

This work was supported by the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan.

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