Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Abstract

The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 AM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln 14 -ghrelin (1 -100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca 2 + current (I Ca ) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60 -120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by desGln 14 -ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 AM) had no effect on the inotropic response induced by des-Gln 14 -ghrelin. No significant effect on I Ca of isolated ventricular cells was observed in the presence of des-Gln 14 -ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin>ghrelin = des-Gln 14 -ghrelin>hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln 14 -ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF 1a .

Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects

“…Ghrelin consists of 28 amino acids and contains a unique fatty acid modification, n-octanoylation, at Ser 3. This acylation is essential for most of ghrelin's biological activities, although unacylated ghrelin has been recently reported to exert biological activities on cell proliferation (2,3). Ghrelin is mainly produced in the stomach and circulates in the blood at a considerable plasma concentration.…”

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

“…The Ghr-GHSR signaling pathway is, therefore, presumably involved in the regulation of vascular tone (21,37). There is increasing evidence supporting the hypothesis that cardiovascular effects of Ghr are mediated by multiple receptors, some of them still to be identified (2,3).…”

Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice

“…Second, the effects of the catalytic antibody were only studied acutely in fasted animals. Resulting issues of future interest include potential compensatory mechanisms, effects of ghrelin degradation in fed animals, long-term effects of chronically degrading ghrelin on non-energy homeostasisrelated functions of ghrelin, and the potential of increasing non-GHSR1a-mediated actions of the hydrolysis product, desacyl ghrelin (55,(61)(62)(63)(64)(65)(66). Each of these caveats, except the last, is not unique to ghrelin degradation immunopharmacotherapy and applies also to small-molecule GHSR1a antagonists.…”