Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans

Abstract

Ghrelin is a novel GH (growth hormone)-releasing peptide isolated from the stomach. The cardiovascular and hormonal effects of the subcutaneous administration of ghrelin in humans remain unknown. Six healthy volunteers each received subcutaneous administration of three doses of ghrelin (1, 5 or 10 microg/kg) and placebo; the order of administration was randomized, and separate doses were given at least 24 h apart. The serum GH level dose-dependently increased from 0.5 +/- 0.4 to 3.6 +/- 2.1 ng/ml (1 microg/kg ghrelin; P=0.99 compared with baseline), 27.1 +/- 12.0 ng/ml (5 microg/kg; P<0.01 compared with baseline) and 45.4 +/- 12.8 ng/ml (10 microg/kg; P<0.01 compared with baseline) 30 min after ghrelin administration. Subcutaneous administration of ghrelin did not significantly alter circulating levels of corticotropin, cortisol, insulin-like growth factor-1, noradrenaline or adrenaline, although 10 microg/kg ghrelin slightly increased the prolactin level. No significant changes in heart rate or mean arterial pressure were observed. In contrast, the left ventricular ejection fraction, as assessed by echocardiography, increased dose-dependently from 63.5 +/- 0.6% to 65.1 +/- 0.9% (1 microg/kg ghrelin; P=0.97 compared with baseline), 69.6 +/- 1.3% (5 microg/kg; P<0.01 compared with baseline) and 71.5 +/- 0.9% (10 microg/kg; P<0.01 compared with baseline) 30 min after ghrelin administration. These haemodynamic and hormonal changes were still apparent 60 min after ghrelin injection. In conclusion, subcutaneous administration of ghrelin dose-dependently induced relatively specific GH release and enhanced cardiac performance in humans.

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

“…The hepatic GH effector IGF-1 levels are not correspondingly increased in conditions with high endogenous plasma ghrelin levels, such as ghrelin-producing tumours (Corbetta et al, 2003;Tsolakis et al, 2004). Furthermore, the administration of ghrelin does not significantly affect the IGF-1 level in healthy volunteers (Enomoto et al, 2003), patients with cardiovascular (Nagaya et al, 2004) or pulmonary diseases (Nagaya et al, 2005), tumour-bearing animals (DeBoer et al, 2007), or our patients with CACS. In contrast, studies using synthetic oral ghrelin mimetics have shown a significant effect on the IGF-1 level in volunteers and in the frail elderly (Smith, 2005) or patients with cancer cachexia (Garcia et al, 2007).…”

“…(Nagaya et al, 2001a;Wren et al, 2001;Akamizu et al, 2004;Schmid et al, 2005;Levin et al, 2006) or subcutaneous (Enomoto et al, 2003;Druce et al, 2006) ghrelin showed safety and tolerability at dosages up to 10 mg kg À1 -sufficient to promote orexigenic, prokinetic, and GH-releasing effects; in those studies, a sensation of warmth, sleepiness, bowel movements, and hunger were reported. Comparable results with i.v.…”

Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers

“…Although ghrelin has been administered subcutaneously to human subjects for evaluation of cardiac effects, the food intake response was not assessed. 8 We performed a double-blind, randomized, crossover trial in order to determine the effect of subcutaneous ghrelin on food intake in man.…”

The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes

“…IGFBP-1 concentrations were associated with ghrelin concentrations only in subjects with IR. Since ghrelin has a powerful GH-releasing effect in experimental settings [1,8,17,18], it has been proposed to serve as a regulator of somatotroph function together with GHRH and somatostatin [39,40]. However, the physiological role of ghrelin in the regulation of GH/IGF-I axis has not yet been established.…”

“…In addition to its marked growth hormone (GH)-releasing activity [1], ghrelin acts as a powerful orexigenic hormone [3,4] and this effect appears to be independent of changes in GH [5]. Recent studies have shown that ghrelin also modulates insulin and glucose metabolism [6], and it has further been shown to have beneficial hemodynamic properties [7,8]. It is a somatotrophic, orexigenic and adipogenic hormone, which may link the regulatory systems for growth and energy balance [9].…”