Hexarelin, a synthetic growth hormone-releasing peptide, can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects. Furthermore, the non-GHSR CD36 had been demonstrated to be a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. When compared with ghrelin, hexarelin is chemically more stable and functionally more potent. Therefore, it may be a promising therapeutic agent for some cardiovascular conditions. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.

Growth hormone secretagogues (GHS) are a class of small synthetic peptides that stimulate growth hormone (GH) release through binding to the growth hormone secretagogue receptor (GHSR) 1a. Moreover, GHSR 1a is a G-protein-coupled receptor originally identified in the hypothalamus and pituitary, and later recognized as the receptor for the endogenous hormone ghrelin. The peripheral distribution of GHSR 1a in the heart, adrenals, fat, prostate, bone, and digestive tract has supported physiological roles of GHSs and ghrelin independent of GH release and neuroendocrine stimulation. For example, GH-independent effects on orexigenic properties, fat metabolism, immune, gastrointestinal, and cardiovascular activities have been reported for GHSs and ghrelin.

Previous studies have revealed that ghrelin administration can improve cardiac function in rats and patients with chronic heart failure, as indicated by increased left ventricle ejection fraction (LVEF), cardiac output, and exercise capacity.  In rodents with acute myocardial infarction (MI), ghrelin administration prevented malignant arrhythmias and reduced mortality in the acute phase, while improving left ventricle (LV) dysfunction and attenuating cardiac remodeling in the subacute phase. However, ghrelin is an unstable natural peptide that is transformed and degraded, which limits its clinical use. The GHS hexarelin is a chemically stable and potent synthetic hexapeptide that can be administered orally, making it a potential alternative to ghrelin. It is comparable to ghrelin with respect to the half-maximal effective concentration for their common receptor, GHSR 1a; although the cardiac action of hexarelin was reported to be mediated in part by GHSR 1a and largely by activation of the CD36 receptor, in isolated working hearts. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.