The effects of hexarelin, administered both pre- and post-experimentally-induced ischemia, on the intracellular calcium levels of cultured murine cardiomyocytes. Asterisks indicate significant differences. From: Ma Y, Zhang L, Edwards JN, Launikonis BS, Chen C. Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS One. 2012;7(4):e35265, reproduced under the terms of a Creative Commons Attribution License.

Introduction 

Hexarelin is a six-amino-acid peptide synthesized with the goal of studying modifications of the growth hormone (GH) pathway. It mimics the action of ghrelin by binding to the growth hormone secretagog receptor 1a (GHS-R1a). Ghrelin, by contrast, has 28 amino acid residues and may require acylation to bind to the GHS-R1a in some tissues¹. Synthetic GHSs such as hexarelin are thought to influence GH release via phospholipid-dependent protein kinase (PKC) signaling². This may affect development in infant animals, normal growth rates and other functions. It may be used in the lab to study these topics, as well as other functions of ghrelin, based on these properties. Ghrelin, hexarelin and other similar synthetic peptides that act as GHSs are known for their effects on appetite and muscle mass³. Hexarelin is also employed in the determination of GHS-R1a presence, locations and functions in new and less-studied species⁴. Hexarelin may elicit a stronger response to GHS-R1a activation (in terms of calcium release) compared to ghrelin in some species, although the ED₅₀ values of the two compounds may be similar⁴. This suggests that, while the gene for GHS-R1a may be conserved across species, the presence of ghrelin may not be.

Hexarelin and Anabolic Effects on Muscle

Hexarelin may instigate an increase in calcium influx through activation of the GHS-R1a, as outlined above. However, it may not have these effects in skeletal muscle. A study using isolated rat muscle fibers found that non-peptide GHSs, but not hexarelin or ghrelin, elicited an increase in intercellular calcium via GHS-R1a-independent pathways. On the other hand, hexarelin (50 or 100μM) has been found to enhance the contractility of isolated rat skeletal muscle in a significant, dose-dependent and calcium-independent manner⁵. This was associated with the activation of the GHS-R1a, as demonstrated by the use of D-Lys3-GHRP-6, which is an antagonist of the GHS-R1a⁵. Interestingly, this beneficial effect (i.e. modulating the mechanical threshold of muscle cell contraction) was only seen in tissue samples from younger rats. The administration of hexarelin to samples from older rats was unable to alleviate deficits in contractility associated with a deficiency in GH⁵. This may be due to the ability of hexarelin to elicit significant decreases in resting conductances conveyed by both chlorine and potassium, whereas muscular contractility essentially derives the most benefit from decreases in potassium-related conductance and increases in chlorine-related conductance⁵.

Hexarelin, Ghrelin and their Differential Roles in Cardiovascular Tissues

Some studies indicate the presence of the GHS-R1a in cardiac tissue, and, therefore, a role for ghrelin in heart tissue function¹. Other researchers have also claimed a similar role for hexarelin in vascular and cardiac cells, and that it is associated with beneficial effects on these tissues, particularly in cases of injury or disease^6-8. There is some evidence that hexarelin may also alleviate lesion development in mouse models of atherosclerosis¹. However, these effects are not associated with GHSR-1a, but with CD36, a cardiovascular receptor at which hexarelin may also be active¹.

Hexarelin in Adipose Tissue

There is some evidence that hexarelin is an agonist of CD36, a protein involved in the control of lipolysis and fatty acid breakdown in fat tissue⁹. Cultured murine adipose tissue was treated with 10μM hexarelin every 12 hours⁹. This resulted in the activation of CD36, which elicited the decreased expression of phosphoenolpyruvate carboxykinase (PEPCK). As PEPCK is associated with fatty acid breakdown, this indicates that CD36 regulates this process, and is activated by hexarelin⁹.

References:

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7. Ma Y, Zhang L, Edwards JN, Launikonis BS, Chen C. Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS One. 2012;7(4):e35265.
8. Xu X, Ding F, Pang J, et al. Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol. 2012;303(6):H703-711.
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