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In addition, both ghrelin and hexarelin are cardioprotective in reducing infarct size, as demonstrated in the isolated working heart subjected to global ischemia followed by retrograde reperfusion [40]. It has been demonstrated recently that hexarelin antagonizes Ang II-induced apoptosis of cardiomyocytes in vitro (Figure 1) [16]. The inhibitory activity of hexarelin on cardiomyocyte cell death might explain, partially at least, its protective effect against cardiac ischemia in rats in vivo. Although the type of GHS receptor that is involved in cardioprotection against myocardial lesions is not characterized, the effect appears to be related to activation of PKC. Interestingly, treatment with GHRP-6 increases the survival rate of dogs with dilated cardiomyopathy that are subject to acute ischemia by coronary-artery occlusion but does not alter infarct size [41]. This might be related to an enhanced non-ischemic compensatory mechanism that is mediated by an, as yet, uncharacterized GHS receptor.
Figure 1. Hexarelin protects cardiomyocytes from Ang II-induced apoptosis. TdT-mediated dUTP-nick end-labeling (TUNEL) analysis was performed to detect cell apoptosis (indicated by brown nuclei). (a) Vehicle-treated cardiomyocytes. (b) Cardiomyocytes incubated with 0.1 μmol−1 Ang II for 48 h. (c) Cardiomyocytes incubated with 0.1 μmol−1 hexarelin for 48 h. (d) Cardiomyocytes incubated with 0.1 μmol−1 hexarelin and 0.1 μmol−1 Ang II for 48 h. (e) The percentage of cardiomyocytes undergoing apoptosis in each experimental group. Data are mean ± SD of 100 cells from three independent experiments. aP<0.05 compared with control; bP<0.05 compared with Ang II. Adapted, with permission, from [16].
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Other agents that display potential aging-modulating properties also seem to affect the axis that connects lipid catabolism and mitochondrial biogenesis. For instance, the growth hormone releasing peptide hexarelin is able to induce both mitochondrial biogenesis and lipid metabolism. Addition of this peptide to 3T3-L1 adipocytes resulted in the depletion of intracellular lipid pools in a CD34-dependent fashion (Rodrigue-Way et al., 2007). Like resveratrol, hexarelin induced the mobilization of fatty acids toward the mitochondrial oxidative phosphorylation process. Also, as in other mechanisms involved in mitochondrial biogenesis, hexarelin induced known targets of PPARγ such as FATP, CPT-1, and F(1)-ATPase, suggesting a PPARγ-dependent activity.
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Growth Hormone (GH) Releasing Peptide Receptors
A class of peptides releasing GH, hexarelin analogs, such as EP 60761 and EP 80661, induces erections when injected in the PVN or even when given systemically in rats. Hexarelin analogs act on specific hypothalamic receptor sites, activating paraventricular oxytocinergic neurons projecting to extrahypothalamic brain areas [114]. Up till now, there is no indication whether hexarelin analogs can influence human erectile function.
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HEXARELIN PROTECTS POST-ISCHEMIC VENTRICULAR DYSFUNCTION IN HEARTS OF AGED RATS
Aging has been shown to alter the spectrum of physiological and biochemical properties of the myocardium, including force production, excitation–contraction coupling, substrate use and mitochondrial oxidative capacity (26). However, new insights into myocardial-reperfusion injury indicate that aged rats, besides a reduction of the myocardial antioxidant defense mechanisms (27), are affected by alteration of calcium handling in cardiac cells (28). In fact, abnormalities of regulation/modulation mechanisms normally involved in the restriction of calcium oscillation between sarcoplasmic reticulum and cytoplasm are associated with strong impairment of cardiac mechanics.
Myocardial ischemia, defined as an imbalance between fractional uptake of oxygen and the rate of cellular oxidation, may have several potential outcomes, especially in senescent hearts that are more prone to this pathologic event. Under these circumstances, when ischemia is brief, a transient post-ischemic ventricular dysfunction may occur, and this condition reflects many disturbances of cardiomyocytes and insufficient cellular antioxidant activity (29).
These findings and the awareness that GH secretion and its biological effects decline with aging in both experimental animals (30) and humans (31) prompted us to investigate the protective action of hexarelin in comparison with that of GH against post-ischemic myocardial dysfunction in hearts from in vivo treated senescent rats. Although strengthening of the somatotropic function would be instrumental in the anti-ischemic activity of hexarelin in aged rats, a direct action on the heart of the hexapeptide cannot be ruled out a priori. Favouring this view, previous findings of our laboratory have demonstrated that hexarelin given to young male rats was very effective in the cardiac ischemia–reperfusion model, despite the lack of an overt stimulation of the GH/IGF-1 axis (8).
Twenty-four-month-old male rats of Sprague–Dawley strain were used in these experiments. They were randomly assigned to three experimental groups and treated subcutaneously with: (a) 1 ml/kg saline; (b) biosynthetic human GH; (c) hexarelin. Hexarelin and GH were given to rats at the dose of 80 μg/kg and 400 μg/kg b.i.d., respectively, for 21 days. Animals were killed by cervical dislocation 14 h after the last injection, pituitaries were removed and used for determination of GH mRNA levels, whereas blood was collected for plasma determination of IGF-1 as reported above. The hearts were isolated and used for ischemia and reperfusion experiments. A moderate ischemia was induced by global reduction of the perfusion flow to 1 ml/min for a period of 20 min. A normal flow rate (15 ml/min) was then restored and reperfusion continued for 30 min.
In the present model of ischemia–reperfusion, hearts from old rats treated for the long term with hexarelin, achieved a strong protection: complete recovery of left ventricular function was present on reperfusion, and simultaneous blunting of creatine kinase (CK) leakage in the heart effluents bespoke the integrity of myocardial cell membranes and the preservation from the contractile impairment that follows oxygen readmission (Figures 7–9).
Figure 7. Left ventricular pressure (LVP) during post-ischemic reperfusion in heart preparations from saline- or hexarelin-treated old rats.
Figure 8. Left ventricular developed pressure (LVDP) and coronary perfusion pressure (CPP) in isovolumic left heart preparations submitted to low flow ischemia and reperfusion from old rats of the following experimental groups: (a) saline (controls, n = 10); (b) human growth hormone (GH, n = 6) and (c) hexarelin (HEXA, n = 9). Each point on the curves depicts mean values, and vertical bars, the SEM. The areas under the curve (AUCs) related to LVDP are: (a) 765 ± 46; (b) 1147 ± 88; (c) 2272 ± 66. Statistical differences: c vs. b and a, P < 0.01; b vs. a, P < 0.05. The AUCs related to CPP (increase in mm Hg over the pre-ischemic values) are: (a) 1284 ± 79; (b) 1008 ± 47 and (c) 235 ± 35. Statistical differences: cvs. b and a, P< 0.01; bvs. a, P < 0.05. AUCs was estimated according the trapezoid method: in ordinate, LVDP or CPP in mm Hg; in abscissa, time from 20 to 50 min.
Figure 9. Creatine kinase (CK) release profile in ischemic and reperfusion conditions of old rat hearts. Caption as in Figure 8. Each point on the curves depicts mean values and vertical bars the SEM. The areas under the curve related to CK release during reperfusion are: (a) 4454 ± 352; (b) 3520 ± 278 and (c) 278 ± 56. Statistical differences: c vs. a and b, P< 0.01; b vs. a, P < 0.05.
Under our experimental conditions, the beneficial effect disclosed by hexarelin in aged rats was not coupled to any apparent stimulation of the somatotropic function, because the levels of pituitary GH mRNA and plasma IGF-1 were unchanged. This would indicate, albeit inferentially, that the hexapeptide had a direct myocardial action divorced from that of GH. As we have reported above, Grilli et al. (17) and Howard et al. (32) recently reported that mRNA coding for a receptor related to GHS is expressed in peripheral organs of male rats, heart included.
We still ignore what kind of intracellular signal transduction is triggered by GH- secretagogue-receptor activation in peripheral organs, a point that deserves a thorough investigation. However, the striking hexarelin-induced inhibition of reperfusion damage in the isolated hearts would call for a restraint in the increase of cytosolic calcium that follows reperfusion. In this context, either the inhibitor of sarcoplasmic reticulum function, ryanodine, or the transsarcolemmal calcium channel blockers, diltiazem and verapamil, were shown capable of improving recovery of left ventricular developed pressure in rabbit hearts exposed to transient ischemia and hypoxia (33). However, because hexarelin, given directly to the heart through the perfusion system, does not depress myocardial contractility, the mechanism/s responsible for its anti-ischemic action may be different from those of calcium entry blockers. In fact, these compounds are known to protect the isolated rabbit hearts against abnormalities produced by transient hypoxia and low flow ischemia by a strong depression of myocardial contractility ultimately related to the inhibition of calcium entry into the myocardial cells. It is then possible that sustained administration of hexarelin in aged rats may have increased cardiomyocyte energy-stores to an extent compatible with the maintenance of basic cell organization that allows a normal recovery of the contractile function at the termination of the ischemic insult. In this vein, it is noteworthy that the amount of CK released during reperfusion from the heart of hexarelin-treated rats was significantly less than that of control preparations (Figure 9). This may indicate, in the former setting, a better preservation of the integrity of myocardial cell membranes, which is indispensable for a favourable osmotic control (prevention of free radicals accumulation and continuance of calcium homeostasis) and that maintenance of energy-rich phosphates had occurred. Our study, however, still lacks data on both the concentration of energy-storing nucleotides and on the grade of density of glycogen granules in ischemic hearts of control and hexarelin-treated rats. These aspects, together with the evaluation of ultrastructural changes of myocardial cells associated with ischemia, deserve further investigations to provide a clearer picture of the mode of action of hexarelin in post-ischemic ventricular dysfunction.
In this regard, unpublished observations of our laboratory showed that mechanical manifestations of the phenomenon called “calcium paradox” (34), (increase in resting tension and impaired contractility of the perfused hearts at the moment of calcium readmission after transient exposure of the organ to a calcium free solution) are markedly inhibited in hearts prepared from young rats treated with hexarelin. These results can be again interpreted to mean that a better control of calcium influx in these hearts could be responsible for the sparing myocardial energy and improved recovery of depressed contractile forces.
Another interesting feature of our studies was the protective effect exerted by GH treatment in the heart preparations from senescent rats. The improvement of post-ischemic ventricular function was, however, modest and by no means comparable, under our experimental conditions, with that elicited by hexarelin, and it is probably attributable to a direct action of the hormone on the heart, where receptors for both GH and IGF-1 have been identified.
In conclusion, these findings clearly indicate that hexarelin, very likely through a mechanism divorced from its GH-releasing effect, strikingly reduces the reperfusion injury in isolated hearts from senescent rats. This action of hexarelin, which under our experimental conditions, overrides that exhibited by GH, opens new perspectives in the therapy of post-ischemic heart dysfunction in the elderly. This subject is of increasing interest because the aged population is continuously growing and is becoming one of the major targets of pharmacology; moreover, cardiac diseases are the first cause of mortality after the age of 65 years.
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Area under the secretory curve (AUC) (μg l−1 60 min−1) of growth hormone (GH) secretion stimulated on three different days with either 1 μg kg−1 intravenous (i.v.) GH-releasing hormone (GHRH), 1 μg kg−1 i.v. GHRP-6, or a combination of GHRH and GHRP-6 at the same doses. The groups tested (patients with hypothalamopituitary disconnection, closed bars) were adults with different tumours located in the hypothalamic area, leaving the pituitary intact but blocking the hypothalamopituitary connection. The children had neonatal stalk transection. Controls (open bars) are age- and sex-matched healthy subjects. *=p=<0.05 vs. GHRH; †=p=<0.05 vs. GHRP-6. Redrawn from Refs 25 and 26.
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Putative signaling pathways that mediate the cardiovascular actions of GHS. There are at least three types of receptors for GHSs and, probably, ghrelin, in the cardiovascular system: GHS-R1a; GHS-Ru; and CD36. The well-established signalling pathways are indicated for GHS-R1a. Activation of GHS-1Ra by GHSs stimulates the cAMP–PKA, the PKC and the Ins(1,4,5)P3 second-messenger pathways. GHS-R1a might also be linked to vasodilation by its effects on the endothelin 1 (ET1) receptor, positive energy homeostasis via regulation of PPAR, and anti-apoptotic effects by inhibition of caspase activity. An, as yet, unknown GHS-Ru might have anti-apoptotic effects through the ERK and PI 3-kinase pathways, and modulate the production of PGFα1 by activating cyclooxygenase. CD36 also binds to GHS, which leads to activation of PKC and coronary constriction.
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As in the animal model, acute administration of hexarelin in humans increases left ventricular ejection fraction without changing left-ventricular end-diastolic pressure, heart rate and mean arterial pressure in normal subjects [32], GH-deficient patients [33], and patients with post-ischemic dilated cardiomyopathy [34]. This hemodynamic effect of hexarelin might indirectly reflect the reduction in vascular resistance following peripheral vasodilation induced by hexarelin. In humans with chronic heart failure, treatment with ghrelin improves left-ventricular function and attenuates left-ventricular remodelling [35]. Ghrelin appears to have similar cardiovascular activity because acute administration in healthy volunteers and in patients with chronic heart failure significantly decreases the systemic vascular resistance, which results in increased cardiac output as shown by increased cardiac index and stroke-volume index [35,18]. The effect of ghrelin and hexarelin on cardiac performance might be mediated by GHS-R1a.
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VI.B.4.b GHS–GHRP-6 (hexarelin)
GHRP-6 is synergistic with GHRH in evoking GH secretion. Combined intravenous administration of a bolus of hexarelin (1 μg/kg; blood sampled before and at 15-min intervals for 30–120 min), simultaneously with, before, or after GHRH administration, is safe, well tolerated, and potently evokes GH secretion; this protocol has also been proposed to replace the ITT. Another advantage of this combination is that although anatomic disruption of the hypothalamic–pituitary unit invalidates the GHRH test alone, this may be reversed by addition of a GHS. The proposed threshold of normality has been 15 μg/liter; however, diagnostic cutoff values ≥20 μg/liter for normality and ≤10 μg/liter for GH deficiency have yielded 100% sensitivity and specificity.
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Other Stimulation Tests
Vasopressin and desmopressin (a synthetic long-acting vasopressin analogue without V1-mediated pressor effects) are thought to stimulate ACTH release in Cushing's disease through the corticotroph-specific V3 (or V1b) receptor. Hexarelin (a growth hormone secretagogue) also stimulates ACTH release to a sevenfold greater extent than human CRH; although the mechanism has not been entirely elucidated, this probably occurs through stimulation of vasopressin release in normal subjects,220 and through stimulation of aberrant growth hormone secretagogue receptors in patients with corticotroph tumors.221 These peptides all have been used in a similar manner to CRH, to try to improve the differentiation of ACTH-dependent Cushing's syndrome, but they generally have proved inferior or of no advantage.222-225 However, desmopressin may be useful in centers where CRH is unavailable. A combined desmopressin (10 μg) and human CRH (100 μg) test initially looked extremely promising.226 However, a later study of this combined test in 26 patients with Cushing's disease and 5 patients with ectopic ACTH syndrome showed significant overlap in responses.227 The disappointing discriminatory outcome of these stimulants is undoubtedly due to the expression of both vasopressin and growth hormone secretagogue receptors by some ectopic ACTH-secreting tumors.129,228
Measurement of marker peptides, such as calcitonin, gastrin, 5-hydroxyindoleacetic acid, serotonin, and catecholamines or their metabolites, may help to identify a neuroendocrine tumor.
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In porcine and bovine studies, synthetic GHS-R analogues such as hexarelin have been shown to stimulate GH secretion directly by peripheral immune cells (Poppi et al., 2002). The ability of GHS to induce GH expression by immune cells suggests that GH may act as an intermediate regulating some of the biological effects of ghrelin or synthetic ghrelin mimetics. Similar to GH, treatment of mice with a synthetic GHS-R agonist for 3 weeks significantly increased thymic cellularity in old mice along with improved bone marrow engraftment using a SCID model (Koo et al., 2001). However, the role of GH as an intermediate in the observed GHS-R agonist effects on the thymus and bone marrow remains to be defined.
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