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European Journal of Heart Failure 2002 4(2):185-191; doi:10.1016/S1388-9842(01)00223-9
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© 2002 European Society of Cardiology

GH-independent cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy

M. Imazioa, M. Bobbioa,*, F. Brogliob, A. Bensob, V. Podioc, M.R. Valettoc, G. Bisic, E. Ghigob and G.P. Trevia

a Division of Cardiology University Internal Medicine Department, Turin, Italy
b Division of Endocrinology University Internal Medicine Department, Turin, Italy
c Division of Nuclear Medicine University Internal Medicine Department, Turin, Italy

* Corresponding author. Divisione Universitaria di Cardiologia, Dipartimento di Medicina Interna, Ospedale ‘Molinette’ corso Dogliotti 14, 10126 Torino, Italy. Tel.: +39-011-633-4028; fax: +39-011-696-7053. E-mail address: marcobobbio{at}libero.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aim: To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP).

Methods and results: We studied the effect of intravenous hexarelin administration on growth hormone (GH) levels and left ventricular ejection fraction (LVEF) evaluated by radionuclide angiography in eight patients with dCMP (age 53.0±2.8, LVEF 16.7±2.1%) and five patients with iCMP (age 52.0±2.8 years, LVEF 22.6±2.1). Results were compared with a group of seven normal subjects (age 37.4±3.4 years, LVEF 64.0±1.5%) and seven patients with severe growth-hormone deficiency (GHD; age 42.0±4.4 years, LVEF 50.0±1.9%) previously studied with the same methodology. In dCMP and iCMP patients hexarelin induced a similar significant (P<0.05) increase in GH levels. In iCMP patients hexarelin induced a LVEF increase (peak LVEF 26.2±2.5%, P<0.05) as observed in normals and GHD, while in dCMP LVEF was unchanged (peak LVEF 17.7±1.7, P = NS). In all groups other hemodynamic parameters were unchanged.

Conclusions: Acute hexarelin administration increases LVEF in iCMP patients (as in normals and GHD) but not in dCMP patients in spite of a similar GH releasing effect and basal LVEF. A possible explanation of the positive inotropic effect of hexarelin in iCMP could be a direct stimulation on viable myocardium or myocardial contractile reserve.

Key Words: Growth hormone • Growth hormone secretagogues • Hexarelin • Ischemic cardiomyopathy • Dilated cardiomyopathy

Received August 21, 2001; Accepted September 13, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Chronic heart failure (CHF) is a clinical syndrome with poor prognosis despite advances in drug therapy. Medical treatment is mainly symptomatic while the only effective treatment for end-stage cases is heart transplantation.

In the past CHF was studied as a hemodynamic disorder but in the last decade interest has focused on neurohormonal activation. It has been found that neurohormonal activation is related to CHF outcome [1–4], and drugs that modulate neurohormonal changes (such as ACE-inhibitors and beta-blockers) showed a positive effect on CHF natural history [5,6].

Evidence of growth hormone (GH) axis alterations in CHF [7] together with observations of GH therapy efficacy to restore left ventricular function in patients with GH deficiency [8] has led to experimental animal studies to investigate GH actions in CHF models. These studies in various models of experimental heart failure showed that GH was able to induce myocyte hypertrophy and improve myocardial contractility and heart metabolic efficiency [9–12].

Beneficial effects of GH therapy were also confirmed in small and uncontrolled human studies in patients with CHF [13–15]. In the most known of these studies Fazio et al. [14] reported a beneficial effect of 3-month intermittent GH-therapy in patients with dilated cardiomyopathy with increased septal thickness and left ventricular mass, improved symptoms, exercise capacity and reduced chamber size and end-systolic wall stress.

Recently two placebo-controlled studies [16,17] reported no significant clinical benefits of GH-therapy in CHF patients. Possible reasons for these discrepancies are acquired GH-resistance in severe CHF and different mode of GH administration (intermittent vs. continuous administration) [18]. So far GH treatment for CHF remains an exciting and open research issue and larger randomized, placebo-controlled studies are needed to assess safety, long-term results and best administration regimen. The search for new neurohormonal agents has led to the study of growth hormone releasing peptides (GHRPs).

GHRPs are a series of hepta (GHRP-1) and hexapeptides (GHRP-2, GHRP-6, hexarelin) that have been shown to be effective GH-releasers in animals and humans after intravenous, subcutaneous, intranasal and even oral administration [19,20]. The most extensively studied GHRP is hexarelin [20,21].

In the cardiovascular system the highest GHRP binding capacity was found in ventricular myocardium followed by atria, aorta, coronary arteries, carotid arteries, endocardium and cava veins [21–23].

In humans GHRPs administration effects have been extensively studied: GH-releasing effect is dose-related [24] and the maximal GH-releasing effect is achieved when given intravenously at 1-2 µg/kg dose [25,26]. The GH-response to GHRPs shows good intraindividual reproducibility [27,28] and is age-dependent [29,30].

Hexarelin and other GHRPs alone and in combination with GH-releasing hormone (GHRH) were found to induce a marked GH-response in children with idiopathic short stature [20,31,32] and even in children and adults with GH deficiency [20,33]. GHRPs response was greatly impaired in patients with pituitary stalk lesions [20,34].

In vitro studies indicate that hexarelin promotes the survival of fetal cardiomyocytes-derived cell lines (H9c2 myocytes) after treatment with cytotoxic agents such as tumor necrosis factor and doxorubicin. In other studies hexarelin showed an anti-apoptotic activity on cardiomyocytes-derived cell lines [21].

In vivo studies of hexarelin showed direct cardiotropic activities in rats. Hexarelin pre-treatment was able to protect against acute myocardial ischemic damage induced by low flow ischemia and reperfusion [35,36]. This protective activity was associated with a prostacyclin release recovery and reduction of angiotensin II activity [36,37]. In aged rats, hexarelin pre-treatment was protective against myocardial stunning [38]. This effect was observed in absence of significant stimulation of somatotroph secretion. In hypophysectomized rats hexarelin maintained the same cardioprotective activities giving evidence of possible direct cardiotropic activities of hexarelin and GHRPs mediated by specific myocardial receptors [39,40].

Since no studies have evaluated GHRPs activity in CHF we decided to investigate possible acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic and dilated cardiomyopathy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Subjects
We studied 13 patients with severe left ventricular dysfunction due to dilated cardiomyopathy [dCMP; eight patients: age 53.0±2.8, left ventricular ejection fraction (LVEF) 16.7±2.1%, body mass index (BMI) 25.7±2.5 kg/m2] and to ischemic cardiomyopathy (iCMP; five patients: age 52.0±2.8 years, LVEF 22.6±2.1%, BMI 25.1±1.0 kg/m2). As part of a comprehensive multi-step protocol we have previously studied seven normal subjects (age 37.4±3.4 years, LVEF 64.0±1.5, BMI 23.3±1.0 kg/m2) and seven patients with severe GH-deficiency (GHD, age 42.0±4.4 years, LVEF 50.0±1.9, BMI 26.2±0.9 kg/m2) with the same methodology [41]. We used these two groups as controls.

Patients with cardiomyopathy with severe left ventricular dysfunction but in NYHA class II and stable clinical condition for the previous 6 months were included in the study. Patients with dCMP were receiving therapy with furosemide (25–50 mg/day), enalapril (10–20 mg/day), aspirin (100 mg/day), carvedilol (25–50 mg/day). Patients with iCMP were receiving therapy with furosemide (25–50 mg/day), enalapril (10–20 mg/day), aspirin (100 mg/day). Two patients were receiving treatment with amiodarone (200 mg/day).

After a complete description of the study purposes and of the diagnostic procedures, all patients gave written informed consent. The investigation conforms with the principles outlined in the Declaration of Helsinki.

On the day of the study subjects were admitted to the study room 2 h before the beginning of the test (16.00 h). The study room was maintained at constant ambient conditions (temperature, light, absence of noise).

2.2. Measurements
An antecubital vein was cannulated for i.v. administration and another one for blood sampling, the latter being kept patent by slow isotonic saline infusion. ECG was continuously monitored in lead II. Blood pressure was monitored by an automated apparatus (SpaceLabs, Inc, Redmond, Washington, USA).

Forty-five minutes after relaxing in recumbent position, all subjects underwent intravenous administration of hexarelin (hex, His-D2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2, Europeptides, Argenteuil, France, 2.0 µg/kg at 0 min).

Before the beginning of hexarelin i.v. administration a basal LVEF was evaluated by equilibrium radionuclide angiocardiography. Equilibrium radionuclide angiography was performed after in vitro labeling of red blood cells with 925 MBq (25 mCi) of 99m Tc. Subjects were imaged supine in the best septal anterior oblique projection.

Acquisition and processing were made using a 400 T GE scintillation camera, equipped with a low energy, all purpose parallel hole collimator, using 24 frames/cycle, 64x64 matrix and a x1.6 zoom factor. Data processing was performed using a standard, highly reproducible, validated semiautomatic procedure, involving multiple regions of interest and background subtraction.

LVEF was calculated from the left ventricular curve. Right ventricle ejection fraction (RVEF) was estimated using a method of two region of interest. Absolute left ventricular end-diastolic volume (LVEDV) was calculated using a validated non-geometric method [42].

In all subjects blood pressure, heart rate, LVEF, left ventricular end-systolic and end-diastolic volumes, cardiac index and systemic vascular resistances were evaluated at baseline and every 15 min for 1 h after hexarelin i.v. administration.

Blood samples for GH assay were collected at baseline and then every 15 min up to 1 h after hexarelin administration. Serum GH levels (µg/l) were measured by immunoradiometric assay (hGH-CTK, Sorin Biomedica, Saluggia, Italy). The sensitivity of the assay was 0.15 µg/l. The inter- and intra-assay coefficients of variation were 2.9–4.5% and 2.4–4.0%, respectively.

2.3. Statistical analysis
Results are expressed as mean±standard deviation. Hemodynamic and hormonal parameters were expressed as absolute values or as percent changes from baseline. Data were analyzed using the paired t-test. A linear correlation coefficient was calculated between LVEF relative variations and GH levels at 30 min (maximal GH secretagogue effect).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Hormonal parameters
Hexarelin stimulated GH release (P<0.05) in patients with dCMP (from 0.2±0.1 to 37.1±12.7 µg/l) and iCMP (from 0.2±0.1 to 31.5±14.8 µg/l).

Peak GH values are reported in Table 1 while GH level variation related to time is shown in Fig. 1.


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  		Table 1 Basal and peak GH levels after hexarelin administration

 


Figure 1
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  		Fig. 1 GH levels (mean±S.D.) related to time after hexarelin i.v. administration.

 
3.2. Hemodynamic parameters
In basal conditions patients with dCMP (LVEF 16.7±2.1%) and iCMP (LVEF 22.6±2.1%) had severe impairment of left ventricular function.

In patients with iCMP hexarelin administration stimulated an increase in LVEF after 30 min (peak LVEF: 26.2±2.5%, P<0.05). However, in patients with dCMP LVEF was unchanged after hexarelin administration (peak LVEF: 17.7±1.7%) (Fig. 2).


Figure 2
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  		Fig. 2 LVEF variations (mean±S.D.) related to time after hexarelin i.v. administration.

 
In all the studied groups other hemodynamic parameters (left ventricular end-diastolic volume, left ventricular end-systolic volume, blood pressure, heart rate, cardiac index, peripheral vascular resistances) were unchanged.

Hemodynamic parameters are shown in Table 2.


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  		Table 2 Hemodynamic parameters in basal condition and 30 min after hexarelin administration

 
No correlation was found between LVEF variation and peak GH in patients with iCMP and dCMP (r=0.34, P=NS) (Fig. 3). The lack of a correlation confirmed that the effect of hexarelin on LVEF was independent from its GH-releasing properties.


Figure 3
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  		Fig. 3 Correlation between LVEF variation (%) and peak GH at 30 min after hexarelin i.v. administration.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Neuroendocrine activities of GH-releasing peptides have been extensively studied [20], particularly hexarelin, which is a well known effective releaser of GH in animals and humans after intravenous, subcutaneous, intranasal, and even oral administration [20,24–28]. Neuroendocrine activities of hexarelin also include an ACTH, cortisol and prolactin stimulatory effect [20,43] while this peptide has some extra-neuroendocrine activities which are only partially known.

These activities are mediated by specific receptors that have been found in pituitary, hypothalamus and other central nervous system areas but even in peripheral tissues and above all in the myocardium [43–45].

Since LVEF is usually considered a surrogate end-point to test the acute activity of treatment for CHF and its increase could be potentially important to treat acutely these patients, we evaluated hexarelin effect in patients with severe impairment of left ventricular function due to iCMP or dCMP.

In this study acute hexarelin administration did not increase LVEF in patients with dCMP and severe left ventricular dysfunction whereas an increase in ejection fraction was observed in patients with iCMP. The effect of hexarelin on LVEF was noted while other hemodynamic parameters were unchanged.

In patients with iCMP hexarelin administration induced an increase in LVEF with the greatest effect at 30 min. In these patients hexarelin had a positive inotropic effect even in the presence of severe left ventricular impairment.

At present this is the first study of hexarelin effects on cardiomyopathies thus no studies are available to make a comparison, however, in animal studies hexarelin showed direct cardiotropic activities in acute ischemia experiments [35,36]. In rats hexarelin was able to protect against acute ischemia and post-ischemic ventricular dysfunction [35,36]; moreover, in aged rats hexarelin pre-treatment was able to reduce myocardium stunning [37]. This effect was observed even in the absence of significant stimulation of somatotroph secretion and also in hypophysectomized rats [39].

Thus a possible explanation of the positive inotropic effect of hexarelin in patients with iCMP could be a direct stimulation on viable myocardium. A possible alternative explanation is that hexarelin could stimulate myocardial contractile reserve.

In a comprehensive protocol we also studied the effects of hexarelin in normal subjects and in patients with severe GHD [41]. As expected we observed GH-release in normal subjects while GH-release was not stimulated in patients with severe GHD (see Table 1, Fig. 1), while we observed a similar increase in LVEF in normal subjects and in patients with severe GHD (see Table 2, Fig. 2).

We observed that in all patients hexarelin GH-releasing properties were maintained with the exception of patients with basal severe GHD. In patients with iCMP, normal subjects and in patients with severe GHD hexarelin had a similar positive inotropic effect. This effect is worthy of further studies to investigate the reproducibility and the physiological mechanism. In patients with dCMP hexarelin had no positive inotropic effect. At present the reason of this difference is unknown, but the receptor down-regulation, as already discovered in heart failure for other molecules such as beta-adrenergic receptors, the lack of sufficient amount of viable myocardium and the presence of stromal disarrangement with diffuse fibrosis as could be present in patients with dCMP, could be a physiopathological explanation.

Since neuroendocrine activity was not correlated with the positive inotropic effect as previously reported [41], the hypothesis of a direct effect of hexarelin on myocardium receptors is strengthened.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In this study acute intravenous administration of hexarelin failed to stimulate heart contractility in patients with severe left ventricular dysfunction due to dCMP, while hexarelin had a positive inotropic effect in patients with severe left ventricular dysfunction due to iCMP. This extra-neuroendocrine activity of hexarelin was independent from its GH-releasing properties (similar effect in normal subjects and in patients with severe GHD) and it was probably mediated by specific heart receptors.

Further studies are needed to explain the reduced positive inotropic effect of hexarelin in patients with dCMP and to investigate hexarelin possible therapeutic use at least in some groups of patients with heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Swedberg K., Eneroth P., Kjeshus J, et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation (1990) 82:1730–1736. for the CONSENSUS Trial Study Group.[Abstract/Free Full Text]
  2. Cohn J.N., Levine T.B., Olivari M.T., et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med (1984) 311:810–823.
  3. Francis G.S., Cohn J.N., Johnson G., et al. for the V-IIeFT VA Cooperative Study Group. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of the therapy in V-IIeFT II. Circulation (1993) 87(VI):VI40–48.[Medline]
  4. Gottlieb S.S., Kukin M.L., Ahem O., Packer M. Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure. J Am Coll Cardiol (1989) 13:1534–1539.[Abstract]
  5. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med (1987) 316:1429–1435.[Abstract]
  6. Waagstein E., Bristow M.R., Swedbetg K., et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet (1993) 342:1441–1446. for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group.[CrossRef][Web of Science][Medline]
  7. Anker S.D., Chua T.P., Ponikowski P., et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation (1997) 96:526–534.[Abstract/Free Full Text]
  8. Amato G., Carella C., Fazio S., et al. Body composition, bone metabolism, heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab (1993) 77:1671–1676.[Abstract]
  9. Yang R., Bunting S., Gillett N., Clark R., Jin H. Growth hormone improves cardiac performance in experimental heart failure. Circulation (1995) 92:262–267.[Abstract/Free Full Text]
  10. Duerr R.L., Huang S., Miralizakbar H.R., Clark R., Chien K.R., Ross J. Jr. lnsulin-Iike growth factor-I enhances ventricular hypertrophy and function during the onset of experimental heart failure. J Clin Invest (1995) 95:619–627.[Web of Science][Medline]
  11. Timsit J., Rion B., Bertherat J., et al. Effects of chronic growth hormone hypersecretion on intrinsic contractility, energetics, isomyosin pattern, and myosin adenosine triphosphatase activity of rat left ventricle. J Clin Invest (1990) 86:507–515.[Web of Science][Medline]
  12. Frustaci A., Perrone G.A., Gentiloni N., Russo M.A. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol (1992) 97:503–511.[Web of Science][Medline]
  13. Cuneo R.C., Wilmshurst P., Lowy C., McGauley G., Sönksen P.H. Cardiac failure responding to growth hormone. Lancet (1989) 333:838–839.[CrossRef]
  14. Fazio S., Sabatini D., Capaldo B., et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med (1996) 334:809–814.[Abstract/Free Full Text]
  15. Volterrani M., Desenzani P., Lorusso R., D'Aloia A., Manelli F., Giustina A. Hemodynamic effects of intravenous growth hormone in congestive heart failure. Lancet (1991) 349:1067–1068.[CrossRef]
  16. Osterziel K.J., Sfrohm O., Schuler J., et al. Randomised, double blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet (1998) 351:1233–1237.[CrossRef][Web of Science][Medline]
  17. Isgaard J., Bergrowth C.H., Caidahl K., Lomsky M., Hjahmarson A., Bengtsson B.A. A placebo controlled study of growth hormone in patients with congestive heart failure. Eur Heart J (1998) 19:1704–1711.[Abstract/Free Full Text]
  18. Anker S.D., Volterrani M., Pflaum C.D., Poole-Wilson P.A., Strasburger C.J., Coats A.J.S. Growth hormone resistance in chronic heart failure [Abstract]. J Am Coll Cardiol (1998) 31(Suppl_A):204A.
  19. Bowers C.Y., Momany F.A., Reynolds G.A., et al. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology (1984) 114:1537–1545.[Abstract/Free Full Text]
  20. Camanni F., Ghigo E., Arvat E. Growth hormone-releasing peptides and their analogs. Front Neuroendocrinol (1998) 19:47–72.[CrossRef][Web of Science][Medline]
  21. Muccioli G., Broglio F., Valetto M.R., et al. Growth hormone-releasing peptides and the cardiovascular system. Ann Endocrinol (2000) 61:27–31.[Medline]
  22. Muccioli G., Ghe’ C., Ghigo M.C., et al. GHRP receptors in pituitary, central nervous system and peripheral human tissues. J Endocrinol Invest (1997) 20(Suppl 4):52.[Web of Science][Medline]
  23. Muccioli G., Papotti M., Ong H., et al. Presence of specific receptors for synthetic growth hormone secretagogues in the human heart. Archiv Pharmacol (1998) 358(Suppl 2):R549.
  24. Gelato M.C., Pescovitz D.H., Cassorla F., et al. Dose-response relationship for the effects of GH-releasing factor 1-44 NH2 in young adult men and women. J Clin Endocrinol Metab (1984) 59:197–203.[Abstract/Free Full Text]
  25. Guan X.M., Yu H., Palyha O.C., et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Mol Brain Res (1998) 48:23–29.
  26. Jacks T., Hickey G., Judith F., et al. Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue on plasma growth hormone, IGF-I, ACTH, cortisol, prolactin, insulin and thyroxine levels in beales. J Endocrinol (1994) 143:399–406.[Abstract/Free Full Text]
  27. Ghigo E., Arvat E., Gianotti L., et al. Growth hormone-releasing activity of Hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal and oral administration in man. J Clin Endocrinol Metab (1994) 78:693–698.[Abstract]
  28. Ghigo E., Arvat E., Rizzi G., et al. Arginine enhances the growth hormone (GH)-releasing activity of a synthetic hexapeptide (GHRP-6) in elderly but not in young subjects after oral administration. J Endocrinol Invest (1994) 17:157–162.[Web of Science][Medline]
  29. Ghigo E., Arvat E., Rizzi G., et al. Growth hormone-releasing activity of growth hormone-releasing peptide-6 is maintained after short-term oral pretreatment with the hexapeptide in normal aging. Eur J Endocrinol (1994) 131:499–503.[Abstract/Free Full Text]
  30. Arvat E., Gianotti L., Grottoli S., et al. Arginine and growth hormone-releasing hormone restore the blunted growth hormone-releasing activity of hexarelin in elderly subjects. J Clin Endocrinol Metab (1994) 79:1440–1443.[Abstract]
  31. Loche S., Colao A., Cappa M., et al. The growth hormone response to Hexarelin in children: reproducibility and effect of sex steroids. J Clin Endocrinol Metab (1997) 82:861–864.[Abstract/Free Full Text]
  32. Leal-Cerro A., Pumar A., Garcia-Garcia E., et al. Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing's syndrome. Clin Endocrinol (1994) 41:649–654.[Medline]
  33. Laron Z., Frenkel J., Deghenghi R., et al. Intranasal administration of the GHRP Hexarelin accelerates growth in short children. Clin Endocrinol (1995) 43:631–635.[Medline]
  34. Van der Berghe G., de Zegher F., et al. Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotropin-releasing hormone in critical illness. Clin Endocrinol (1996) 45:341–351.[CrossRef][Medline]
  35. De Gennaro Colonna V., Rossoni G., Bernareggi M., et al. Cardiac ischemia and impairment of vascular endothelium function in hearts from growth hormone deficient rats: protection by hexarelin. Eur J Pharmacol (1997) 334:201–207.[CrossRef][Web of Science][Medline]
  36. De Gennaro Colonna V., Rossoni G., Bernareggi M., et al. Hexarelin, a growth hormone-releasing peptide, discloses protectant activity against cardiovascular damage in rats with isolated growth hormone deficiency. Cardiologia (1997) 42:1165–1172.[Medline]
  37. De Gennaro Colonna V., Rossoni G., Bernareggi M., et al. Protectant activity of growth hormone against postischemic ventricular dysfunction in hearts from aged rats. J Cardiovascular Pharmacol (1998) 32:260–265.[CrossRef][Web of Science][Medline]
  38. Bodart V., Bouchard I.F., McNicoll N., et al. Identification and characterization of a new growth hormone releasing peptide receptor in the heart. Circulation Res (1999) 85:796–802.[Abstract/Free Full Text]
  39. Locatelli V., Rossoni G., De Gennaro Colonna V., et al. Evidence for direct cardiac effects of Hexarelin in the hypophisectomized rat. In: 80th Annual Meeting of the Endocrine Society, New Orleans, Louisiana (1998) 2–247.
  40. Muccioli G., Ghe’ C., Papotti M., et al. Tissue distribution of GHRP receptors in humans. In: Proceedings of the IV European Congress of Endocrinology, Sevilla, Spain, 9–13 May 1998 (1998) p. 15.
  41. Bisi G., Podio V., Valetto M.R., et al. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest (1999) 22:266–272.[Web of Science][Medline]
  42. Links J.M., Becker L.C., Shindledecker J.G., et al. Measurement of absolute left ventricular volume from gated blood pool studies. Circulation (1982) 65:82–91.[Free Full Text]
  43. Bowers C.Y., Reynolds G.A., Durham D., et al. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab (1990) 70:975–982.[Abstract/Free Full Text]
  44. Bodart V., McNicoll N., Carriere P., et al. Identification and characterization of a new GHRP receptor in the heart. In: Proceedings of the 80th Annual Meeting of the Endocrine Society, New Orleans, Louisiana, June 24th 1998 (1998) 2–239.
  45. Ong H., Bodart V., McNicoll N., et al. Binding sites for growth hormone-releasing peptide. Gh IGF-I Res (1998) 8:137–143.

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Ghrelin Plays a Minor Role in the Physiological Control of Cardiac Function in the Rat
Endocrinology, May 1, 2003; 144(5): 1787 - 1792.
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