The Experts below are selected from a list of 930 Experts worldwide ranked by ideXlab platform

Romano Deghenghi - One of the best experts on this subject based on the ideXlab platform.

  • Hexarelin, a novel GHRP-6 analog, counteracts the inhibitory effect of hydrocortisone on growth hormone secretion in acromegaly.
    Endocrine Research, 2012
    Co-Authors: Andrea Giustina, Romano Deghenghi, Bruno P Imbimbo, Giovanna Bugari, Enrico Bresciani, Anna Rosa Bussi, G. Giustina
    Abstract:

    Hexarelin (His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a GHRP-6 analog with the substitution of D-tryptophan with its 2-methyl derivative. The aim of our study was to ascertain whether Hexarelin was able to counteract the glucocorticoid-mediated increase in hypothalamic somatostatin tone and consequent inhibition on serum GH levels in acromegalic patients. Ten patients (5 males, 5 females; age range 27–71 years; BMI range 23.3–35 kg/m2) with active acromegaly underwent: 1) hydrocortisone alone: a bolus iv injection of 100 mg hydrocortisone succinate in 2 mL saline, at time −60 followed by a 120 min iv infusion of 250 mg hydrocortisone succinate in 250 mL saline, from −60 to 60 min; 2) Hexarelin+hydrocortisone: a bolus iv injection of Hexarelin 100 μg, 60 min after initiation of a 2-hour hydrocortisone infusion; 3) Hexarelin alone: a bolus iv injection of Hexarelin at time 0, 60 min after initiation of a 2-hour saline infusion. The mean GH peak, expressed as percent change with respect to baseline level (...

  • Natural (ghrelin) and synthetic (Hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation.
    Journal of Endocrinology, 2002
    Co-Authors: I Pettersson, Romano Deghenghi, Ezio Ghigo, Giampiero Muccioli, Riccarda Granata, Claes Ohlsson, Jörgen Isgaard
    Abstract:

    Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) Hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide Hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 µM (1473% of control, P

  • natural ghrelin and synthetic Hexarelin gh secretagogues stimulate h9c2 cardiomyocyte cell proliferation
    Journal of Endocrinology, 2002
    Co-Authors: I Pettersson, Romano Deghenghi, Ezio Ghigo, Giampiero Muccioli, Riccarda Granata, Claes Ohlsson, Jörgen Isgaard
    Abstract:

    Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) Hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide Hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 µM (1473% of control, P<0·01) and elicited maximal effects at concentrations around 30 µM. This activity was seen already after 12 h of incubation with a maximal effect after 18 h (1769% of control, P<0·01). Ghrelin also had a significant stimulatory effect on thymidine incorporation (1292% of control at 3 µM and 18 h, P<0·05). The stimulatory effect on thymidine incorporation of Hexarelin, Tyr-Ala-Hexarelin, EP80317 and ghrelin was specific and no stimulatory effect was observed with the truncated GH-releasing peptide EP51389 or the non-peptidyl GHS MK-0677. In competitive binding studies, 125 I-labeled Tyr-AlaHexarelin was used as radioligand and competition curves showed displacement with Hexarelin, Tyr-Ala-Hexarelin, EP80317 and ghrelin, whereas MK-0677 and EP51389 produced very little displacement at 1 µM concentration, adding further support for an alternative subtype binding site in the heart compared with the pituitary. In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes. These findings support potential peripheral effects of GHS on the cardiovascular system independent of an increased GH secretion.

  • effects of acute Hexarelin administration on cardiac performance in patients with coronary artery disease during by pass surgery
    European Journal of Pharmacology, 2002
    Co-Authors: Fabio Broglio, Romano Deghenghi, Giampiero Muccioli, A Benso, Riccarda Granata, Fabio Guarracino, Cristina Gottero, Flavia Prodam, Enrico Avogadri, Ezio Ghigo
    Abstract:

    Abstract Growth hormone (GH) secretagogues are synthetic molecules with neuroendocrine but also cardiovascular activities mediated by specific GH secretagogue-receptors. The acute administration of Hexarelin, a peptidyl GH secretagogue, increases left ventricular ejection fraction in normal subjects and even in patients with severe GH deficiency. We evaluated cardiac performances in patients with coronary artery disease after acute administration of Hexarelin (2.0 μg/kg, i.v.) compared to that in patients given with GH-releasing hormone (GHRH; 2.0 μg/kg, i.v.), recombinant human (rh)-GH (10.0 μg/kg, i.v.) or placebo. Cardiac performance was studied in 24 male patients (age [mean±S.E.M.]: 59.5±1.1 years; body mass index: 24.6±0.9 kg/m2; left ventricular ejection fraction: 57.2±1.4%) with coronary artery disease undergoing by-pass surgery during general anesthesia. Left ventricular ejection fraction, left ventricular end diastolic volume, cardiac index and cardiac output were evaluated by intraoperative omniplane transoesophageal echocardiography while wedge pressure, central venous pressure, mean arterial pressure and systemic vascular resistance index were evaluated by systemic and pulmonary arterial catheterization. RhGH, GHRH and placebo did not exert any hemodynamic effect while Hexarelin induced a prompt (after +10 min) increase in left ventricular ejection fraction (P

  • Effects of acute Hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery.
    European journal of pharmacology, 2002
    Co-Authors: Fabio Broglio, Romano Deghenghi, Giampiero Muccioli, Riccarda Granata, Fabio Guarracino, Andrea Benso, Cristina Gottero, Flavia Prodam, Enrico Avogadri, Ezio Ghigo
    Abstract:

    Growth hormone (GH) secretagogues are synthetic molecules with neuroendocrine but also cardiovascular activities mediated by specific GH secretagogue-receptors. The acute administration of Hexarelin, a peptidyl GH secretagogue, increases left ventricular ejection fraction in normal subjects and even in patients with severe GH deficiency. We evaluated cardiac performances in patients with coronary artery disease after acute administration of Hexarelin (2.0 microg/kg, i.v.) compared to that in patients given with GH-releasing hormone (GHRH; 2.0 microg/kg, i.v.), recombinant human (rh)-GH (10.0 microg/kg, i.v.) or placebo. Cardiac performance was studied in 24 male patients (age [mean +/- S.E.M.]: 59.5 +/- 1.1 years; body mass index: 24.6 +/- 0.9 kg/m(2); left ventricular ejection fraction: 57.2 +/- 1.4%) with coronary artery disease undergoing by-pass surgery during general anesthesia. Left ventricular ejection fraction, left ventricular end diastolic volume, cardiac index and cardiac output were evaluated by intraoperative omniplane transoesophageal echocardiography while wedge pressure, central venous pressure, mean arterial pressure and systemic vascular resistance index were evaluated by systemic and pulmonary arterial catheterization. RhGH, GHRH and placebo did not exert any hemodynamic effect while Hexarelin induced a prompt (after +10 min) increase in left ventricular ejection fraction (P < 0.001), cardiac index (P < 0.001) and cardiac output (P < 0.001) lasting up to +90 min without any variation in left ventricular end diastolic volume. Accordingly, Hexarelin induced a reduction of wedge pressure (P < 0.01). These changes occurred in the presence of increased mean arterial pressure (P < 0.05) and transient decrease of central venous pressure (P < 0.05 at +30 min only) but no change in systemic vascular resistance index. Heart rate after Hexarelin was similar to that after placebo. Hexarelin induced a slight increase in GH levels which was similar to that after GHRH but far lower (P < 0.01) than that after rhGH. Thus, in patients with coronary artery disease undergoing by-pass surgery, the acute administration of Hexarelin clearly improves cardiac performance without any relevant variation in systemic vascular resistance. The cardiotropic effect of Hexarelin is not shared by GHRH or by rhGH, indicating that it is not mediated by the increase in circulating GH levels but more likely reflects activation of specific cardiovascular GH secretagogue receptors.

Ezio Ghigo - One of the best experts on this subject based on the ideXlab platform.

  • d lys ghrp 6 does not modify the endocrine response to acylated ghrelin or Hexarelin in humans
    Neuropeptides, 2007
    Co-Authors: A Benso, Ezio Ghigo, Giampiero Muccioli, Flavia Prodam, Barbara Lucatello, Elena Gramaglia, Fabrizio Riganti, H Schneider, A J Van Der Lely, Fabio Broglio
    Abstract:

    Abstract Acylated ghrelin exerts numerous endocrine and non-endocrine activities via the GH Secretagogue receptor type 1a (GHS-R1a). d -Lys-GHRP-6 has been widely studied in vitro and in vivo in animal studies as GHS-R1a antagonist; its action in humans has, however, never been tested so far. Aim of our study was to verify the antagonistic action of d -Lys-GHRP-6 on the endocrine responses to acylated ghrelin and Hexarelin, a peptidyl synthetic GHS, in humans. The effects of different doses of d -Lys-GHRP-6 (2.0 μg/kg iv as bolus or 2.0 μg/kg/h iv as infusion) on both spontaneous and acylated ghrelin- or Hexarelin (1.0 μg/kg iv as bolus) -stimulated GH, PRL, ACTH and cortisol levels were studied in six normal volunteers (age [mean ± SEM]: 25.4 ± 1.2 yr; BMI: 22.3 ± 1.0 kg/m 2 ). The effects of d -Lys-GHRP-6 (2.0 μg/kg iv as bolus + 4.0 μg/kg/h iv) on the GH response to 0.25 μg/kg iv as bolus acylated ghrelin was also studied. During saline, spontaneous ACTH and cortisol decrease was observed while non changes occurred in GH and PRL levels. Acylated ghrelin and Hexarelin stimulated ( p d -Lys-GHRP-6 administered either as bolus or a continuous infusion did not modify both spontaneous and acylated ghrelin- or Hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. d -Lys-GHRP-6 did not modify even the GH response to 0.25 μg/kg iv acylated ghrelin. In conclusion, d -Lys-GHRP-6 does not affect the neuroendocrine response to both ghrelin and Hexarelin. These findings question d -Lys-GHRP-6 as an effective GHS-R1a antagonist for human studies.

  • GH-independent cardiotropic activities of Hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy.
    European Journal of Heart Failure, 2002
    Co-Authors: Massimo Imazio, Ezio Ghigo, Fabio Broglio, Marco Bobbio, Valerio Podio, M R Valetto, G Bisi, Andrea Benso, Giampaolo Trevi
    Abstract:

    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

  • Natural (ghrelin) and synthetic (Hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation.
    Journal of Endocrinology, 2002
    Co-Authors: I Pettersson, Romano Deghenghi, Ezio Ghigo, Giampiero Muccioli, Riccarda Granata, Claes Ohlsson, Jörgen Isgaard
    Abstract:

    Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) Hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide Hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 µM (1473% of control, P

  • natural ghrelin and synthetic Hexarelin gh secretagogues stimulate h9c2 cardiomyocyte cell proliferation
    Journal of Endocrinology, 2002
    Co-Authors: I Pettersson, Romano Deghenghi, Ezio Ghigo, Giampiero Muccioli, Riccarda Granata, Claes Ohlsson, Jörgen Isgaard
    Abstract:

    Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) Hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide Hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 µM (1473% of control, P<0·01) and elicited maximal effects at concentrations around 30 µM. This activity was seen already after 12 h of incubation with a maximal effect after 18 h (1769% of control, P<0·01). Ghrelin also had a significant stimulatory effect on thymidine incorporation (1292% of control at 3 µM and 18 h, P<0·05). The stimulatory effect on thymidine incorporation of Hexarelin, Tyr-Ala-Hexarelin, EP80317 and ghrelin was specific and no stimulatory effect was observed with the truncated GH-releasing peptide EP51389 or the non-peptidyl GHS MK-0677. In competitive binding studies, 125 I-labeled Tyr-AlaHexarelin was used as radioligand and competition curves showed displacement with Hexarelin, Tyr-Ala-Hexarelin, EP80317 and ghrelin, whereas MK-0677 and EP51389 produced very little displacement at 1 µM concentration, adding further support for an alternative subtype binding site in the heart compared with the pituitary. In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes. These findings support potential peripheral effects of GHS on the cardiovascular system independent of an increased GH secretion.

  • Effects of acute Hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery.
    European journal of pharmacology, 2002
    Co-Authors: Fabio Broglio, Romano Deghenghi, Giampiero Muccioli, Riccarda Granata, Fabio Guarracino, Andrea Benso, Cristina Gottero, Flavia Prodam, Enrico Avogadri, Ezio Ghigo
    Abstract:

    Growth hormone (GH) secretagogues are synthetic molecules with neuroendocrine but also cardiovascular activities mediated by specific GH secretagogue-receptors. The acute administration of Hexarelin, a peptidyl GH secretagogue, increases left ventricular ejection fraction in normal subjects and even in patients with severe GH deficiency. We evaluated cardiac performances in patients with coronary artery disease after acute administration of Hexarelin (2.0 microg/kg, i.v.) compared to that in patients given with GH-releasing hormone (GHRH; 2.0 microg/kg, i.v.), recombinant human (rh)-GH (10.0 microg/kg, i.v.) or placebo. Cardiac performance was studied in 24 male patients (age [mean +/- S.E.M.]: 59.5 +/- 1.1 years; body mass index: 24.6 +/- 0.9 kg/m(2); left ventricular ejection fraction: 57.2 +/- 1.4%) with coronary artery disease undergoing by-pass surgery during general anesthesia. Left ventricular ejection fraction, left ventricular end diastolic volume, cardiac index and cardiac output were evaluated by intraoperative omniplane transoesophageal echocardiography while wedge pressure, central venous pressure, mean arterial pressure and systemic vascular resistance index were evaluated by systemic and pulmonary arterial catheterization. RhGH, GHRH and placebo did not exert any hemodynamic effect while Hexarelin induced a prompt (after +10 min) increase in left ventricular ejection fraction (P < 0.001), cardiac index (P < 0.001) and cardiac output (P < 0.001) lasting up to +90 min without any variation in left ventricular end diastolic volume. Accordingly, Hexarelin induced a reduction of wedge pressure (P < 0.01). These changes occurred in the presence of increased mean arterial pressure (P < 0.05) and transient decrease of central venous pressure (P < 0.05 at +30 min only) but no change in systemic vascular resistance index. Heart rate after Hexarelin was similar to that after placebo. Hexarelin induced a slight increase in GH levels which was similar to that after GHRH but far lower (P < 0.01) than that after rhGH. Thus, in patients with coronary artery disease undergoing by-pass surgery, the acute administration of Hexarelin clearly improves cardiac performance without any relevant variation in systemic vascular resistance. The cardiotropic effect of Hexarelin is not shared by GHRH or by rhGH, indicating that it is not mediated by the increase in circulating GH levels but more likely reflects activation of specific cardiovascular GH secretagogue receptors.

Chen Chen - One of the best experts on this subject based on the ideXlab platform.

  • enhanced pulsatile growth hormone secretion and altered metabolic hormones by in vivo Hexarelin treatment in streptozotocin induced diabetic rats
    International Journal of Molecular Sciences, 2018
    Co-Authors: Xinli Zhang, Jinkui Yang, Chen Chen
    Abstract:

    Significant growth hormone (GH) reductions have been reported in diabetic animal models with disturbed metabolic balance coinciding with GH deficiency. Therefore, enhanced GH secretion may have beneficial effects in controlling diabetes. Thus, we aim to investigate the effect of Hexarelin, a synthetic GH secretagogue (GHS), on GH secretion in streptozotocin (STZ, 65 mg/kg)-induced diabetic rats. Daily Hexarelin (100 μg/kg) treatment was performed for two weeks in four-week-long STZ-diabetic and vehicle control rats. Pulsatile GH secretion in STZ-rats was significantly reduced in total, pulsatile, basal, and mass of GH secretion per burst. In addition, impaired GH secretion was followed by an increase in fasting-level free fatty acids (FFAs) and a decrease in insulin-like growth factor 1 (IGF-1) compared to control rats. After Hexarelin treatment, pulsatile GH secretion in STZ-rats was significantly increased in total, pulsatile, and basal, but not in the mass GH secretion per burst, compared to STZ-rats without Hexarelin treatment. However, there was no significant elevation in GH secretion in the Hexarelin-treated control group. In addition, Hexarelin-treated STZ-rats showed a significant decrease in fasting level FFAs, whereas suppression of fasting level for IGF-1 was maintained. These results suggest that STZ-induced diabetic rats have impaired pulsatile GH secretion, causing increased FFAs and decreased IGF-1 levels in circulation. Hexarelin injections for two weeks is able to normalize impaired pulsatile GH secretion with normal fasting levels of FFAs, but fails to recover IGF-1 levels.

  • improvement of cardiomyocyte function by in vivo Hexarelin treatment in streptozotocin induced diabetic rats
    Physiological Reports, 2018
    Co-Authors: Xinli Zhang, Linbing Qu, Ling Chen, Chen Chen
    Abstract:

    Diabetic cardiomyopathy is characterized by diastolic and systolic cardiac dysfunction, yet no therapeutic drug to specifically treat it. Hexarelin has been demonstrated to improve heart function in various types of cardiomyopathy via its receptor GHS-R. This experiment aims to test the effect of Hexarelin on cardiomyocytes under experimental diabetes. Streptozotocin (STZ, 65 mg/kg)-induced diabetic rat model was employed with vehicle injection group as control. Daily Hexarelin (100 μg/kg) treatment was performed for 2 weeks after 4-week STZ-induced diabetes. Cardiomyocytes were isolated by enzyme treatment under O2-saturated perfusion for single-cell shortening, [Ca2+]i transient, and electrophysiology recordings. GHS-R expression and apoptosis-related signaling proteins Bax, Bcl-2, caspase-3 and 9, were assessed by western blot. Experimental data demonstrated a reduced cell contraction and relaxation in parallel with depressed rise and fall of [Ca2+]i transients in diabetic cardiomyocytes. Hexarelin reversed the changes in both contraction and [Ca2+]i. Action potential duration and transient outward potassium current (Ito) density were dramatically increased in diabetic cardiomyocytes and Hexarelin treatment reverse such changes. Upregulated GHS receptor (GHS-R) expression was observed in both control and diabetic groups after Hexarelin treatment, which also caused antiapoptotic changes of Bax, Bcl-2, caspase-3 and 9 expression. In STZ-induced diabetic rats, Hexarelin is able to improve cardiomyocyte function through recovery of Ito K+ currents, intracellular Ca2+ homeostasis and antiapoptotic signaling pathways.

  • Hexarelin a growth hormone secretagogue improves lipid metabolic aberrations in nonobese insulin resistant male mkr mice
    Endocrinology, 2017
    Co-Authors: Rasha Mosa, Lili Huang, Yeda Wu, Chungyan Fung, Oshini Mallawakankanamalage, Derek Leroith, Chen Chen
    Abstract:

    Despite the occurrence of dyslipidemia and its contribution to the development of insulin resistance in obese subjects, a growing number of studies have described abnormal lipid profiles among leaner persons. For example, individuals with an abnormal paucity or distribution of fat (lipodystrophy) develop severe insulin resistance, dyslipidemia, and hepatic steatosis. Deranged adipocyte metabolism and differentiation contribute to ectopic fat deposition and consequent development of insulin resistance. Growth hormone (GH) therapy has been shown to correct body composition abnormalities in some lipodystrophy patients. However, little is known about the effects of GH-releasing peptides in this regard. Hexarelin, a GH secretagogue, has recently been shown to have beneficial effects on fat metabolism via the CD36 receptor. In this study, the effects of twice daily intraperitoneal injections of Hexarelin (200 μg/kg body weight) were examined in nonobese insulin-resistant MKR mice and corresponding wild-type FVB mice for 12 days. Hexarelin treatment significantly improved glucose and insulin intolerance and decreased plasma and liver triglycerides in MKR mice. These beneficial metabolic effects could be due to the improved lipid metabolism and enhanced adipocyte differentiation of white adipose tissue with Hexarelin treatment. Interestingly, although food intake of Hexarelin-treated MKR mice was significantly increased, this did not change total body weight. Moreover, Hexarelin treatment corrected the abnormal body composition of MKR mice, as demonstrated by a decrease in fat mass and an increase in lean mass. Our results suggest a possible application of Hexarelin in treatment of lipid disorders associated with the metabolic syndrome.

  • Implications of ghrelin and Hexarelin in diabetes and diabetes-associated heart diseases
    Endocrine, 2015
    Co-Authors: Rasha Mofeed Habeeb Mosa, Zhen Zhang, Renfu Shao, Chao Deng, Jiezhong Chen, Chen Chen
    Abstract:

    Ghrelin and its synthetic analog Hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and Hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase (JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration reduces glucose levels and increases insulin-producing beta cell number, and insulin secretion in pancreatectomized rats and in newborn rats treated with streptozotocin, suggesting a possible role of GHS in pancreatic regeneration. Therefore, the discovery of GHS has opened many new perspectives in endocrine, metabolic, and cardiovascular research areas, suggesting the possible therapeutic application in diabetes and diabetic complications especially diabetic cardiomyopathy. Here, we review the physiological roles of ghrelin and Hexarelin in the protection and regeneration of beta cells and their roles in the regulation of insulin release, glucose, and fat metabolism and present their potential therapeutic effects in the treatment of diabetes and diabetic-associated heart diseases.

  • chronic administration of Hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat
    American Journal of Physiology-heart and Circulatory Physiology, 2012
    Co-Authors: Xiangbin Xu, Fan Ding, Jinjiang Pang, Rongkun Xu, Chen Chen
    Abstract:

    Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of Hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with Hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, Hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of Hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by Hexarelin treatment. In summary, our data demonstrate that Hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of Hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

Eugenio E Muller - One of the best experts on this subject based on the ideXlab platform.

  • Hexarelin modulates the expression of growth hormone secretagogue receptor type 1a mrna at hypothalamic and pituitary sites
    Neuroendocrinology, 2004
    Co-Authors: Elena Bresciani, Antonio Torsello, Vittorio Locatelli, Ralf Nass, Bruce D Gaylinn, Roberta Avallone, Michael O Thorner, Eugenio E Muller
    Abstract:

    Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS Hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, Hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that Hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

  • Hexarelin but not growth hormone protects heart from damage induced in vitro by calcium deprivation replenishment
    Endocrine, 2001
    Co-Authors: Antonio Torsello, Eugenio E Muller, Vittorio Locatelli, Giuseppe Rossoni, Vito De Gennaro Colonna, Micaela Bernareggi, Maura Francolini, F Berti
    Abstract:

    The effects of Hexarelin, a growth hormone (GH) secretagogue, and human GH on the mechanical and metabolic changes measured in isolated rat hearts submitted to 5 min of Ca2+ deprivation followed by reperfusion with Ca2+-containing medium, the so-called calcium paradox phenomenon, were studied. Hexarelin (80 μg/kg bid, subcutaneously) administered for 7 d to male rats effectively antagonized the sudden increase in resting tension measured in vitro on Ca2+ repletion. Moreover, during Ca2+ repletion the release of creatine kinase activity (an index of cell damage) in the perfusate of these hearts was reduced up to 40% compared with controls. By contrast, administration of Hexarelin for 3 d or GH (400 μg/kg bid, subcutaneously) for 7 d did not affect the mechanical and metabolic alterations induced by the calcium paradox. To assess its direct and acute cardiac effects, Hexarelin (8 μg/mL) was perfused in vitro in recirculating conditions for 60 min through the hearts of normal rats. In this case, Hexarelin did not stimulate heart contractility and failed to prevent ventricular contracture upon Ca2+ readmission, whereas diltiazem, a Ca2+ channel blocker, effectively antagonized the calcium paradox phenomenon. We conclude that short-term in vivo exposure to Hexarelin, but not GH, enables cardiac myocyites to prevent cytoplasmatic electrolytic unbalance and to control intracellular Ca2+ gain, two functions largely impaired during the calcium paradox phenomenon. Moreover, because the effect of Hexarelin is not acute but dependent on the length of in vivo treatment, we suggest that it requires modifications of myocardiocyte physiology.

  • differential orexigenic effects of Hexarelin and its analogs in the rat hypothalamus indication for multiple growth hormone secretagogue receptor subtypes
    Neuroendocrinology, 2000
    Co-Authors: Antonio Torsello, Romano Deghenghi, Eugenio E Muller, Vittorio Locatelli, Maria Rosaria Melis, Salvatora Succu, Maria Sabrina Spano, Antonio Argiolas
    Abstract:

    We have previously reported that Hexarelin and some of its analogs, including EP 50885, stimulated GH secretion and feeding after systemic administration in the rat, whereas EP 40904 selectively stimu

  • endocrine metabolic and cardioprotective effects of Hexarelin in obese zucker rats
    Journal of Endocrinology, 2000
    Co-Authors: V De Gennarocolonna, Antonello E Rigamonti, Giuseppe Rossoni, F Berti, D Cocchi, Eugenio E Muller
    Abstract:

    Genetically obese male Zucker rats have an impaired secretion of GH, coupled to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with Hexarelin, a synthetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with obesity in male obese Zucker rats. Furthermore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of Hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucker rats. Obese and lean male rats of the Zucker strain were treated with Hexarelin (80 µg/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute Hexarelin injection (80 µg, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in lean but not in obese rats (pretreated or not with Hexarelin); lean rats chronically treated with Hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH mRNA levels were significantly reduced in obese rats and Hexarelin administration failed to increase pituitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatment with Hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left unaltered the high triglyceride levels but significantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in creatine kinase released in the perfusates. Hexarelin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with Hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.

  • Hexarelin a growth hormone secretagogue protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium free medium
    Pharmacological Research, 2000
    Co-Authors: Giuseppe Rossoni, Eugenio E Muller, Vittorio Locatelli, Vito De Gennaro Colonna, F Berti
    Abstract:

    The effect of Hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH were studied on the mechanical and metabolic changes elicited by the calcium-paradox phenomenon in isolated rat hearts submitted to 5 min Ca2+-depletion followed by reperfusion with reintegrated Ca2+medium. Hexarelin, (80μ g kg−1s.c.) administered to normal male young rats for 3 and 7-day, time-dependently antagonized the sudden increase in resting tension of the isolated perfused hearts upon Ca2+-repletion. The beneficial effect of Hexarelin was particularly evident in the 7-day treatment. In this instance, ventricular contraction peaked at 30 ± 2 mmHg (controls, 76 ± 7 mmHg) and the recovery of left ventricular developed pressure (LVDP) was two times higher (P< 0.001) than that recorded in controls (LVDP, 29 ± 2 mmHg). Moreover, the release of creatine kinase into the heart effluent during Ca2+-repletion was reduced by 40% (P< 0.001) as compared to controls. The protecting activity of Hexarelin against the damage induced by calcium-paradox in the heart was apparently divorced from any stimulation of the GH/insulin-like growth factor (IGF) axis, since plasma and heart concentrations of IGF-1 were similar to those measured in control rats. In contrast to Hexarelin, administration of GH (400 μ g kg−1s.c.) for 7 days did not affect the mechanical and metabolic manifestations of calcium-paradox in the perfused rat hearts. Hexarelin (8 μ g ml−1) perfused for 60 min through the hearts in recirculating conditions did not modify heart contractility and failed to prevent ventricular hypercontractility developed on Ca2+-readmission. In conclusion, the mode of action of Hexarelin in protecting the rat heart from calcium-paradox events is presently unknown; it would seem, however, that only prolonged exposure to Hexarelin makes myocardial cells competent to maintain cytoplasmatic electrolyte balance and to control of Ca2+gain, two functions that are impaired during the ‘calcium-paradox’ phenomenon.

Vittorio Locatelli - One of the best experts on this subject based on the ideXlab platform.

  • beneficial effects of desacyl ghrelin Hexarelin and ep 80317 in models of status epilepticus
    European Journal of Pharmacology, 2011
    Co-Authors: Giuseppe Biagini, Antonio Torsello, Elena Bresciani, Carla Marinelli, Fabio Gualtieri, R Vezzali, Silvia Coco, Vittorio Locatelli
    Abstract:

    Abstract It has been reported that ghrelin exerts anticonvulsive effects in models of epilepsy. In this study we aimed to characterize the anticonvulsive activity of ghrelin and other growth hormone secretagogue receptor 1a (GHSR1a) ligands in rats exposed to status epilepticus induced by pilocarpine or kainate. Firstly, in three independent experiments, before receiving pilocarpine (380 mg/kg, i.p.), rats were pretreated with one among ghrelin (1.5 mg/kg), desacyl-ghrelin (1.5 mg/kg), Hexarelin (330 μg/kg), EP-80317 (330 μg/kg), JMV-1843 (330 μg/kg), JMV-2959 (330 μg/kg) or saline. Secondly, in the fourth experiment, rats were pretreated with i.p. ghrelin, desacyl-ghrelin, Hexarelin, EP-80317 or saline, followed by kainate (15 mg/kg, i.p.). We evaluated: induction of generalized seizures, latency to generalized seizures, status epilepticus, latency to status epilepticus (the time lag between the first tonic–clonic convulsion and the switch to continuous seizures) and mortality. In the pilocarpine model, 60% of rats pretreated with EP-80317 (P

  • feeding behavior during long term Hexarelin administration in young and old rats
    Journal of Endocrinological Investigation, 2008
    Co-Authors: Elena Bresciani, M Luoni, Vittorio Locatelli, D Cocchi, Nikolaos Pitsikas, Laura Tamiazzo, I Bulgarelli, Antonio Torsello
    Abstract:

    Ghrelin, a 28-amino-acid peptide isolated from the stomach, is the natural ligand of the GH-secretagogues receptor-1a (GHS-R1a) and, so far, the only discovered circulating appetite-stimulating hormone. Similarly to ghrelin, many synthetic compounds belonging to the GHS family stimulate both GH secretion and feeding, whereas some stimulate GH secretion only. In the past years, studies have focused on the potential of the GHS to stimulate GH release during long-term treatment in humans and experimental animals. Few data are available about the extraendocrine effects of the GHS during several weeks of treatment, particularly in old rats. The aim of the present study was first to identify the lowest dose of Hexarelin giving maximal stimulation of food intake both in young (3-month-old) and old rats (24-month-old). A dose-response study (80–320 µg/kg, sc) revealed that Hexarelin at the dose of 80 µg/kg gave reproducibly maximal stimulation of food consumption in young as well as in old rats. Second, we evaluated the effect of 8-week daily sc treatment with Hexarelin in young and old male rats. The outcome of the chronic study was that Hexarelin (80 µg/kg, sc, once daily) maintained a persistent significant orexigenic action throughout the treatment period, both in young and old rats. Interestingly, Hexarelin treatment did not affect body weight gain either in young or old rats. We conclude that Hexarelin is endowed with long-lasting orexigenic activity and might represent a potential therapeutic approach for pathological conditions characterized by a decline in food intake.

  • Hexarelin modulates the expression of growth hormone secretagogue receptor type 1a mrna at hypothalamic and pituitary sites
    Neuroendocrinology, 2004
    Co-Authors: Elena Bresciani, Antonio Torsello, Vittorio Locatelli, Ralf Nass, Bruce D Gaylinn, Roberta Avallone, Michael O Thorner, Eugenio E Muller
    Abstract:

    Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS Hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, Hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that Hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

  • permeability of the peptidic gh secretagogues Hexarelin and ep 51389 across rat jejunum
    Peptides, 2001
    Co-Authors: Marie Roumi, Sylvie Marleau, Patrick Du Souich, Romano Deghenghi, Vittorio Locatelli, Elizabeth Kwong, Richard Beliveau
    Abstract:

    Abstract The intestinal permeability of Hexarelin and EP 51389, two growth hormone releasing hexa- and tri- peptide analogues, was assessed in vitro with side-by-side diffusion chambers in the apical-to-basolateral (AP-to-BL) and in the basolateral-to-apical (BL-to-AP) direction using excised rat jejunal segments. The effect of EP 51389 on P-glycoprotein (P-gp) was evaluated by rhodamine 123 accumulation on monolayers of CH R C5 cells with increasing concentrations of EP 51389. Hexarelin and EP 51389 permeability were found to be app ) were 18.87 ± 2.86 (×10 −7 cm/s) and 5.87 ± 0.45 (×10 −7 cm/s) for Hexarelin and EP 51389, respectively. Bidirectional studies revealed that Hexarelin transport was similar in both directions. EDTA did not influence Hexarelin permeability. Permeability was predominantly secretory for EP 51389 as P app in the BL-to-AP direction [32.56 ± 6.11 (×10 −7 cm/s)] was greater than AP-to-BL. Confirming involvement of a secretory transport system, chlorpromazine inhibited EP 51389 transport across the jejunum. EP 51389 inhibited P-gp in a dose dependent manner resulting in the intracellular accumulation of rhodamine in CH R C5 cells. These results suggest that: 1) the intestinal permeability of Hexarelin and EP 51389 is poor; 2) the passage of Hexarelin is mainly via a transcellular passive pathway since the contribution of paracellular permeability to the overall permeability is rather low; 3) P-gp may act as a potential barrier for the intestinal absorption of EP 51389.

  • Hexarelin but not growth hormone protects heart from damage induced in vitro by calcium deprivation replenishment
    Endocrine, 2001
    Co-Authors: Antonio Torsello, Eugenio E Muller, Vittorio Locatelli, Giuseppe Rossoni, Vito De Gennaro Colonna, Micaela Bernareggi, Maura Francolini, F Berti
    Abstract:

    The effects of Hexarelin, a growth hormone (GH) secretagogue, and human GH on the mechanical and metabolic changes measured in isolated rat hearts submitted to 5 min of Ca2+ deprivation followed by reperfusion with Ca2+-containing medium, the so-called calcium paradox phenomenon, were studied. Hexarelin (80 μg/kg bid, subcutaneously) administered for 7 d to male rats effectively antagonized the sudden increase in resting tension measured in vitro on Ca2+ repletion. Moreover, during Ca2+ repletion the release of creatine kinase activity (an index of cell damage) in the perfusate of these hearts was reduced up to 40% compared with controls. By contrast, administration of Hexarelin for 3 d or GH (400 μg/kg bid, subcutaneously) for 7 d did not affect the mechanical and metabolic alterations induced by the calcium paradox. To assess its direct and acute cardiac effects, Hexarelin (8 μg/mL) was perfused in vitro in recirculating conditions for 60 min through the hearts of normal rats. In this case, Hexarelin did not stimulate heart contractility and failed to prevent ventricular contracture upon Ca2+ readmission, whereas diltiazem, a Ca2+ channel blocker, effectively antagonized the calcium paradox phenomenon. We conclude that short-term in vivo exposure to Hexarelin, but not GH, enables cardiac myocyites to prevent cytoplasmatic electrolytic unbalance and to control intracellular Ca2+ gain, two functions largely impaired during the calcium paradox phenomenon. Moreover, because the effect of Hexarelin is not acute but dependent on the length of in vivo treatment, we suggest that it requires modifications of myocardiocyte physiology.