hexarelin and Ventricular-Dysfunction--Left

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 recep

Topics: Analysis of Variance; Coronary Artery Bypass; Coronary Artery Disease; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Oligopeptides; Statistics, Nonparametric; Stroke Volume; Ventricular Dysfunction, Left

Acute myocardial ischemia and reperfusion injury (IRI) underly the detrimental effects of coronary heart disease on the myocardium. Despite the ongoing advances in reperfusion therapies, there remains a lack of effective therapeutic strategies for preventing IRI. Growth hormone secretagogues (GHS) have been demonstrated to improve cardiac function, attenuate inflammation and modulate the autonomic nervous system (ANS) in models of cardiovascular disease. Recently, we demonstrated a reduction in infarct size after administration of hexarelin (HEX), in a murine model of myocardial infarction. In the present study we employed a reperfused ischemic (IR) model, to determine whether HEX would continue to have a cardioprotective influence in a model of higher clinical relevance. Myocardial ischemia was induced by transient ligation of the left descending coronary artery (tLAD) in C57BL/6 J mice followed by HEX (0.3 mg/kg/day; n = 20) or vehicle (VEH) (n = 18) administration for 21 days, first administered immediately prior-to reperfusion. IR-injured and sham mice were subjected to high-field magnetic resonance imaging to assess left ventricular (LV) function, with HEX-treated mice demonstrating a significant improvement in LV function compared with VEH-treated mice. A significant decrease in interstitial collagen, TGF-β1 expression and myofibroblast differentiation was also seen in the HEX-treated mice after 21 days. HEX treatment shifted the ANS balance towards a parasympathetic predominance; combined with a significant decrease in cardiac troponin-I and TNF-α levels, these findings were suggestive of an anti-inflammatory action on the myocardium mediated via HEX. In this model of IR, HEX appeared to rebalance the deregulated ANS and activate vagal anti-inflammatory pathways to prevent adverse remodelling and LV dysfunction. There are limited interventions focusing on IRI that have been successful in improving clinical outcome in acute myocardial infarction (AMI) patients, this study provides compelling evidence towards the translational potential of HEX where all others have largely failed.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Inflammation; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Oligopeptides; Troponin I; Ventricular Dysfunction, Left; Ventricular Function, Left

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.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Collagen Type I; Collagen Type III; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Heart Diseases; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardium; Oligopeptides; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Ghrelin; RNA, Messenger; Time Factors; Tissue Inhibitor of Metalloproteinase-1; Ventricular Dysfunction, Left; Ventricular Function, Left

Growth hormone (GH)-releasing peptides (GHRP), a class of synthetic peptidyl GH secretagogues, have been reported to exert a cardioprotective effect on cardiac ischemia. However, whether GHRP have a beneficial effect on chronic heart failure (CHF) is unclear, and the present work aims to clarify this issue. At 9 wk after pressure-overload CHF was created by abdominal aortic banding in rats, one of four variants of GHRP (GHRP-1, -2, and -6 and hexarelin, 100 mug/kg) or saline was injected subcutaneously twice a day for 3 wk. Echocardiography and cardiac catheterization were performed to monitor cardiac function and obtain blood samples for hormone assay. GHRP treatment significantly improved left ventricular (LV) function and remodeling in CHF rats, as indicated by increased LV ejection fraction, LV end-systolic pressure, and diastolic posterior wall thickness and decreased LV end-diastolic pressure and LV end-diastolic dimension. GHRP also significantly alleviated development of cardiac cachexia, as shown by increases in body weight and tibial length in CHF rats. Plasma CA, renin, ANG II, aldosterone, endothelin-1, and atrial natriuretic peptide were significantly elevated in CHF rats but were significantly decreased in GHRP-treated CHF rats. GHRP suppressed cardiomyocyte apoptosis and increased cardiac GH secretagogue receptor mRNA expression in CHF rats. GHRP also decreased myocardial creatine kinase release in hypophysectomized rats subjected to acute myocardial ischemia. We conclude that chronic administration of GHRP alleviates LV dysfunction, pathological remodeling, and cardiac cachexia in CHF rats, at least in part by suppressing stress-induced neurohormonal activations and cardiomyocyte apoptosis.

Topics: Animals; Apoptosis; Blood Pressure; Cachexia; Catecholamines; Creatine Kinase; Heart Failure; Hypophysectomy; Myocardial Ischemia; Myocytes, Cardiac; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Ghrelin; RNA, Messenger; Ventricular Dysfunction, Left; Ventricular Remodeling

To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP).. 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.. 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.

Topics: Adult; Cardiomyopathy, Dilated; Hemodynamics; Human Growth Hormone; Humans; Middle Aged; Myocardial Ischemia; Oligopeptides; Severity of Illness Index; Statistics as Topic; Stroke Volume; Time Factors; Ventricular Dysfunction, Left

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 Ca(2+)-depletion followed by reperfusion with reintegrated Ca(2+)medium. Hexarelin, (80 microg kg(-1)s.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 Ca(2+)-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 Ca(2+)-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 microg kg(-1) s.c.) for 7 days did not affect the mechanical and metabolic manifestations of calcium-paradox in the perfused rat hearts. Hexarelin (8 microg 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 Ca(2+)-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 Ca(2+)gain, two functions that are impaired during the 'calcium-paradox' phenomenon.

Topics: Animals; Calcium; Creatine Kinase; Culture Media; Growth Substances; Heart; Human Growth Hormone; Insulin-Like Growth Factor I; Male; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Oligopeptides; Rats; Rats, Wistar; Ventricular Dysfunction, Left; Ventricular Pressure

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 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute hexarelin injection (80 microgram, 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. Hexare! lin 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

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Blood Glucose; Cholesterol; Growth Hormone; Insulin; Insulin-Like Growth Factor I; Male; Myocardial Reperfusion Injury; Myocardium; Obesity; Oligopeptides; Perfusion; Pituitary Gland; Rats; Rats, Zucker; RNA, Messenger; Triglycerides; Ventricular Dysfunction, Left

The ability of hexarelin, a recently synthesized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against postischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats. Heart preparations from control (saline-treated) senescent rats, subjected to moderate ischemia, showed at reperfusion: (a) a low recovery of postischemic left ventricular developed pressure (LVDP; 37% of the preischemic values; from 90 +/- 5.7 to 33.5 +/- 3.8 mm Hg; p < 0.01; n = 10) coupled to a substantial increase in coronary perfusion pressure (CPP; 71% over baseline; from 68.3 +/- 5.2 to 116.8 +/- 4.6 mm Hg; p < 0.01; n = 10); (b) a marked increase of creatine kinase (CK) released in the perfusates (6.6-fold increase over preischemic values; from 45 +/- 4 to 298 +/- 25 mU/min/g wet tissue; p < 0.001; n = 10). In vivo administration of hexarelin (80 microg/kg, b.i.d., s.c.) for 21 days resulted in a striking heart protection against reperfusion stunning. In fact, the recovery of LVDP at reperfusion was almost complete (90% of the preischemic values; from 93 +/- 5.8 to 83.7 +/- 5.9 mm Hg; p > 0.05; n = 9), and the increase in coronary resistance was minimal (from 67 +/- 5.8 to 79.7 +/- 6.9 mm Hg; p > 0.05; n = 9). Furthermore, the concentration of CK in the perfusates was increased only twofold (from 45.8 +/- 5.5 to 90 +/- 7.2 mU/min/g wet tissue; p < 0.05; n = 9), with a gradual return toward basal values at the end of reperfusion. The protectant activity of hexarelin was divorced from any detectable alteration of the somatotropic function, as assessed by pituitary GH messenger RNA (mRNA) and plasma insulin-like growth factor I levels. In vivo administration of GH (400 microg/kg b.i.d., s.c.) for the same time lapse resulted in only a partial protectant activity: 55% of LVDP recovery (from 91.5 +/- 6.2 to 50 +/- 3.5 mm Hg; p < 0.01; n = 6); 65% increase of coronary resistance (from 68 +/- 4.3 to 112.2 +/- 5.2 mm Hg; p < 0.01; n = 6); 5.3-fold increase of CK concentrations in heart perfusates on reperfusion (from 43.8 +/- 3.8 to 232 +/- 16 mU/min/g wet tissue; p < 0.001; n = 6). Evaluation of the rate of release of 6-keto-prostaglandin F1alpha (PGF1alpha), the stable metabolite of prostacyclin, in heart perfusates, and assessment of the vasopressor activity of angiotensin II on the coronary vasculature, did not show any change in these parameters among the three experimental groups. Colle

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Angiotensin II; Animals; Growth Hormone; Heart; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligopeptides; Protective Agents; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left