GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure.

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.

Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro.

Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Angiotensin II (ANG II), an important neurohormonal factor during heart failure, can induce cardiomyocyte apoptosis. Inasmuch as hexarelin has been reported to have protective effects in this process, we examined whether hexarelin can prevent cardiomyocytes from ANG II-induced cell death. Cultured cardiomyocytes from neonatal rats were stimulated with ANG II. Apoptosis was evaluated using fluorescence microscopy, TdT-mediated dUTP nick-end labeling (TUNEL) method, flow cytometry, DNA laddering, and analysis of cell viability by (3,4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). It was found that incubation with 0.1 micromol/l ANG II for 48 h increased cardiomyocyte apoptosis. Administration of 0.1 micromol/l hexarelin significantly decreased this ANG II-induced apoptosis and DNA fragmentation and increased myocyte viability. To further investigate the underlying mechanisms, caspase-3 activity assay and mRNA expression of Bax, Bcl-2, and growth hormone secretagogue receptor (GHS-R; the supposed hexarelin binding site) were examined. GHS-R mRNA was abundantly expressed in cardiomyocytes and was upregulated after administration of hexarelin. These results suggest that hexarelin abates cardiomyocytes from ANG II-induced apoptosis possibly via inhibiting the increased caspase-3 activity and Bax expression induced by ANG II and by increasing the expression of Bcl-2, which is depressed by ANG II. Whether the upregulated expression of GHS-R induced by hexarelin is associated with this antiapoptotic effect deserves further investigation.

Inhibition of beta-estradiol on trachea smooth muscle contraction in vitro and in vivo.

AIM: To investigate the effect of beta-estradiol on trachea smooth muscle contraction in vitro and in vivo. METHODS: (1) Rabbit tracheas were incubated in organ baths filled with Krebs solution and supplied with a mixed gas of 95 % O2 and 5 % CO2. The isometric force was measured by ink-writing recorders. (2) The incubation period of asthma induced by histamine and acetylcholine (ACh) in guinea pig were measured before and after beta-estradiol (1 mg/kg) were given intramuscularly. RESULTS: (1) Administration of beta-estradiol (0.1 mmol/L) caused relaxation of isolated trachea muscle strips (TMS) in rabbits pre-contracted by ACh and KCl (39 % +/- 5 % and 45 % +/- 19 %). The presence of indomethacin or methylene blue partly decreased the relaxation to beta-estradiol (26 % +/- 8 % and 28 % +/- 13 %), but Nomega-nitro-L-arginine (L-NNA) and propranolol and epithelium removal did not affect it (38 % +/- 10 %, 40 % +/- 15 %, 37 % +/- 8 %). beta-Estradiol can shifted the concentration-response curves of ACh and CaCl2 to the rightward (pD2 = 3.98 and 4.75). In addition, it could also significantly inhibit the contraction of phase caused by ACh, but did not affect the contraction of phase II caused by CaCl2. (2) The incubation period of asthma in guinea pig were delayed by beta-estradiol (1 mg/kg) given intramuscularly. CONCLUSION: (1) The relaxation of beta-estradiol in vitro was epithelium independent and associated with the inhibition of potential-dependent channel and release of Ca2+ from sarcoplasm reticulum induced by ACh. In addition, release of prostaglandins from trachea smooth muscle cells and relaxation through cGMP approach were also included. beta-Adrenoceptor-mediated relaxation was not involved. (2) beta-Estradiol can relax the trachea in vivo in guniea pig.