© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Growth hormone preserves cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors) and enhances cardiac function in cardiomyopathic hamsters
Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi 755, Japan
* Corresponding author: Tel. 81-836-22-2248; Fax. 81-836-22-2246; e-mail: ohkusa@po.cc.yamaguchi-u.ac.jp
Received 23 October 1997; accepted 12 March 1998
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Abstract |
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Objective: Growth hormone (GH) improves cardiac function in experimental models of heart failure and human dilated cardiomyopathy. However, the mechanism by which GH increases myocardial contractility is not entirely clear. Our aim was to examine the effects of GH on cardiac function and cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors, RyR) in the hearts of UM-X7.1 cardiomyopathic hamsters during the development of heart failure. Methods: Experimental and healthy control hamsters were examined at the age of 20 weeks. Recombinant human GH (2 mg/kg/day, sc) or vehicle was then administered for 3 weeks. We examined (i) the in vivo left ventricular (LV) size and LV systolic function using transthoracic echocardiography, (ii) the density (Bmax) and affinity (Kd) of high-affinity [3H] ryanodine binding sites in crude homogenates from normal and cardiomyopathic hamster hearts. Results: Vehicle-treated UM-X7.1 hamsters exhibited significant increases in left ventricular end-diastolic diameter and end-systolic diameter (LVESd), and a significant decrease in LV fractional shortening (FS). GH-treatment attenuated the increase in LVESd and reduced the LV chamber size, and also significantly increased LVFS. Vehicle-treated UM-X7.1 hamsters exhibited a significantly lower Bmax than control hamsters (0.34±0.04 vs 0.44±0.06 pmol/mg, p<0.05), and the treatment with GH in UM-X7.1 hamsters significantly attenuated the reduction of Bmax {0.42±0.03 pmol/mg vs vehicle-treated group (0.34±0.04 pmol/mg), p<0.05}. Kd did not differ significantly between the experimental groups. In normal control hamsters, GH treatment with this dose did not significantly enhance LV systolic function or the density of RyRs. There was no significant difference in terms of the connective-tissue volume- fraction, myocyte size and capillary density between the GH- and vehicle-treated groups of UM-X7.1 hamsters. Conclusions: GH treatment may improve cardiac function by preserving the density of RyRs and enhancing cellular function in cardiomyopathic hamster hearts.
KEYWORDS Cardiomyopathic hamster; Growth hormone; Heart failure; Ryanodine receptor; Sarcoplasmic reticulum
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1 Introduction |
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TopAbstract1 Introduction2 Materials and methods3 Results4 DiscussionReferences |
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Chronic hypersecretion of growth hormone (GH) induces further growth of most organs and may contribute to a modulation of cardiac function. Previous studies have shown that, in normal rats, chronic hypersecretion of GH caused by implantation of a GH-secreting tumor is associated with an increase in the maximum isometric force of the left ventricular papillary muscle [23, 30, 31]. A modulation of the force developed by papillary muscles contraction could result from an alteration at any step in excitation-contraction coupling, from alterations in sarcoplasmic reticulum (SR) Ca2+-release and -uptake functions, and/or from alterations in the characteristics of the myofibrillar apparatus itself.
The Syrian cardiomyopathic hamster (BIO 14.6 strain or UM-X7.1 strain) displays hereditary abnormalities in cardiac and skeletal muscle [15]. These strains develop a hypertrophic form of cardiomyopathy resulting in a greatly thickened ventricular wall and septum. This hamster model provides a unique opportunity to study factors that might underlie the frequent involvement of the myocardium in human primary muscle disorders. Changes in the failing myocardium of the myopathic hamster include a deficient production of cyclic AMP [39], a decrease in Na+, K+-ATPase [24], a decrease in the function of the SR [8, 27, 38], an inhibition of the Na+/Ca2+ exchanger [26], excessive Ca2+ accumulation [4, 19], fibrosis [28], high inorganic phosphate [18], and a depressed phosphorylation potential [40].
Cardiac SR has the ability to sequester Ca2+, and plays a crucial role in the regulation of intracellular Ca2+. The contraction of cardiac myocytes is triggered by Ca2+ release from the SR, via a Ca2+ release channel that is also referred to as the ryanodine receptor (RyR) [17]. Their relaxation is initiated by an ATP-dependent transport of Ca2+ (via Ca2+-ATPase) back into SR. Thus, the cardiac SR plays an important role in excitation-contraction coupling, and consequently, an abnormality of its functions may result in the systolic and diastolic dysfunctions seen in heart failure. Recently, we studied the alterations of cardiac function and cardiac RyR density that occurred during the development of heart failure in UM-X7.1 cardiomyopathic hamster hearts [34]. Our study showed that the RyRs in the UM-X7.1 cardiomyopathic hamster were preserved at both the hypertrophic stage and the early stage of heart failure (with a possibly compensatory increase in the level of protein expression), even though at this time the cardiac function already showed a tendency to be impaired. As heart failure advanced, the density of RyR gradually decreased.
Although the effects of GH on cardiac function have been studied in experimental heart failure [32] and in human idiopathic dilated cardiomyopathy [9], the mechanism by which GH increases myocardial contraction function is not entirely clear. The goal of the present study was to investigate the effects of GH on cardiac function and cardiac RyRs, which play an important role on the excitation-contraction coupling mechanism, in cardiomyopathic hamsters.
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2 Materials and methods |
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2.1 Animals
Nineteen cardiomyopathic (UM-X7.1) hamsters (kindly provided by Dr. Lemanskie, SUNY Health Science Center, Syracuse, NY, and inbred in our laboratory) and 15 sex-, and age-matched normal golden hamsters (control, Japan SLC Inc., Hamamatsu, Japan) were used as experimental animals. Both the cardiomyopathic and normal hamsters were housed 5 hamsters per cage in an air-conditioned room with automatic 12-h day/12-h night cycling in the Experimental Animal Facility of the Yamaguchi University School of Medicine. They were all maintained under identical conditions on a normal laboratory diet with ad libitum access to tap water. Recombinant human GH (1 mg/kg twice a day) (Norditropin, Novo Nordisk A/S, Denmark) or vehicle was injected subcutaneously in both cardiomyopathic and normal hamsters for 3 weeks as described previously [42]. Our choice of this dose of GH was based on a previous study [42]in which the results showed that this dose could produce a significant increase in myocardial contractility in rats with cardiac dysfunction. According to our previous report [34], in the UM-X7.1 hamster at the age of 18-20 weeks, although the cardiac function was impaired (LVEDd and LVESd were increased and LVFS was decreased), the content of ryanodine protein was compensated and the Bmax value showed no significant difference from the control hamster. Based on these results, we decided to start the GH treatment at 20 weeks when the Bmax value was almost equivalent with control hamster. The care of the animals and the protocols used conformed with the Guiding Principles in the Care and Use of Animals and were in accord with guidelines laid down by the Animal Ethics Committee of Yamaguchi University School of Medicine. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985).
2.2 General protocols and study objectives
To enable us to determine the left ventricular (LV) dimension and assess the contractile state in vivo, transthoracic echocardiography [21]was performed before and after 1,2, or 3 weeks treatment with GH or vehicle (echocardiograph model SSD-280, Aloka, Tokyo, Japan, with a 7.5-MHz sector scan probe). For recording the echocardiogram, the animal was placed on its back under mild anesthesia produced with pentobarbital sodium (15 mg/kg, im) [32]. This relatively small dose of pentobarbital sodium did not affect the level of blood pressure, heart rate, or the state of respiration in either type of hamster at any stage [16]. The probe was gently placed in contact with the middle of the thorax through an ultrasound transmission medium (Aquasonic 100, Parker Laboratories, Orange, NJ). M-mode echocardiograms at the papillary muscle level were then obtained, with guidance from two-dimensional long-axis images [10], and recorded on an image printer (UP-500, Sony, Tokyo, Japan). We took the LV end-diastolic diameter (LVEDd) as the widest, and the end-systolic diameter (LVESd) as the narrowest dimension in the M-mode recording. From these measurements, the LV fractional shortening (LVFS) was calculated using previously reported formulas [16]. Assessment of both inter- and intraobserver variability was performed according to the method of Bland and Altman [3]. To determine interobserver variability, 36 M-mode tracings were photocopied, and LVEDd and LVESd were measured independently by two different observers (T. Ueyama and T. Ohkusa). Another set of copies was measured (by T. Ueyama) for intraobserver variability.
At the age of 23 weeks (i.e., after 3 weeks administration of GH), and after the echocardiographic examination was completed, the hamsters were given additional pentobarbital sodium (30 mg/kg, im) and the chest was quickly opened. The heart was excised from each hamster and immersed in ice-cold 0.9% NaCl. After atrial tissue, visible fat, and connective tissues had all been removed, the biventricular tissue was weighed and a crude homogenate immediately prepared for the assay of ryanodine receptor binding.
2.3 Morphology
The hearts were immersion-fixed in 10% buffered formalin. Specimens for histological examination were obtained from each heart, cross slices being cut mid-way between apex and base. The samples were embedded in paraffin and sections 4 µm thick were cut and stained. Myocyte size was quantitatively evaluated in hematoxylin-eosin preparation by method previously described [33]. Intramyocardial small arteries and capillaries were examined as well. Especially, we quantitatively analyzed the capillary density in preparations stained with hematoxylin-eosin: the number of the capillaries was counted that were cut at the nuclear level of the endothelial cells in randomly selected ten high power fields (x400) from the transversely sectioned myocardial area, and then calculated the density per square millimeter. This method probably underestimates the capillary density. But we used it because it was possible to correctly identify capillaries even under a light microscope. The connective-tissue volume-fraction was assessed with the aid of Azan staining [12]. Each field was transferred to a digitizing pad connected to a cursor-computer assembly (NIH image 1.60). The connective-tissue volume-fraction was calculated as the sum of all the connective tissue areas divided by the sum of all connective tissue and muscle areas in all fields [37].
2.4 Blood analysis
Blood samples were obtained at the time of sacrifice. Serum was prepared and frozen at –20°C for subsequent analysis. Human GH was measured in hamster serum by ELISA, according to previously described methods [1].
2.5 Whole ventricle crude homogenate prepartion
A crude homogenate for the [3H]ryanodine binding assay was prepared as previously described, with some modifications [36, 43]. The whole ventricular tissue was homogenized twice for 20s each time, using a Brinkmann Polytron, in 20 mM Tris-maleate containing 0.3 M sucrose, 0.1 M KCl, 5 mg/l leupeptin, and 0.1 mM phenylmethyl sulfonyl fluoride (PMSF), at pH 7.0. The homogenate was filtered through two layers of cheesecloth. Protein concentration was determined by the method of Lowry et al. [22], using bovine serum albumin as standard. Aliquots of homogenate were frozen in liquid nitrogen and stored at -80°C until used.
2.6 Assay of [3H]ryanodine binding
[3H]ryanodine binding assays were carried out according to previously described methods [25, 37, 43]. Briefly, aliquots of crude homogenate (0.4 mg/ml) were incubated for 90 min at 37°C in 25 mM imidazole (pH 7.4), 1.0 M KCl, 1.103 mM CaCl2, 0.95 mM EGTA (20 µM free Ca2+), in each case with a concentration of [3H]ryanodine (specific activity 68.3 Ci/mmol, DuPont, Boston, MA, USA) from within the range 0.6-20 nM. The reaction was terminated by rapid filtration of 1 ml of the incubation mixture through a glass fiber filter (Whatman GF/C, Maidstone, UK) under reduced pressure. To minimize the nonspecific binding component, each filter was immediately washed with 5 ml of ice-cold buffer (25 mM imidazole, 1.0 M KCl, 1.103 mM CaCl2, 0.95 mM EGTA, at pH 7.4) and removed while under vacuum. After addition of 5 ml of scintillation fluid, the radioactivity was counted in a scintillation counter with an efficiency of ~50% (LSC-5100, Aloka, Tokyo, Japan). Nonspecific binding was determined in the presence of 2 µM unlabelled ryanodine.
2.7 Statistical analysis
All data are presented as mean±standard deviation (SD). Comparisons were performed by two-way analysis of variance with Scheffe's test. Differences were taken to be significant at p<0.05.
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3 Results |
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3.1 Somatic and cardiac growth
Both UM-X7.1 and golden hamsters treated with GH showed a significantly greater increase in body weight (BW) than vehicle-treated or untreated animals (Table 1). Moreover, the% change in BW of GH-treated UM-X7.1 hamsters was greater than that of GH-treated golden hamsters at both 1 (18 vs 6% increase, respectively) and 3 weeks (47 vs 26% increase, respectively). Although the BW of golden hamsters was significantly greater at each stage than that of UM-X7.1 hamsters, the value of biventricular-to-body weight ratio (calculated using wet weights) was significantly higher in each UM-X7.1 group than that in the corresponding group of golden hamsters. After 3 weeks of treatment, a severe congestive heart failure associated with significant cardiac hypertrophy could be observed both in untreated and vehicle-treated UM-X7.1 hamsters, while the GH-treated hamsters showed no significant heart failure and there was no marked increase in biventricular weight when normalized with respect to BW. In the golden hamsters, GH treatment did not significantly increase the ratio of biventricular weight to BW; in fact, it caused a decrease (Table 1). Treatment with GH elevated the serum level of GH in both UM-X7.1 and golden hamsters (Table 1).
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3.2 Transthoracic echocardiography
Fig. 1 shows representative M-mode echocardiograms of the LV at the papillary muscle level under baseline conditions and after 3 weeks of treatment in each group of UM-X7.1 hamsters. Table 2 shows serial changes in LV dimensions and fractional shortening (FS) in UM-X7.1 and golden hamster groups. At baseline (20 weeks of age), both LVEDd and LVESd were significantly greater in UM-X7.1 hamsters than those in the golden hamsters. After 3 weeks (at 23 weeks of age), both LVEDd and LVESd in untreated UM-X7.1 hamsters were increased and LV motion was reduced compared with baseline group, although not significant (Table 2). In UM-X7.1 hamsters, there was no significant difference of LVEDd between vehicle-treated and GH-treated animals at 3 weeks treatment stage. However, LVESd was slightly, although not significantly, reduced and FS was significantly increased in GH-treated group, compared with the vehicle-treated group at 3 weeks treatment stage (Table 2). On the other hand, among the golden hamsters, the GH-treated group did not show significant changes in LVEDd, LVESd, or FS after 3 weeks of treatment (Table 2). GH treatment did not produce significant alterations in heart rate in either UM-X7.1 or golden hamsters (Table 2).
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3.3 [3H] ryanodine binding assay
Fig. 2 shows representative examples of [3H] ryanodine binding curves from the hearts of UM-X7.1 and golden hamsters at baseline and after 3 weeks of treatment. In each case, data were best interpreted as indicating a single binding site, and there was a well-fitted linear regression for the bound ligand versus bound/free ligand. The mean values for the number of binding sites (Bmax) and the dissociation constant (Kd) for all the groups are shown in Table 3. At base line (20 weeks of age), the Bmax for the crude homogenate did not differ significantly between UM-X7.1 and golden hamster hearts. At 23 weeks of age, a greater reduction in Bmax had occurred in the un-treated or vehicle-treated UM-X7.1 hamsters than in the corresponding golden hamsters. On the other hand, GH treatment prevented the decrease in Bmax otherwise seen in UM-X7.1 hamsters. However, GH treatment did not significantly change the level of Bmax in golden hamsters. The Kd of the [3H] ryanodine binding did not differ significantly between UM-X7.1 and golden hamsters at any stage, nor between vehicle-treated and GH-treated groups.
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) and after 3 weeks treatment either with vehicle (
) or with growth hormone (GH) (
). Nonspecific binding was <10% of total binding at [3H] ryanodine concentrations of 
2.5 nM. Each data point is the average of duplicate determinations.
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3.4 Morphology
The GH-treated and vehicle-treated UM-X7.1 hamster groups showed qualitatively similar morphological abnormalities (Fig. 3). The most obvious feature was the disintegration of cardiomyocytes. This occurred either by myofibrillar dissolution, leaving sarcolemmal remnants and occasionally a few nuclei, or by coagulation of the sarcoplasm, which became substantial scarring throughout the wall of both ventricles. The scar tissues often distributed parallel to the myocardial fascicular runnings, constituting whirlpool-like figures. No active degenerative changes of myocytes were noted, but calcified fragments sequestrated within scars were observed.
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Mean myocyte size was similar among the groups (n=5 in each group): 18.45±0.25 µm in the group of UM-X7.1 hamsters at 20 weeks of age; 18.47±0.12 µm in the group of UM-X7.1 hamsters at 23 weeks of age without GH treatment; and 18.53±0.23 µm in the group of UM-X7.1 hamsters at 23 weeks of age with GH treatment.
There was no apparent small artery disease, i.e., luminal narrowings due to intimal or medial thickening, in any groups. The capillary density (n=5 in each group) was 1199±68/mm2 in the group of UM-X7.1 hamsters at 20 weeks of age, 1130±49/mm2 in the group of UM-X7.1 hamsters at 23 weeks of age without GH treatment, and 1174±63/mm2 in the group of UM-X7.1 hamsters at 23 weeks of age with GH treatment.
There was no significant difference in terms of the connective-tissue volume-fraction between the GH-treated and vehicle-treated groups of UM-X7.1 hamsters at 23 weeks of age (12.0±2.4 vs 11.8±2.5%, respectively, n=5 in each group). These results indicated that, in UM-X7.1 hamsters, the degenerative changes have subsided by 20 weeks of age (connective-tissue volume-fraction at 20 weeks of age was 12.7±2.7%) and that calcified fragments are sequestrated within scar tissue. Moreover, GH treatment at the dose used in the present study (2 mg/kg/day) did not enhance tissue repair and did not prevent structural damage.
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4 Discussion |
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The major findings of this study were as follows: 1) recombinant human GH, given at 2 mg/kg/day for 3 weeks to cardiomyopathic hamsters suffering heart failure, significantly enhanced LV systolic function without any change of LVEDd, whereas the same dose of GH did not affect cardiac function significantly, and did not induce cardiac hypertrophy in age-matched golden (control) hamsters; 2) GH prevented the decrease in the density of cardiac SR ryanodine receptors (RyRs) that otherwise occurred during the development of heart failure in cardiomyopathic hamsters. The second of the effects may contribute to an improvement in cellular function and thus to the improvement in cardiac contractility known to occur with GH. To our knowledge, this is the first investigation that GH treatment can improve cardiac function in cardiomyopathic hamsters (which display a hereditary abnormality in both cardiac and skeletal muscle), and that GH treatment markedly attenuated the reduction of the density of cardiac RyRs in cardiomyopathic hamsters with congestive heart failure. The improvement in cardiac function might be secondary to an increase in myocardial contractility probably attributable to an enhancement of RyRs in damaged myocytes.
4.1 Effects of GH on cardiomyopathic and healthy hamster hearts
This study was designed to assess the in vivo effects of GH administration on cardiac morphology, function, and cardiac SR RyRs in cardiomyopathic and healthy hamsters, and to determine whether such GH treatment might be beneficial or detrimental during the development of heart failure. Absolute biventricular weight increased with GH treatment (2 mg/kg/day) in normal control hamsters, however the biventricular/body weight ratio remained within the normal range. In untreated and vehicle-treated UM-X7.1 cardiomyopathic hamsters, a severe congestive heart failure associated with significant cardiac hypertrophy could be detected. However, with GH treatment, there was no significant increase in biventricular weight when normalized with respect to body weight. These results indicate that the dose of GH used in the study dose not induce a disproportionate growth of the heart in normal hamsters. A previous study [29]also showed that cardiac hypertrophy did not develop with GH treatment: i.e., the ventricular mass remained in the same proportion to body weight in the experimental models used. In the present study, the same dose of GH significantly improved the disproportionate cardiac hypertrophy that occurs during the development of heart failure in cardiomyopathic hamsters.
Previous studies with human acromegalic hearts have shown that the key feature of such hearts is the marked growth of the collagen component, which in part accounts for the increased ventricular mass [13, 20, 35]. On the other hand, in studies of animal models, histological examination has excluded an increase in interstitial tissue as a major component of the cardiac growth [2, 5, 7, 11]. In our study, the connective-tissue volume-fraction did not differ between the GH-, and vehicle-treated groups. Moreover, there was no significant difference in the connective-tissue volume-fraction, which was measured before or after treatment. These results indicate that, in UM-X7.1 cardiomyopathic hamster hearts, the degenerative changes have subsided by 20 weeks of age and that calcified fragments are sequestered within scar tissue in consistent with Jasmin's report [18], and that GH treatment at this dose (2 mg/kg/day) was not acting to prevent structural damage and/or to enhance tissue repair. We suspect that GH may have direct effects on cellular metabolism with a prompt stimulation of protein anabolism and a diversion of amino acid from oxadative to protein synthetic pathways [6, 14] by improving the function of compromised cardiac myocytes or by tending to prevent further functional decline. Our data, which indicate no difference in the connective-tissue volume-fraction as a consequence of GH-treatment, is not consistent with the results of GH hypersecretion on human hearts [13, 20, 35]. The following may explain this inconsistency: 1) we used a moderate dose of GH [5]for short duration (3 weeks), 2) the UM-X7.1 hamsters were treated with GH from the age of 20 weeks, by which time the degenerative changes had subsided and calcified fragments were sequestered within scar tissue.
4.2 Mechanisms by which GH might increase myocardial contractility
The short-term effects of an excess of GH on the heart produce a hyperkinetic state characterized by high cardiac output and decreased peripheral vascular resistance [29]. There have been some reports proposing the mechanisms by which GH might increase myocardial contractility. For instance, studies with a GH-excess model have demonstrated improved contractile performance and a significant increase in the Ca2+ sensitivity of the contractile proteins [23, 30]. Interestingly, GH excess also produced a prolonged action potential [41], which in turn may facilitate Ca2+ influx through L-type Ca2+ channels. This could explain, at least in part, the enhanced myocardial contractility. In addition, chronically high circulating GH levels have been found to induce a myosin phenoconversion consisting of a marked shift toward the low ATPase-activity V3 isoform [23, 30]. Recently, Yang et al. [42]have reported that the reduction in afterload that forms part of the hyperkinetic state was also a beneficial effect of GH in heart failure. Although GH excess would seem to evoke a unique pattern of myocardial responses with a simultaneous improvement in both force and economy of contraction, few studies have been made of the involvement of the Ca2+-regulatory proteins (RyR, Ca2+-ATPase, calsequestrin, etc.) of the SR, which play a crucial role in the regulation of intracellular Ca2+. Recently, we reported that, in the UM-X7.1 cardiomyopathic hamster, the cardiac RyRs were preserved at both the hypertrophic (6-8 weeks of age) and early stages of heart failure (18-20 weeks of age) with a possibly compensatory increase in the level of protein expression; however, the Bmax of these RyR decreased significantly during the development of the congestive heart failure [34]. In the present study, GH treatment largely prevented the decrease otherwise seen in the Bmax of the cardiac RyR in UM-X7.1 hamsters. This might contribute to an alteration in Ca2+ handling and play a part in increasing the amount of intracellular Ca2+ available to activate the myofilaments, which would in turn alter cardiac contractility. We suspect that GH activates protein synthesis [6, 14]in the cardiomyopathic hamster heart and thus limits or prevents the decrease in the number of cardiac RyRs that occurs in the non-GH-treated animal.
4.3 Conclusions
Treatment with a moderate daily dose of GH for 3 weeks improved cardiac function, at least in part, by preserving the density of RyRs in the cardiomyopathic hamster heart. We could not evaluate the long term effect of GH on cardiomyopathic hamster hearts because administration of human GH for a longer period (more than 3 weeks) leads to the production of antibodies against human GH in hamsters. For example, we found that the serum human GH level decreased from 1796±550 ng/ml after 3 weeks administration (see Table 1) to 365±175 ng/ml after 4 weeks. Nevertheless, the present study suggests that administration of exogenous GH in the short-term at an optimal dose may be beneficial, insofar as it appears to have favorable effects on the cardiovascular system in cardiomyopathic animals during the development of heart failure. If we can extrapolate from this result to humans, GH therapy might have great potential as a new and rational therapeutic approach to the treatment of at least some forms of heart failure.
Time for primary review 31 days
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Acknowledgements |
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We thank Dr. G. Takemura, Gifu University School of Medicine, for helpful discussion on histology and Dr. T. Sakumura, Yamaguchi University School of Medicine, for his assistance with the experiments.
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