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2.2 - 12th October 1997



Br J Pharmacol 1997 Jun;121(3):369-374

Effects of chronic growth hormone treatment in aged rats on the biophysical and pharmacological properties of skeletal muscle chloride channels.

De Luca A, Pierno S, Cocchi D, Conte Camerino D

Dipartimento Farmacobiologico, Facolta di Farmacia, Universita di Bari, Italy.

1. The effects of a 4-month daily treatment with recombinant human growth hormone (GH) (150 micrograms kg-1) to aged rats were evaluated on the passive and active membrane electrical properties of extensor digitorum longus (EDL) muscle fibres in vitro by means of a two intracellular microelectrode technique. 2. Chronic GH treatment completely restored the diameter and the membrane capacitance of aged EDL muscle fibres and significantly lowered the membrane resistance towards the adult value. There was also an increase of the threshold current, a shortening of the latency and an increase of the amplitude of the action potential and a significant amelioration of the membrane firing capability. 3. The effects were almost fully attributable to a significant 50% increase of resting conductance to chloride ions (GCl), although an observed restoration of potassium conductance and a possible effect on voltage-activated sodium channels could contribute to the effects. 4. EDL muscle fibres of untreated aged rats showed a different pharmacological response to 2-(p-chlorophenoxy) propionic acid (CPP) enantiomers from that seen in adult rats; the S-(-) isomer was less potent in blocking GCl and the R-(+) isomer always increased GCl instead of producing the typical biphasic effect observed in adult fibres (an increase of GCl at 1-10 microM and a decrease at higher concentrations). The 4-month-GH-treated aged rats showed a pharmacological sensitivity to CPP enantiomers similar to that of adults. 5. The in vitro application of insulin-like growth factor I (IGF-I), the peripheral mediator of GH, produced a significant and irreversible increase of GCl of EDL muscle of EDL muscle of untreated aged rats, an effect not observed in adults. This effect was completely inhibited by preincubation with 0.5 microM okadaic acid, suggesting that the IGF-I receptor transduction pathway can act on the phosphorylation state of the chloride channel through a serine-threonine protein phosphatase. 6. The results show that the skeletal muscle chloride channel is a target of the impairment of GH/IGF-I axis occurring in aged subjects. The acute and chronic effects observed on GCl of aged muscle fibres suggest that the GH/IGF-I stimuli act through a modulation of channel phosphorylation state and through the synthesis of 'adult'-like type chloride channels.

Eur J Endocrinol 1997 Apr;136(4):377-381

Growth hormone increases and insulin-like growth factor-I decreases circulating lipoprotein(a).

Laron Z, Wang XL, Klinger B, Silbergeld A, Wilcken DE

Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, Israel.

BACKGROUND: Elevated serum lipoprotein(a) (Lp(a)) is a strong risk factor for coronary artery disease (CAD). Genetic factors appear to account for the major variance in Lp(a) levels but the contribution hormones make in modulating Lp(a) levels is not yet clear. In the present investigation we determined the effects of human growth hormone (hGH) and insulin-like growth factor-I (IGF-I) on circulating Lp(a). METHODS: Four groups of patients were studied. Group a: adults with GH deficiency (n = 7) treated with hGH (0.05 U/kg/day, s.c.); group b: girls with Turner syndrome (n = 7) treated with hGH (0.1 U/kg/day, s.c.); group c: prepubertal boys with idiopathic short stature (n = 6) treated with the GH secretagogue (GHRP) hexarelin (60 micrograms t.i.d. intranasally); group d: Laron syndrome patients (n = 10) treated with IGF-I (100-200 micrograms/kg/day, s.c.). Following overnight fasting, serum was sampled before the initiation of treatment and during 6-9 months treatment. RESULTS: Serum IGF-I rose significantly in all the subjects in all four groups. In the first three groups in which IGF-I was elevated by exogenous or endogenous GH stimulation, serum Lp(a) increased significantly (119 +/- 35%, P < 0.01; 126 +/- 44%, P < 0.05; 102 +/- 29%, P < 0.01 for groups a, b, and c respectively). By contrast, serum Lp(a) levels decreased in group d to whom exogenous IGF-I was administered (-66 +/- 5%, P < 0.001). The differential effect of endogenous vs exogenous IGF-I on serum Lp(a) paralleled the behaviour of serum insulin. Insulin was significantly increased in all the subjects receiving hGH or GHRP (65.2 +/- 31%, P = 0.109; 93.7 +/- 53%, P = 0.062; 353.8 +/- 52.7%, P < 0.01 for groups a, b, and c respectively) whereas insulin levels were reduced following exogenous administration of IGF-I (-34.1 +/- 9.1%, P < 0.01). CONCLUSIONS: We conclude that long-term GH treatment increases and IGF-I decreases circulating levels of Lp(a). These findings may have clinical relevance in view of the increasing use of hGH in children and adults and the role of Lp(a) as a CAD risk factor.

Neuroendocrinology 1997 Feb;65(2):98-106

Hypophysiotropic somatostatin expression during postnatal development in growth hormone-deficient Ames dwarf mice: mRNA in situ hybridization.

Hurley DL, Wee BE, Phelps CJ

Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.

Lifelong deficiency of growth hormone (GH) in spontaneous or transgenic dwarf mice has been shown to be accompanied by reduced hypophysiotropic somatostatin (somatotropin release-inhibiting hormone, SRIH) expression in hypothalamic anterior periventricular nucleus (PeN). However, the postnatal developmental pattern of SRIH expression in the absence of GH is unknown. Therefore, SRIH mRNA levels in GH-deficient Ames dwarf (df/df) mice and normal (DF/?) littermates were determined both in adults, to compare with other GH-deficient models, and at selected days of postnatal development, to determine the effects of GH deficiency on SRIH neuron development. DF/? and df/df mice of both sexes at postnatal ages 1, 3, 7, 14, 21 and 60 days (adult) were examined. In situ hybridization and image analysis were used to quantify the relative abundance of total SRIH mRNA in the PeN, and SRIH mRNA per cell was determined in PeN and medial basal hypothalamus (MBH). In adult df/df mice, total PeN SRIH mRNA was 45% (p < 0.05) of that in DF/? littermates, which is consistent with studies of other GH-deficient dwarf mice. In developing animals, SRIH expression in the PeN of DF/? mice began at 3 days of age and increased at subsequent ages to reach adult levels. In df/df mice, PeN SRIH mRNA levels at 60 days were significantly greater than at 1-21 days of age (p < 0.05). However, levels were not different over 1-21 days of age, and were consistently lower in df/df than DF/? mice. The difference in total PeN SRIH mRNA between df/df and DF/? mice was statistically significant at 7 days, and at each subsequent age. There were no differences between DF/? and df/df mice in the number of grains per cell in either PeN or MBH at any age. Thus, the reduced total hypophysiotropic SRIH mRNA in GH-deficient Ames dwarf mice appears developmentally shortly after initial detectability of SRIH in the PeN. Because SRIH mRNA per cell was the same for DF/? and df/df mice, the decreased total mRNA in dwarfs suggested reduced SRIH cell numbers in PeN, which was corroborated by immunocytochemical findings. The reduction of SRIH in df/df mice at 7 days of age suggests that GH production during embryonic or very early postnatal development is important to activation of PeN SRIH transcription.

Mol Cell Endocrinol 1997 Jan 3;126(1):49-58

Effects of chronically elevated growth hormone levels on polyamine metabolism in elderly transgenic mice.

Gritli-Linde A, Bjorkman U, Holm I, Tornell J, Linde A

Department of Oral Biochemistry, Goteborg University, Sweden.

The polyamines are ubiquitous, multifunctional aliphatic amines with roles in cell growth, proliferation, differentiation, and malignant development. After growth stimulation, rapid and transient changes occur in polyamine regulatory enzymes. In this respect, acute effects of growth hormone (GH) injection on polyamine metabolic enzymes have earlier been shown. The present investigation comprises studies of the effects on polyamine metabolism of constitutively elevated levels of circulating GH in elderly transgenic (tg+) mice, overexpressing bovine GH. Polyamine levels were found to be constitutively altered in the liver and kidney of tg+ mice. Less changes were found in the spleen and none in the brain. The cellular uptake of polyamines in the liver from tg+ mice showed an increase and considerable changes were observed in the activity of ornithine decarboxylase (ODC) in the liver and kidney and S-adenosylmethionine decarboxylase (AdoMetDC) in the liver. A conspicuous finding was the distribution pattern of ODC protein in the liver and both tg- and tg+ animals. The results show that the effects of chronically elevated GH levels are organ-dependent and complex, and differ from acute GH effects. Despite high ODC activity and polyamine levels in liver, these mice did not display any malignant transformation even at an advanced age, indicating that high ODC activity is not sufficient to induce tumorigenesis in vivo.



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