& Stewart 2005 ). There are two isozymes of 11β-HSD in the body ( Seckl 1993 , Draper & Stewart 2005 ). 11β-HSD1 is ubiquitously distributed in glucocorticoid (GC) target organs where it enhances the binding of cortisol to the relatively low-affinity GR by
Zhen Yang, Chunming Guo, Ping Zhu, Wenjiao Li, Leslie Myatt and Kang Sun
R. G. Glencross, R. D. Lovell and A. T. Holder
The enhancing effect of bovine FSH monoclonal antibody (bFSH-MAb) on the gonadotrophic activity of FSH was investigated in dwarf mice using a uterine weight bioassay.
Increasing doses of bovine FSH (NIH-FSH-B1; 3.3, 10 or 30 μg/day) were administered for 5 days to dwarf mice (groups of five) with or without administration of a bFSH-MAb preparation (USDA-bFSH-MC28; 100 μg protein/day) which at a dilution of 1:15 000 bound 50% of 125I-labelled bFSH (USDA-bFSH-BP3). The bFSH, at the doses given, gave no increases in uterine weight; when, however, these doses were given with bFSH-MAb, significant (three- to four fold) increases in uterine weight resulted.
P. BOIS and H. SELYE
Experiments on intact Sprague-Dawley rats indicate that the adrenal enlargement produced by somatotrophic hormone (STH) can be greatly augmented by simultaneous treatment with comparatively small doses of thyroxine. Within a certain dosage range, the corticotrophic effect of STH is even proportionate to the dose of thyroxine given. The adrenal enlargement produced by adrenocorticotrophic hormone (ACTH), on the other hand, is not enhanced by concurrent treatment with thyroxine.
Attention is called to the fact that, in rats in which adrenocortical hypertrophy is produced, either by STH plus thyroxine or by ACTH plus thyroxine, many of the changes in the extra-adrenal organs, which are generally considered to be indicative of increased glucocorticoid production (inhibition of body weight gain, splenic atrophy, involution of the thymus and lymph nodes, inhibition of inflammatory exudate formation), do not parallel the increase in adrenal weight.
H Yamamoto, C Maake and LJ Murphy
We have recently identified in serum an acid protease which is capable of generating des(1-3)IGF-I from intact IGF-I. Here we have utilized a synthetic substrate with the sequence, biotin-G-P-E-T-L-C-BSA which contains the N-terminal sequence of IGF-I, to investigate the levels of this protease activity in streptozotocin-diabetic rats. Protease activity, quantified in terms of the amount of the biotin label lost, was determined in serum and hepatic extracts from normal control rats, diabetic rats and insulin-treated diabetic rats. Both the serum protease activity and protease activity in hepatic extracts were significantly increased in diabetic rats compared with control rats (P<0.02 and P<0.005). Following acute administration of insulin, a rapid and marked reduction in serum protease activity was observed; with an approximately 50% reduction apparent at 30 min (P<0.001). Chronic insulin treatment of diabetic rats also significantly reduced the serum and hepatic protease activity to the levels seen in control rats. A positive correlation between protease activity and serum glucose level was observed (r=0.58, P<0.005). The abundance of Spi 2.1 mRNA, a serine protease inhibitor, capable of inhibiting the IGF-I protease activity in vitro, was significantly decreased in the liver of diabetic rats and insulin treatment of diabetic rats did not normalize Spi 2.1 mRNA levels. These data suggest that the conversion of IGF-I to the more active des(1-3)IGF-I variant may be enhanced in diabetic animals. Since serum IGF-I levels are reduced in diabetic rats, increased des(1-3)IGF-I-generating protease activity would enhance the functional activity of the circulating IGF-I.
PB Colligan, HM Brown-Borg, J Duan, BH Ren and J Ren
Growth hormone (GH) plays a key role in cardiac growth and function. However, excessive levels of GH often result in cardiac dysfunction, which is the major cause of death in acromegalic patients. Transgenic mice with GH over-expression serve as useful models for acromegaly and exhibit impaired cardiac functions using echocardiography, similar to those of human acromegaly. However, the mechanism underscoring the impaired ventricular function has not been well defined. This study was designed to evaluate the cardiac excitation-contraction coupling in GH over-expressing transgenic mice at the single ventricular myocyte level. Myocytes were isolated from GH and age-matched wild-type mouse hearts. Mechanical properties were evaluated using an IonOptix MyoCam system. The contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS) and time-to-90% relengthening (TR(90)), and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca2+ properties were evaluated by fura-2. GH transgenic mice exhibited significantly increased body weights and enlarged heart and myocyte size. Myocytes from GH transgenic mice displayed significantly enhanced PS and+/-dL/dt associated with similar TPS and TR(90) compared with the wild-type littermates. Myocytes from GH transgenic mice displayed a similar resting intracellular Ca2+ level and Ca2+ removal rate but exhibited an elevated peak intracellular Ca2+ level compared with the wild-type group. Myocytes from both groups were equally responsive to increases in extracellular Ca2+ concentration and stimulating frequency. These results suggest that GH over-expression is associated with enhanced contractile function in isolated myocytes and that the impaired cardiac function observed in whole hearts may not be due to defects at the myocyte level.
M Quinkler, H Troeger, E Eigendorff, C Maser-Gluth, A Stiglic, W Oelkers, V Bahr and S Diederich
The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11beta-HSD type 1 (11beta-HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11beta-HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11beta-HSDs in guinea pig liver and kidney. Tissue slices of untreated guinea pigs were incubated with (3)H-labelled cortisol or cortisone and ACTH(1-24) (10(-10) and 10(-9) mol/l). The 11beta-HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH(1-24). In addition, guinea pigs were treated with ACTH(1-24) or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with (3)H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11beta-HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5alphaTHF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment. The enhanced reductase activity of the hepatic and renal 11beta-HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.
Darryl L Hadsell, Albert F Parlow, Daniel Torres, Jessy George and Walter Olea
also be mediated through the actions of IGF-I ( Dehoff et al . 1988 , Prosser et al . 1990 ). In dairy cows, GH allows for milk production to maintain at higher levels for a longer period of time producing enhanced ‘lactation persistence’ ( Bauman
S. B. Richardson and S. Twente
The precise roles of GH-releasing factor (GRF) and somatostatin (SRIF) in the orchestration of pulsatile GH secretion have not yet been fully determined. We examined the interactions of rat GRF and SRIF, in the concentration ranges present in rat hypophysialportal blood, on the secretion of GH from dispersed male rat anterior pituitary cells in monolayer culture. The effects of exposing cells to GRF and/or SRIF (0·01–1·nmol/l) for 1 h were compared with the effects of preincubation of cells with SRIF before experimental incubations. As anticipated, the stimulatory effects of 0·1–1 nmol GRF/l were abolished by concurrent incubation with SRIF at an equimolar concentration, although SRIF, at these concentrations, did not significantly inhibit basal GH secretion. Conversely, pre-exposure to 0·1 nmol SRIF/l for 30 or 60 min, resulted in an increase in GH secretion during a subsequent 60-min incubation period, both in the absence or in the presence of GRF (0·01–1 nmol/l). Pretreatment with GRF caused increased responsivity to GRF rather than significant sensitization of the GH response to GRF.
These observations demonstrate actions of SRIF, at low and probably physiological concentrations, which are more complex than those of a pure inhibitor of GH secretion. Pre-exposure of the pituitary to SRIF enhances subsequent GH secretion, suggesting that SRIF may play an additional physiological role in amplifying the GRF signal.
Journal of Endocrinology (1991) 128, 91–95
RM Kimble, BH Breier, PD Gluckman and JE Harding
Infants with upper gut atresia often have impaired intrauterine growth and gut function. IGF-I is important in fetal growth and is contained in amniotic fluid. We therefore wanted to test the hypothesis that IGF-I infused into fetal gut would reverse the effects of an upper gut obstruction on gut structure and growth in fetal sheep. At 90 days gestation fetuses (n=6 per group) underwent oesophageal ligation, followed by continuous infusion of IGF-I (1-8 microgram/day) or saline into the gut beyond the ligation until 137 days. Controls underwent sham ligation only. Oesophageal ligation tended to reduce fetal body and organ weights. IGF-I treatment prevented this reduction and increased body length and spleen weight above those of controls. The decrease in bowel wall thickness induced by oesophageal ligation was also prevented by IGF-I treatment. Amniotic fluid IGF-I concentrations did not change over gestation and were higher in the IGF-I treated group. No change in fetal plasma IGF-I concentrations were detectable. We conclude that enterally administered IGF-I may enhance fetal growth and gut development in utero and that IGF-I in amniotic fluid may play a physiological role in gut development in the fetus.
Y Yang, J Cao, W Xiong, J Zhang, Q Zhou, H Wei, C Liang, J Deng, T Li, S Yang, L Xu and L Xu
It has been documented that stress or glucocorticoids have conflicting effects on memory under different conditions. However, it is not fully understood why stress can either impair or enhance memory. Here, we have examined the performance of six age groups of Wistar rats in a water maze spatial task to evaluate the effects of stress under different conditions. We found that the impairment or enhancement effect of an 'elevated platform' (EP) stress on memory was dependent on previous stress experience and on age. EP stress impaired memory retrieval in water maze naive animals, but enhanced rather than impaired memory retrieval in young water maze stress-experienced animals. Furthermore, exogenously applied corticosterone or foot shock stress before water maze training prevented the impairment of memory retrieval that should be induced by treatment with corticosterone or foot shock before the 'probe trial'. Again, memory retrieval was enhanced in young animals under these conditions, and this enhancement can be prevented by the glucocorticoid receptor antagonist RU 38486. Thus, glucocorticoid receptor activation not only induced impairment of memory but also increased the capacity of young animals to overcome a later stress. The present findings suggest that the effect of stress on memory can be switched from impairment to enhancement dependent on both stress experience and age.