Rat pituitary tumours of the GH3 cell line, secreting growth hormone (GH), were induced to grow in Wistar-Furth rats and the effect of prolonged excessive secretion of GH on various organs was investigated. Total body weight of the tumour-bearing animals increased by over 100% compared with control animals and there was widespread visceromegaly affecting especially the liver, kidney, spleen and adrenals. The heart was also considerably enlarged. The effects of excessive GH on skeletal muscle were not uniform and, using a histochemical technique, it was found that the size type 1 muscle fibres was increased to the greatest extent whereas fibre type 2A was unaffected. Synthesis of DNA in the heart and skeletal muscle was also increased in tumour-bearing animals. Removal of the tumours was followed by a considerable regression in the size of most organs, although hypertrophy of the heart was affected least by a return to normal plasma levels of GH. It was concluded that animals bearing GH3 cell tumours provide a useful experimental model for the study of the tissue changes in acromegaly.
The 'spontaneous' development of pituitary tumours has been studied in the Wistar-Furth strain of rat. In females aged 64--135 weeks the incidence was as high as 69% whereas in males aged 72--116 weeks only 6% developed tumours. Hyperprolactinaemia was invariably associated with these spontaneous pituitary tumours but excessive secretion of growth hormone (GH) was found in one animal only. Bromocriptine inhibited secretion of prolactin and DNA synthesis of the tumours. In a mixed GH- and prolactin-secreting tumour transplanted to a peripheral site, bromocriptine reduced the size of the tumour as well as the secretion of both hormones. Oestradiol reversed the inhibitory action of bromocriptine on prolactin secretion and tumour growth but failed to influence the reduction in GH secretion caused by the drug.
The growth of two human prolactin-secreting cell lines developed in our laboratory has been investigated in response to a number of factors. Oestrogen stimulated the synthesis of DNA and protein and increased prolactin secretion. Dexamethasone had the opposite effect to oestrogen. In the presence of serum, epidermal growth factor (EGF) inhibited cell growth at concentrations of 5 ng/ml. Known secretagogues of prolactin (vasoactive intestinal peptide (VIP), TRH, bombesin and neurotensin) were investigated for their action on cell growth but only VIP had a stimulatory effect. Two preparations of fibroblast growth factor (FGF) were studied. One form, derived from bovine pituitary glands, stimulated human pituitary cell growth. In contrast, another FGF, of the basic type (rFGF), was inhibitory to cell growth, increasing the time for cell doubling from 30 to 72 h. This inhibitory effect of rFGF was modified but not abolished by serum, oestradiol, platelet-derived growth factor or EGF. We conclude that bovine pituitary contains at least two fibroblast growth factors, both of which stimulate fibroblast cell growth, but one stimulates and the other inhibits human pituitary tumour cell growth.
The concentrations of immunoreactive oxytocin and arginine vasopressin (AVP) and their respective neurophysins (NpI and NpII) were compared in bovine adrenal cortex and medulla. While the concentration of AVP was similar in both tissues there was more NpII in the medulla. The medulla also contained much more oxytocin and NpI than the cortex. The extracted AVP and oxytocin had identical retention times to those of the synthetic peptides on high-performance liquid chromatography (HPLC) and were biologically active in assays for antidiuretic and milk-ejection activity (with potencies of 310 units/mg and 340 units/mg respectively). Adrenal NpI and NpII behaved identically to commercially available neurohypophysial proteins on HPLC. Oxytocin, NpI and AVP were assayed in five subcellular fractions of bovine adrenal medulla prepared on discontinuous sucrose gradients. A high proportion of each co-localized with noradrenaline and adrenaline in the chromaffin granule fraction. Binding of [3H]AVP and [3H]oxytocin to crude bovine adrenal medulla membranes was dependent upon both time and temperature. The binding sites were specific and saturable: studies with the V1 AVP antagonist d(CH2)5Tyr(Me)AVP and the V2 agonist 1-deamino-8-D-AVP indicated that the AVP receptor was V1 in specificity. Scatchard plots showed that each ligand interacted with a single high-affinity, low-capacity binding site: oxytocin dissociation constant (Kd) 3.1 +/- 0.29 nmol/l, maximum binding capacity (Bmax) 89.6 +/- 18.4 fmol/mg protein (n = 3); AVP Kd 0.73 +/- 0.02 nmol/l, Bmax 26.5 +/- 8.3 fmol/mg protein (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)
Treatment with a high dose of oestradiol for 6 months caused hyperprolactinaemia and pituitary hyperplasia in female Wistar-Furth rats. Changes in the vasoactive intestinal peptide (VIP) and dopamine content of the hypothalamus and pituitary were also found. The hypothalamic dopamine concentration was only slightly reduced and, although the concentration of dopamine in the pituitary was less in treated animals, the total pituitary content was increased. The concentration of VIP in the pituitary was increased by oestradiol treatment but decreased in the non-median eminence hypothalamus. In the median eminence the VIP content was increased by oestradiol treatment and the amount present correlated positively and significantly with pituitary wet weight in animals treated with both oestradiol and fluphenazine. In Fischer 344 rats, oestradiol produced greater incremental changes in pituitary wet weight and plasma concentrations of prolactin than in Wistar controls and the increase in the pituitary concentration of VIP was five times greater. Although peptide turnover has not been measured, these results suggest that oestradiol, as well as having a direct action, stimulates pituitary lactotrophs by increasing pituitary concentrations of VIP.
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