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M. L. Forsling and L. A. Aziz

Plasma vasopressin, arterial blood gas tensions, pH, arterial blood pressure, heart rate and respiration were monitored in conscious rats breathing room air or exposed to varying degrees of hypoxia. A similar series of observations was made in a group of anaesthetized rats and in rats treated with α- and β-adrenergic and dopaminergic blocking agents. The effect of two opioid antagonists on the vasopressin response was also noted. Hypoxia produced an increase in circulating vasopressin concentrations in both conscious and anaesthetized rats. In the conscious animals the increase reached statistical significance when the animals were exposed to 12% oxygen in nitrogen, which produced a fall in arterial PaO2 of 44·7 ± 5·0%. Guanethidine, phentolamine and propranolol all produced a significant fall in the basal concentrations of vasopressin, while guanethidine, phenoxybenzamine and propranolol blocked the increase seen on breathing 12% oxygen in nitrogen. Naloxone and levallorphan also reduced the vasopressin response to hypoxia. Thus it appears that aminergic pathways play a role in the maintenance of circulating concentrations of vasopressin and in the response to hypoxia. Endogenous opioids also appear to be involved in the hypoxic response.

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A Baldysiak-Figiel, GK Lang, J Kampmeier and GE Lang

Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries. The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation. Particularly, hypoxia and growth factors, such as VEGF, IGF-1, bFGF and TGF beta(2), show a complex interaction in the onset and progression of the diseases. Therefore, to date, most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors. Recently, a synthetic analog of somatostatin, octreotide, has been shown to inhibit the proliferation of various cells in vitro, including endothelial cells. In this study, we have investigated the proliferative response of bovine retinal endothelial cells (BREC) to growth factors under hypoxic conditions and the modulation by octreotide. We found a dose-dependent increase of cell proliferation with VEGF, IGF-1 and bFGF, and inhibition of hypoxia-induced cell proliferation with TGF beta(2). Moreover, growth factor-induced, but not hypoxia-induced, cell proliferation was attenuated in the presence of octreotide. In contrast, TGF beta(2) abolished hypoxia-induced BREC proliferation. Similar to octreotide BIM23027, a somatastatin receptor subtype 2 (SSTR2) receptor agonist was able to attenuate the growth factor-induced proliferation of BREC expressing mRNA and protein for SSTR2. Therefore, we postulate that octreotide exerts its effects mainly through binding to the SSTR2. Taken together, our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor-dependent proliferation of endothelial cells.

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J. R. Gosney

ABSTRACT

When a group of adult male Wistar rats was exposed to a barometric pressure of 380 mmHg for 28 days in an hypobaric chamber, profound changes occurred in their hypothalamic-pituitary-thyroidal axes in comparison with normobaric controls. The thyroid glands of the hypoxic animals had an inactive appearance, comprising large colloid-filled follicles lined by low epithelium. The thyrotrophs of the pars distalis of the pituitary glands were markedly decreased in number. They occupied only 0·41% of the total cell population in contrast with 1·34% in the controls (P<0·001); a total population which is itself decreased in the hypoxic animals. Classical 'thyroidectomy cells' were not seen. These observations support previous studies which indicate suppression of thyroid function in an hypoxic environment, and tend to suggest that this is a consequence of a direct effect of hypoxia on the hypothalamus or pituitary gland, rather than on the thyroid itself.

J. Endocr. (1986) 109, 119–124

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J. R. Gosney

ABSTRACT

A group of ten young adult male Wistar albino rats was exposed to hypobaric hypoxia at a barometric pressure of 380 mmHg for 28 days. After this period their testes were of smaller weight (and volume) in comparison with matched controls (1·220 vs 1·553 g; P < 0·005). Histological examination revealed degeneration and sloughing of spermatogenic cells in occasional tubules. Quantitative methods also revealed a marked difference in the volume of the testis occupied by Leydig cells. These were of a significantly smaller total volume in the hypoxic animals (0·046 vs 0·083 ml; P < 0·001) and this could not be accounted for merely by the smaller overall testicular volume.

J. Endocr. (1984) 103, 59–62

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A Aversa, S Basciani, P Visca, M Arizzi, L Gnessi, G Frajese and A Fabbri

Platelet-derived growth factor (PDGF) overactivity has been implicated in atherosclerosis and several fibrotic conditions including lung and kidney fibrosis, liver cirrhosis and myelofibrosis. Low oxygen tension (hypoxia) is a known stimulus for transcriptional induction of PDGF ligand and receptor genes in different tissues. We studied the expression and localization of PDGF-A, PDGF-B, and PDGF receptor (PDGFR)-alpha and -beta subunits in adult rat isolated corpus cavernosum (CC) under generalized transient hypoxia (pO(2) 10%) in comparison with normoxic conditions. Semi-quantitative RT-PCR analysis of mRNA extracted from rat penis showed higher amounts of PDGF-A, PDGF-B and PDGFR-beta mRNA transcripts in hypoxic versus normoxic animals. The immunohistochemical analysis showed that the localization of PDGF subunits and PDGFR-beta was confined to the cytoplasm of the perivascular smooth muscle cells, endothelium and trabecular fibroblasts. Our findings indicate that transient low oxygen tension induces PDGF overexpression in rat CC, which in the long term may lead to an increase of connective tissue production. We suggest that a local impairment of the PDGF/PDGFR system may contribute to CC fibrosis, which is an established cause of erectile dysfunction in man.

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S S Jonker and S Louey

, these levels are more than 25 times higher than in the prepartum period but then decline soon after ( Velaphi et al . 2007 ). Fetal hypoxia and cortisol can both increase circulating plasma renin activity (PRA) and AII levels ( Broughton Pipkin et al

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R. E. TUFFLEY, D. RUBENSTEIN, J. D. H. SLATER and E. S. WILLIAMS

SUMMARY

Changes of serum renin activity, heart rate, blood pressure, renal sodium, potassium and metadrenaline excretion and alveolar gas tensions were recorded during two 2–3 h exposures to 446 mmHg barometric pressure (simulated altitude of 4279 m or 14000 ft). Serum renin activity rose considerably during the first exposure and only slightly during the second. This effect was positively correlated with the changes of heart rate. There was little change in blood pressure or in the rate of renal excretion of sodium, potassium or the metadrenalines.

It is suggested that the change of serum renin activity cannot be explained by a direct effect of hypoxaemia, emotion, posture or the diurnal rhythm of renin secretion but that it may be correlated with changes of cardiovascular function.

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C. T. M. DAVIES and J. D. FEW

MRC Environmental Physiology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT

(Received 8 April 1976)

Reports on the changes in plasma cortisol level induced by exercise are uncommon, but contradictory. We have previously shown that exercise for 1 h, only leads to a rise in plasma cortisol concentration if the work load exceeds about 60% of the subject's maximal aerobic power (V̄O2, max); that is if his oxygen consumption exceeds 60% of the maximum of which he is capable (Davies & Few, 1973). We have now obtained further evidence of the importance of relative work load (% V̄O2, max) in eliciting an adrenocortical response to exercise, by comparing the changes in plasma cortisol at a given work load under normoxic and hypoxic conditions. The hypoxic condition was breathing 13% oxygen which was expected to reduce V̄O2, max by about 25% (Davies & Sargeant, 1974).

Five

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M Fraser, GA Braems and Challis JR

Responsiveness of the fetal sheep adrenal gland to adrenocorticotrophin (ACTH) increases in late pregnancy, resulting in increased glucocorticoid production. Development of this responsiveness is an important determinant of fetal hypothalamic-pituitary-adrenal function and depends, in part, on the potential for ACTH binding to adrenal tissue. In the present study, we have examined the developmental pattern of ACTH receptor (ACTH-R) expression during the latter half of pregnancy and in neonatal and adult life. As hypoxaemia induces increases in cortisol and ACTH secretion, in addition to increasing fetal adrenal responsiveness, a further aim of this study was to investigate whether hypoxaemia was associated with altered expression of the ACTH-R gene. Whole adrenal glands were removed from fetal sheep, lambs and adult sheep at different stages of development for measurement of ACTH-R mRNA. Moderate hypoxaemia was induced for 48 h beginning on days 124-128, or on days 132-134 of gestation, by decreasing the maternal fractional inspired oxygen. ACTH-R mRNA was detected by northern blotting using a cDNA cloned in our laboratory and by in situ hybridisation. ACTH-R mRNA (3.6 kb major transcript) was detected in adrenal tissue at day 63 of gestation. Its relative abundance increased significantly (P<0.05) between days 126-128 and 140-141 of pregnancy, increased further with the onset of spontaneous labour, and remained increased in newborn lambs at 7 h-7 days after birth. ACTH-R mRNA levels then decreased in adrenal tissue from lambs and adult sheep (P<0.05). Hypoxaemia for 48 h significantly increased ACTH-R mRNA expression in adrenals of the older fetuses (days 134-136) compared with that in controls (P<0.05), but was without effect in younger fetuses. We conclude that levels of ACTH-R mRNA in the fetal adrenal gland increase as term approaches, coincident with the endogenous prepartum surge in plasma ACTH and cortisol. Sustained hypoxaemia resulted in an upregulation of mRNA encoding for ACTH-R, but only in older fetuses and in association with a sustained increase in plasma cortisol. These results are consistent with cortisol, ACTH, or both, contributing to increased fetal adrenal responsiveness, by increasing expression of fetal adrenal receptors for ACTH.

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K S Wilson, C S Tucker, E A S Al-Dujaili, M C Holmes, P W F Hadoke, C J Kenyon and M A Denvir

, results from controls of the dexamethasone group were not different from the controls in the hypoxia and GR morpholino group which were not exposed to ethanol. Previous work involving a dose-ranging study (1–200μM) established 100µM dexamethasone as the