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Brit H Boehmer, Sean W Limesand and Paul J Rozance

CK Lyarmush M 1993 Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans . Diabetes 42 12 – 21 . ( doi:10.2337/diab.42.1.12 ) 8420809 10.2337/diab.42.1.12 Doliba NM Wehrli SL Vatamaniuk MZ

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A Martinez, L Saldise, MJ Ramirez, S Belzunegui, E Zudaire, MR Luquin and F Cuttitta

Adrenomedullin (AM) immunoreactivity has been found in granules of the glomus (type I) cells of the carotid bodies in rats. The identity of these cells was ascertained by colocalization of immunoreactivities for AM and tyrosine hydroxylase in their cytoplasm. Exposure of freshly isolated carotid bodies to synthetic AM resulted in a concentration- and time-dependent degranulation of glomus cells as measured by dopamine (DA) release. DA release reached a zenith 30 min after exposure to AM (94.2% over untreated controls). At this time-point, the response to AM was similar to the one elicited by 5 min of exposure to 100 mM K+. Nevertheless, injection of 1 micro l 60 nM AM/g body weight into the tail vein of the rats did not induce statistical differences in DA release from the carotid bodies. Exposure of the oxygen-sensitive cell line PC-12 to hypoxia elicited an increase in AM mRNA expression and peptide secretion into serum-free conditioned medium. Previous data have shown that elevation of AM expression under hypoxia is mediated through hypoxia-inducible factor-1, and that exposure of chromaffin cells to AM results in degranulation. All these data suggest that AM is an important autocrine regulator of carotid body function.

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1. Mice were irradiated at normal body temperatures, at 1–2° C, at 13–15° C, and after cysteamine injections.

2. Damage to the testis by irradiation was assessed after 28 days by testicular weight and histology.

3. Cooling to 1–2° C during irradiation afforded considerable protection to testes. Cysteamine gave slight protection, and cooling to 13–15° C offered none.

4. It seems probable that the protective effect of hypothermia is due, in part at least, to the associated hypoxia produced when animals are cooled by the method described.

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The effect of repeated increases in plasma ACTH on the production of corticosteroids and androstenedione in the sheep foetus has been investigated. Elevation of foetal plasma ACTH for up to 2 h every 24 h by repeated periods of hypoxia increased the output of cortisol. No consistent effects on foetal or maternal androstenedione concentrations or on maternal oestrogen levels were observed. Repeated short periods of increased foetal plasma ACTH concentration may promote maturation of the foetal adrenal, but there is no increase in androgen secretion by the gland nor is there an increase in oestrogen production by the placenta under such conditions.

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Measurements have been made of hormonal changes relevant to salt and water balance during prolonged exposure to hypoxia to improve our understanding of the syndrome of acute mountain sickness. We have attempted to delineate the detailed inter-relationships between the renin–aldosterone and the vasopressin systems by a metabolically controlled study, involving an orthostatic stress (45° head-up tilt) and an injection of a standard dose of ACTH to test adrenal responsiveness. Three Caucasian medical students underwent a 7-day equilibration at 150 m (Lima, Peru), followed by a 6-day sojourn at 4350 m (Cerro de Pasco, Peru) and a final 7 days at 150 m. Measurements were made of sodium and potassium balance, body weight and the 24-h renal excretion of vasopressin, cortisol and aldosterone 18-glucuronide. These variables showed little change, except for that of aldosterone 18-glucuronide, which fell sharply at altitude and rebounded even more sharply on return to sea level. At altitude, basal plasma levels of renin activity and aldosterone fell, and the response to orthostasis was attenuated, but the fall of plasma renin activity, as compared to plasma aldosterone, was delayed; on return to sea level this dissociation was exacerbated with the return of normal renin responsiveness lagging behind that of aldosterone. We suggest that unknown factors which dissociate the orthodox renin–aldosterone relationship, other than the activity of the angiotensin I-converting enzyme, are operative on exposure to hypoxia.

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1. Male rats which had been exposed to a combination of hypoxia, hypercapnia and cold, and in which body temperature had fallen to between + 15° and + 20° C, showed reduced sex drive and fertility during the subsequent 1–2 weeks.

2. Male rats further cooled until respiration and circulation had been arrested for 1 hr, and until the body temperature was between 0° and + 1·5° C, showed reduced sex drive and fertility for 8 weeks after reanimation.

3. In rats exposed to severe hypothermia, developing spermatozoa and spermatids were damaged, but not the spermatogonia and spermatocytes in the majority of seminiferous tubules. Recovery was well advanced by the 8th week.

4. During the first week after cooling a high proportion of the epididymal spermatozoa became decapitated. Their acrosomes were distorted and their mid-pieces and tail sheaths disrupted.

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Fung M-L, SY Lam, X Dong, Y Chen and PS Leung

In the present study, the effects of postnatal hypoxemia on the AT1 angiotensin receptor-mediated activities in the rat carotid body were studied. Angiotensin II (Ang II) concentration-dependently increased the chemoreceptor afferent activity in the isolated carotid body. Single- or pauci-fiber recording of the sinus nerve revealed that the afferent response to Ang II was enhanced in the postnatally hypoxic carotid body. To determine whether the increased sensitivity to Ang II is mediated by changes in the functional expression of Ang II receptors in the carotid body chemoreceptors, cytosolic calcium ([Ca2+]i) was measured by spectrofluorimetry in fura-2 acetoxymethyl ester-loaded type I cells dissociated from carotid bodies. Ang II (25-100 nM) concentration-dependently increased [Ca2+]i in the type I cells. The proportion of clusters of type I cells responsive to Ang II was higher in the postnatally hypoxic group than in the normoxic control (89 vs 66%). In addition, the peak [Ca2+]i response to Ang II was enhanced 2- to 3-fold in the postnatally hypoxic group. The [Ca2+]i response to Ang II was abolished by pretreatment with losartan (1 microM), an AT1 receptor antagonist, but not by PD-123177 (1 microM), an AT(2) antagonist. Double-labeling immunohistochemistry confirmed that an enhanced immunoreactivity for AT1 receptor was co-localized to the lobules of type I cells in the hypoxic group. In addition, RT-PCR analysis of subtypes of AT1 receptors showed an up-regulation of AT1a but a down-regulation of AT1b receptors, indicating a differential regulation of the expression of AT1 receptor subtypes by postnatal hypoxia in the carotid body. These data suggest that postnatal hypoxemia is associated with an increased sensitivity of peripheral chemoreceptors in response to Ang II and an up-regulation of AT1a receptor-mediated [Ca2+]i activity of the chemoreceptors. This modulation may be important for adaptation of carotid body functions in the hypoxic ventilatory response and in electrolyte and water homeostasis during perinatal and postnatal hypoxia.

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To study the effects of chronic maternal hypoxia on the growth and functional development of foetal and neonatal adrenal glands, Long–Evans rats were acclimatized to high altitude (3800 m) before mating and were maintained at this height throughout gestation. The body growth of the progeny at high altitude was essentially normal during the perinatal period, but adrenal weight and adrenocortical function showed marked differences from those of control rats maintained at sea level. The adrenal glands were larger in foetuses but smaller in neonates, compared with the adrenal glands of control animals maintained at sea level. Differences in the protein content of the adrenal glands between the two groups paralleled differences in adrenal weight. The concentration and content of corticosterone in the adrenal glands of both foetuses and neonates kept at high altitude were markedly lower than values in animals kept at sea level. The lower adrenal corticosterone content was not reflected in the concentration of the hormone in the peripheral plasma, since this was essentially the same at high altitude and at sea level in both mothers and perinatal animals. The reduction in the adrenal corticosterone content was accompanied by and may have resulted from, a reduction in the concentration of cytochrome P-450 in the adrenal tissue of foetuses maintained at high altitude. Possible explanations for the dichotomous results are discussed.

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F. M. Sidey, A. C. Wardlaw and B. L. Furman


Intranasal infection of mice with a sublethal dose of Bordetella pertussis produced hypoglycaemia and hyperinsulinaemia. Exposure to ether vapour did not modify serum insulin concentrations in control mice, but produced a marked transient hyperinsulinaemia in mice infected with B. pertussis. A similar hyperinsulinaemia in infected, but not control, mice was also seen after a brief (10–15 s) period of anoxia (produced by exposure to an atmosphere of 100% N2 or 100% CO2), or following the injection of histamine or 2-deoxyglucose. Exposure to cold (2–4 °C) or hypoxia (8% O2 in 92% N2), however, did not alter serum concentrations of insulin in control or infected mice.

The hyperinsulinaemic response to ether stress observed in mice infected with B. pertussis was abolished by pretreatment with alloxan.

The hyperglycaemic effects of histamine and 2-deoxyglucose were attenuated or abolished in mice infected with B. pertussis. However, none of the stimuli which produced hyperinsulinaemia in the infected mice resulted in any further lowering of the blood glucose concentration.

Pretreatment of mice with pertussis toxin (150 ng/mouse, i.v.) produced hypoglycaemia similar in magnitude to that found in animals infected with B. pertussis. Moreover, exposure of mice treated with pertussis toxin to ether vapour produced marked hyperinsulinaemia.

It is suggested that the metabolic alterations seen in animals infected with B. pertussis may be mediated by pertussis toxin.

J. Endocr. (1987) 112, 113–122

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The effect of s.c. injections of cadmium chloride (3 μmole/100 g. body wt.) on the blood flow and vascular permeability of the testis, epididymis and accessory reproductive organs of rats has been examined. Sapirstein's indicator fractionation technique was used to measure blood flow with [131I]iodoantipyrine and [86Rb]-rubidium chloride. A rubidium-rejecting compartment was found in the testis similar to, but smaller than, that in the brain and pineal body.

Testicular blood flow started to decrease within 3 hr. of giving cadmium (Cd) and by 12 hr. was only 2–9 % of the control values; it then started to recover but after 14 days it was still only 31 % of the control values.

Apart from a small reduction of blood flow to the first part of the head of the epididymis 6 hr. after Cd administration, blood flow was not strikingly reduced in any part of the epididymis by Cd treatment. However, blood flow to all parts of the epididymis had increased markedly when examined 7 days after giving Cd; this was most evident in the first part of the head of the epididymis.

Blood flow through the accessory reproductive organs was reduced within 6 hr. of Cd injection. Blood flow in the seminal vesicles returned to normal between 1 and 14 days after treatment but blood flow in the prostate gland did not recover.

The movement of albumin from intravascular to extravascular compartments was used as an index of vascular permeability. This index increased in the testis in the period 1–6 hr. after Cd administration and the change occasionally occurred before blood flow decreased. A similar increase was seen in the first part of the head of the epididymis 3–6 hr. after Cd, but no change was seen in the rest of the epididymis.

The evidence suggests that Cd acts by damaging the endothelium of the capillaries in the testis leading to prolonged stoppage of blood flow which would lead to hypoxia in the spermiogenic epithelium.