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R Hardy and M S Cooper

Chronic inflammatory diseases of almost any cause are associated with bone loss. Bone loss is due to direct effects of inflammation, poor nutrition, reduced lean body mass, immobility and the effects of treatments, especially glucocorticoids. These mechanisms are complex and interrelated but are ultimately mediated through effects on the bone remodelling cycle. Inflammatory disease can increase bone resorption, decrease bone formation but most commonly impacts on both of these processes resulting in an uncoupling of bone formation from resorption in favour of excess resorption. This review will illustrate these interactions between inflammation and bone metabolism and discuss how these are, and might be, manipulated as therapies for inflammation related bone loss.

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W. G. North, F. T. LaRochelle Jr and G. R. Hardy

Radioimmunoassays are described for vasopressin-associated rat neurophysin (VP-RNP), oxytocin-associated rat neurophysin (OT-RNP) and a major metabolic derivative of oxytocin-associated rat neurophysin (OT-RNP′). The cross-reactions in the radioimmunoassay for VP-RNP with preparations of OT-RNP and OT-RNP′ were 4 and 2%. However, the very small values found for VP-RNP using this radioimmunoassay in concentrated extracts of neural lobes from rats homozygous for the condition of hypothalamic diabetes insipidus (DI) indicate that the sum of the cross-reactions of OT-RNP and OT-RNP′ in the assay is <0·02%. The radioimmunoassay for OT-RNP showed a 100% cross-reaction with OT-RNP′ and a 4% cross-reaction with VP-RNP, while cross-reactions in the radioimmunoassay for OT-RNP′ with OT-RNP and VP-RNP were 17 and 3%. All three radioimmunoassays had a range of measurement from 20 to 1280 pg protein (2–132 fmol). The radioimmunoassays for VP-RNP and OT-RNP were used to measure neurophysin levels in the neural lobes and serum of Long–Evans rats and rats homozygous and heterozygous for DI. Neurophysin values in neural lobes were compared with values for oxytocin and vasopressin obtained by radioimmunoassay. On a molar basis the storage levels of vasopressin in Long–Evans rats were similar to those of VP-RNP; oxytocin levels were similar to the levels of total OT-RNP (OT-RNP + OT-RNP′). The storage levels in oxytocinergic and vasopressinergic neurones were similar. Total OT-RNP and oxytocin levels were similar in homozygous DI rats, while vasopressin and VP-RNP in these animals were <0·013 and <0·1% of the oxytocin and OT-RNP levels respectively. Long–Evans rats given 2% NaC1 for 96 h had drastically reduced storage of all four neurohypophysial peptides, but there was no significant change in their subcellular distribution when compared with control animals. This is taken as evidence that the readily releasable pool is not extragranular. Oxytocin and total OT-RNP were reduced to about 50% by depriving homozygous DI rats of water for 24 h. The storage levels of oxytocin and OT-RNP in female homozygous DI rats were twice those of their male counterparts. Normal serum values of VP-RNP and OT-RNP were 221±41 and 312±43 ng/l for males, and 280 ± 40 and 462±116 ng/l for females. Heterozygous DI rats (all female) had serum values of 165 ± 5 ng VP-RNP/1 and 1130±136 ng OT-RNP/1. In the serum of homozygous DI rats VP-RNP levels were below detectable limits; OT-RNP levels of rats with free access to water were 442± 37 ng/l for males and 959 ± 121 ng/l for females. These values are approximately twice those in Long–Evans rats. In water-deprived homozygous DI rats values of OT-RNP were increased threefold to 1202± 87 ng/l in males and twofold to 1822± 259 ng/l in females. Data indicate that female DI rats have twice the production/release rate of OT-RNP as males.

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R Salemi, JG McDougall, KJ Hardy and EM Wintour

In vivo and in vitro studies have shown conflicting effects of adrenomedullin (ADM) on the secretion of steroid hormones from the adrenal gland. While some investigators report no effect of this peptide on the output of various hormones, others have reported both stimulatory and inhibitory roles for ADM. We have shown that basal aldosterone secretion rate (ASR), in conscious sheep with cervical adrenal autotransplants, did not change when ADM was infused directly into the adrenal arterial supply. While not affecting basal ASR, ADM did produce pronounced increases in adrenal blood flow (BF). This elevation of BF in association with ADM infusion was seen in all subsequent experiments. When aldosterone output was acutely stimulated by angiotensin II (AngII), potassium chloride (KCl) and adrenocorticotrophic hormone (ACTH), ADM was seen to drastically reduce the secretion of aldosterone with all agonists studied. After pre-exposure to ADM, all three agonists increased ASR but the magnitude of the responses were somewhat blunted. ADM did not have the same effect on cortisol secretion stimulated by ACTH, suggesting that the ability of this peptide to influence adrenal gland function is limited to the zona glomerulosa. In conditions of chronic elevation of aldosterone levels, such as in Na deficiency, ADM did not display the same inhibitory abilities seen in the acute stimulation experiments. Hence, ADM has been shown to have a direct, inhibitory role on the acute stimulation of aldosterone by AngII, KCl and ACTH while not affecting basal or chronic aldosterone secretion or cortisol secretion stimulated by ACTH.

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K. W. MALINOWSKA, R. N. HARDY and P. W. NATHANIELSZ

SUMMARY

Plasma cortisol and corticosterone were separated by Sephadex LH-20 chromatography. The high concentration of plasma cortisol immediately after birth in the guinea-pig coincided with the decline in 125I-labelled polyvinyl pyrrolidone (PVP) uptake (closure) between 48 and 72 h. Similarly, in the rabbit, plasma cortisol concentration was increasing at the time of closure, 18–21 days after birth. These results suggest that there is a correlation between the time when the concentration of the main plasma adrenocortical steroid rises and the time when the neonatal small intestine ceases to take up PVP.

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K. G. Braslis, A. Shulkes, D. R. Fletcher and K. J. Hardy

ABSTRACT

Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism.

The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain.

The metabolic clearance rate at steady state was 22·6 ± 2·1 (s.e.m.) and 15·0±1·7 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3·6±0·3 min for the first phase and 13·6±1·0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1–37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial–renal vein gradient of 14%, and the liver, with a portal– hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP. The specific organ clearance, however, accounted for only one-third of the whole body metabolic clearance rate of CGRP, suggesting that other more generalized degradative systems are involved, such as endothelial-bound enzymes of blood vessels. This information on clearance and organ-specific metabolism should form a basis for evaluating the physiological roles and modes of action of CGRP.

J. Endocr. (1988) 118,25–31

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V. G. DANIELS, R. N. HARDY, K. W. MALINOWSKA and P. W. NATHANIELSZ

The villous epithelial cells of the terminal part of the rat small intestine readily absorb maternal antibodies and certain other macromolecules up to the 18th day after birth. Between 18 and 21 days, however, these cells are progressively replaced by more mature cells, and the uptake of macromolecules declines to zero (Clarke & Hardy, 1969a, b). This process has been termed 'closure'.

Closure can be induced at least 9 days before the normal time by the administration of deoxycorticosterone acetate or cortisone acetate (Halliday, 1959). Furthermore, bilateral adrenalectomy at 15–18 days after birth has been shown to delay the time of closure (Daniels & Hardy, 1971). These results suggest that the functional development of the adrenal cortex may determine the maturation of the small intestine with respect to its ability to absorb macromolecules.

In order to investigate further the possible role of the adrenal gland in the mechanism of

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J. R. BLAIR-WEST, J. P. COGHLAN, D. A. DENTON, D. T. W. FEI, K. J. HARDY, B. A. SCOGGINS and R. D. WRIGHT

Comparisons of aldosterone responses to [des-Asp1]-angiotensin II and angiotensin II, often at single dose levels, have shown a wide range of potency ratios. Therefore four-point dose–response comparisons were performed in sodium-replete sheep, using i.v. infusion rates of angiotension II and angiotensin II amide that reproduced the physiological range of blood concentration of angiotensin II for sheep. Angiotensin III was infused i.v. at the same rates. Effects on arterial blood pressure, cortisol secretion rate, adrenal blood flow and plasma levels of Na+ and K+ were also compared. The potency ratio, angiotensin III: angiotensin II amide, was 0·87 for actual aldosterone secretion rate and 0·90 for the calculated increase in aldosterone secretion. For angiotensin III: angiotensin II the ratios were 0·80 and 0·91 respectively. These ratios were not significantly different from 1·00 but the tendency for angiotensin II to be slightly more potent was probably due to a contribution from derived angiotensin III during infusion of angiotensin II. Angiotensin II or angiotensin II amide was ∼ four times as potent as angiotensin III in raising arterial blood pressure. Cortisol secretion rate was slightly but significantly increased by all peptides at the higher infusion rates. Infusions had no effect on adrenal blood flow or plasma levels of Na + but raised plasma levels of K + slightly. These results confirm the conclusion from adrenal arterial infusion experiments that angiotensin II and III are almost equipotent in stimulating aldosterone secretion in sheep.

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J. G. McDOUGALL, B. A. SCOGGINS, ALDONA BUTKUS, J. P. COGHLAN, D. A. DENTON, D. T. FEI, K. J. HARDY and R. D. WRIGHT

Metoclopramide (10 mg i.v. injection followed by 10 mg/h i.v. for 2 h) caused a transient rise in blood concentrations of aldosterone in sodium-replete and sodium-depleted sheep. Infusion of metoclopramide into the adrenal artery of sheep with an autotransplanted adrenal gland, at a rate to give a similar concentration of metoclopramide at the adrenal cell level (calculated from rate of infusion and adrenal blood flow), resulted in no alteration in aldosterone secretion rate in either sodium-replete or sodium-depleted animals, even though intravenous metoclopramide caused transient stimulation of aldosterone secretion in the same sheep when sodium replete.

Dopamine administered either into the adrenal arterial blood supply or intravenously had no significant effect on aldosterone secretion and did not reverse the stimulatory effects of angiotensin II on aldosterone secretion in the adrenal transplant.

The data do not support the suggestion that direct dopaminergic elements play a tonic inhibitory role in aldosterone secretion. It is possible that the agonist effect of metoclopramide on aldosterone secretion may occur by some non-dopaminergic mechanism and it is tempting to speculate that the effect is centrally mediated.

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Anthony Raffo, Kolbe Hancock, Teresa Polito, Yuli Xie, Gordon Andan, Piotr Witkowski, Mark Hardy, Pasquale Barba, Caterina Ferrara, Antonella Maffei, Matthew Freeby, Robin Goland, Rudolph L Leibel, Ian R Sweet and Paul E Harris

Abstract

Despite different embryological origins, islet β-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human β-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by β-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous l-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in β-cells.