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B Thom, B J Canny, M Cowley, P J Wright, and I J Clarke

Abstract

The μ, δ and κ opioid receptor subtypes were measured across the oestrous cycle of the ewe and in ovariectomised (OVX) ewes treated with oestrogen and/or progesterone. We have used a subtype-specific opioid receptor binding assay, in which [3H]diprenorphine non-preferentially labelled each receptor subtype in the presence of blocking concentrations of site-specific opioid analogues. The density and affinity of each receptor subtype was measured in the preoptic area (POA) of the hypothalamus and the mediobasal hypothalamus (MBH). Normally cycling ewes were killed during the luteal phase of the oestrous cycle and at various times after an injection of a synthetic prostaglandin (cloprostenol) to synchronise the onset of the follicular phase. OVX ewes were either untreated as controls (n=4) or treated with oestrogen (n=4), progesterone (n=4) or oestrogen and progesterone combined (n=4). The total number of opioid receptors did not alter across the oestrous cycle or with steroid hormone treatment. In the POA, the mean (± s.e.m.) number of δ receptors was significantly (P<0·05) greater during the luteal phase than 24 h into the follicular phase (133 ± 45 vs 35 ± 8 fmol/mg protein). A significantly (P<0·05) greater number of δ receptors was also found in the OVX progesterone-treated ewes compared with the control animals (172 ± 9 vs 39 ± 4 fmol/mg protein). In the MBH, the number of δ receptors was significantly (P<0·01) greater in ewes killed 56 h after prostaglandin than luteal-phase ewes (184 ± 40 vs 51 ± 7 fmol/mg protein). The number of μ receptors in both the POA and the MBH was also significantly (P<0·05) higher in the 56-h group than in the 12-h group. A similar trend was also observed in the steroid-treated animals, although differences did not reach statistical significance. The δ:μ ratio in the POA was significantly (P<0·05) higher in the luteal-phase animals than any of the other groups killed after a cloprostenol injection that causes luteolysis. Similarly the ratio of δ receptor density to μ receptor density was greater (P<0·05) in the OVX progesterone-treated ewes than in the OVX control ewes. No differences were found in the κ receptor density across the cycle or with different steroid treatments. These data suggest that the relative proportions of the δ and μ subtypes of the opioid receptor in the hypothalamus change during the oestrous cycle. Regulation appears to be due to the feedback effects of ovarian steroids with progesterone altering the δ:μ ratio. In the MBH, there was a general increase in both δ and μ subtypes during the follicular phase of the oestrous cycle. This may explain, in part, how the responsiveness of the GnRH/LH axis to opioid peptides and antagonists changes across the cycle.

Journal of Endocrinology (1996) 149, 509–518

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J. T. PENTO, R. J. WRIGHT, R. A. MAGARIAN, and A. F. HOGE

College of Pharmacy and The Oklahoma Medical Research Foundation, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma 73190, U.S.A.

(Received 6 February 1978)

Diethylstilboestrol (DES) has been observed to stimulate the growth of oestrogen-sensitive tumours in premenopausal women and yet DES therapy has been reported to increase survival significantly in 30% of postmenopausal women with breast cancer (Kelley, 1971). It has been suggested that in premenopausal women, DES may be metabolically converted by the ovary to a closed-ring system which resembles a natural oestrogen and therefore possesses true oestrogenic activity (Hoge, Shaw, Bottomley & Hartsuck, 1975). However, in postmenopausal women, because the ovarian tissue is atrophied, DES would not be converted into a natural oestrogen and could act as an antioestrogen (Hoge et al. 1975). The purpose of the present study was to examine the influence of endocrine ablation on the oestrogenic activity of DES in young mice. It

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R. D. Wright, J. R. Blair-West, J. F. Nelson, G. W. Tregear, and M. Rosenblatt

ABSTRACT

Infusion of bovine parathyroid hormone (bPTH) preparations into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep increases salivary phosphate concentration and gland blood flow rate with rapid onset and offset of action. These responses have been used as a bioassay for PTH and PTH analogues and for assessing the properties of an in-vitro inhibitory analogue [Nle-8, Nle-18, Tyr-34]bPTH-(3–34)amide. [Nle-8, Nle-18, Tyr-34]bPTH-(1–34)amide at 10− 9 to 10 −8 mol/l was four to five times more potent than bPTH(1–34) on both salivary phosphate and blood flow assays. Human PTH(1–34) was not significantly more potent than bPTH(1–34). The [Nle-8, Nle-18, Tyr-34]bPTH-(3–34)amide analogue had very slight agonist activity at 3 × 10−7 mol/l and at a 100:1 ratio of analogue to PTH it completely inhibited the action of bPTH(1–34) on phosphate secretion and gland blood flow. It caused partial inhibition at 10:1 and had no evident effect at 1:1. These results differ from previous in-vitro results and indicate that the preparation may be valuable for evaluation of agonist and antagonist analogues of PTH. The vascularly isolated parotid gland of the sheep permits repeated random testing of analogues in a control–test–control sequence and the results indicate high sensitivity to PTH in a rapidly reactive invivo system with two responding parameters.

J. Endocr. (1984) 102, 375–379

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R. D. Wright, J. R. Blair-West, J. F. Nelson, and G. W. Tregear

Administration of bovine parathyroid hormone (PTH) preparations increased the phosphate concentration in the parotid saliva of sheep. Data on the site of action of PTH (1–84) were obtained by (a) equimolar infusions of PTH (1–84) and (1–34) directly into the arterial blood supply of the vascularly isolated parotid gland in anaesthetized sheep, (b) intravenous infusion of PTH (1–84) at a similar rate and (c) intra-arterial infusion of PTH (1–84) with complete drainage of the venous effluent from the gland during the infusion. Results showed substantial time– and dose–response identity of the two peptides, at 10−9 to 4 × 10−9 mol/l in arterial blood, in raising salivary phosphate concentration. The effect of PTH (1–84) was not due to recirculated fragments because the response was obtained when recirculation was prevented by complete venous drainage and little or no response occurred when the same infusion was given i.v.

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L R Ranganath, J A Christofides, J W Wright, and V Marks

Abstract

Oestrogen replacement therapy has been shown to protect postmenopausal women from ischaemic heart disease, strokes and hypertension. The mechanism of protection conferred by oestrogen, although partly attributable to changes in serum lipoproteins, is not fully understood. The present study was undertaken to assess the effect of hormone replacement therapy on the composition of platelet membrane fatty acids in postmenopausal women. These were analysed by gas-liquid chromatography before and six weeks after continuous conjugated equine oestrogen therapy (0·625 mg daily) combined with cyclical therapy with 75 μg l-norgestrel from day 17 to 28 of a 28-day cycle. Each subject acted as her own control. The principal findings of the study were that, following treatment, there was a 16·2% reduction in platelet membrane polyunsaturated fatty acids (P<0·001), an increase of 9·1 and 7·1% in saturated fatty acids and monounsaturated fatty acids respectively (P<0·001) and a 17·8% reduction in arachidonic acid (P<0·003). There was no correlation between changes in membrane fatty acids and serum lipoproteins. This suggests that the changes in membrane composition noted in this study may be a primary effect of hormone replacement therapy, especially oestrogen.

Journal of Endocrinology (1996) 148, 207–212

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R. M. Elliott, L. M. Morgan, J. A. Tredger, S. Deacon, J. Wright, and V. Marks

ABSTRACT

The acute effects of different macronutrients on the secretion of glucagon-like peptide-1(7–36)amide (GLP-1(7–36)amide) and glucose-dependent insulinotropic polypeptide (GIP) were compared in healthy human subjects. Circulating levels of the two hormones were measured over a 24-h period during which subjects consumed a mixed diet. In the first study, eight subjects consumed three equicaloric (375 kcal) test meals of carbohydrate, fat and protein. Small increases in plasma GLP-1(7–36) amide were found after all meals. Levels reached a maximum 30 min after the carbohydrate and 150 min after the fat load. Ingestion of both carbohydrate and fat induced substantial rises in GIP secretion, but the protein meal had no effect. In a second study, eight subjects consumed 75 g glucose or the equivalent portion of complex carbohydrate as boiled brown rice or barley. Plasma GIP, insulin and glucose levels increased after all three meals, the largest increase being observed following glucose and the smallest following the barley meal. Plasma GLP-1(7–36)amide levels rose only following the glucose meal. In the 24-h study, plasma GLP-1(7–36)amide and GIP concentrations were increased following every meal and remained elevated throughout the day, only falling to fasting levels at night. The increases in circulating GLP-1(7–36)amide and GIP levels following carbohydrate or a mixed meal are consistent with their role as incretins. The more sustained rises observed in the daytime during the 24-h study are consistent with an anabolic role in lipid metabolism.

Journal of Endocrinology (1993) 138, 159–166

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SW Lockley, DJ Skene, K James, K Thapan, J Wright, and J Arendt

Although melatonin treatment has been shown to phase shift human circadian rhythms, it still remains ambiguous as to whether exogenous melatonin can entrain a free-running circadian system. We have studied seven blind male subjects with no light perception who exhibited free-running urinary 6-sulphatoxymelatonin (aMT6s) and cortisol rhythms. In a single-blind design, five subjects received placebo or 5 mg melatonin p.o. daily at 2100 h for a full circadian cycle (35-71 days). The remaining two subjects also received melatonin (35-62 days) but not placebo. Urinary aMT6s and cortisol (n=7) and core body temperature (n=1) were used as phase markers to assess the effects of melatonin on the During melatonin treatment, four of the seven free-running subjects exhibited a shortening of their cortisol circadian period (tau). Three of these had taus which were statistically indistinguishable from entrainment. In contrast, the remaining three subjects continued to free-run during the melatonin treatment at a similar tau as prior to and following treatment. The efficacy of melatonin to entrain the free-running cortisol rhythms appeared to be dependent on the circadian phase at which the melatonin treatment commenced. These results show for the first time that daily melatonin administration can entrain free-running circadian rhythms in some blind subjects assessed using reliable physiological markers of the circadian system.

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Casey D Wright, Ryan J Orbus, Timothy R H Regnault, and Russell V Anthony

Ovine GH (oGH) is synthesized in placental tissue during maximal placental growth and development. Our objectives were to localize oGH mRNA in the placenta, and study the impact of exogenous GH on twin pregnancies during the normal window (35–55 days of gestational age; dGA) of placental expression. In situ hybridization localized oGH mRNA in uterine luminal epithelium but not in tissues of fetal origin. While maternal GH and IGF-I concentrations were increased (P<0.001) approximately tenfold, uterine, uterine fluid, placental, and fetal weights were unaffected by treatment at either 55 or 135 dGA. Fetal length, liver weight, and liver weight per kg of body weight were unaffected by maternal GH treatment. However, in the cotyledon, IGF-binding protein (BP)-1 and IGFBP-4 mRNA concentrations were increased (P<0.05), while IGFBP-2 mRNA was decreased (P<0.05). The concentration of mRNA for IGFBP-3 was unaffected by treatment. Within the caruncle, IGFBP-1 mRNA was decreased (P<0.05), while IGFBP-3 and IGFBP-4 mRNA were increased (P<0.05), and IGFBP-2 mRNA was unchanged due to GH treatment. While our data indicate that elevated maternal GH and IGF-I concentrations during early and mid-gestation do not enhance placental and fetal growth in twin pregnancies, localization of GH mRNA in uterine luminal epithelium could explain GHs transitory expression from 35 to 55 dGA, since by the end of this period the majority of the uterine luminal epithelium has fused with chorionic binucleate cells forming the placental syncytium.

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Clyde J. Wright, Sarah McKenna, Robyn De Dios, Brit H. Boehmer, Leanna Nguyen, Sankar Ghosh, Jeryl Sandoval, and Paul J Rozance

The β-cell response to injury may be as critical for the development of diabetes as the specific insult. In the current study, we use streptozotocin (STZ) to injure the β-cell in order to study the response with a focus on NFκB. MIN6 cells were exposed to STZ (0.5-8mM, 0-24h) ±TNFα (100ng/mL) and ±IκBβ siRNA to lower the threshold to NFκB activation. Cell viability was determined by trypan blue exclusion. NFκB activation was determined by expression of the target genes Nos2 and Cxcl10, localization of the NFκB proteins p65 and p50, and expression and localization of the NFκB inhibitors, IκBβ and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBβ expression using siRNA resulted in STZ-induced expression of NFκB target genes and increased cell death, while co-incubation with STZ and TNFα enhanced cell death compared to either exposure alone. Adult male IκBβ-/- and wild type (WT) mice were exposed to STZ and monitored for diabetes. The IκBβ-/- mice developed hyperglycemia and diabetes more frequently than controls following STZ exposure. Based on these results we conclude that STZ exposure alone does not induce NFκB activity. However, lowering the threshold to NFκB activation by co-incubation with TNFα or lowering IκBβ levels by siRNA sensitizes the NFκB response to STZ and results in a higher likelihood of developing diabetes in vivo. Therefore, increasing the threshold to NFκB activation through stabilizing NFκB inhibitory proteins may prevent β-cell injury and the development of diabetes.

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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.