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Search for other papers by V. C. JORDAN in
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SUMMARY
Four-day cyclic rats fed 7,12-dimethylbenz(a)anthracene (DMBA) (20 mg) at 50 days of age had peak prolactin, oestradiol and uterine wet weights at pro-oestrus. Tamoxifen (50, 200 and 800 μg daily), administered to ovariectomized rats, produced significant (P < 0·05) decreases in oestrogen-stimulated prolactin levels but was unable to reduce prolactin to control values. Tamoxifen (12·5, 50 and 200 μg daily) produced decreases in size in DMBAinduced rat mammary carcinomata in intact rats although some tumours did not respond to therapy. The ability of the pituitary to produce prolactin was not impaired. Decreases in uterine wet weights and peripheral oestradiol levels occurred during tamoxifen treatment.
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Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545, U.S.A.
(Received 28 August 1974)
Harper & Walpole (1967 reported the potent antioestrogenic activity of ICI 46,474, the trans-isomer of 1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, in the rat; however, in the mouse the compound exhibited only oestrogenic properties. However, Emmens (1971) showed that large doses of ICI 46,474 or the related compound H774 (1-(p-β-diethylaminoethoxyphenyl)-1,2-di(p-methoxyphenyl)-but-1-ene citrate) caused vaginal refractoriness to oestradiol for several weeks after s.c. administration to ovariectomized mice. The present study was undertaken to determine the ability of ICI 46,474 and H774 to inhibit binding of [3H]oestradiol to the 8 S oestrogen receptor derived from ovariectomized mouse uterus and vagina.
Mature, Charges River CD strain mice were ovariectomized under ether anaesthesia, primed with 1 μg oestradiol-17β in 0·05 ml peanut oil and used for experimentation 2 weeks later. Animals were killed by cervical dislocation and the uteri and vaginae were dissected out, weighed and immediately
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Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545, U.S.A.
(Received 8 November 1974)
Oestrogens have been found to stimulate prolactin release in the rat (Chen & Meites, 1970) and increases in prolactin in the circulation have been reported to be essential for the maintenance and growth of dimethylbenz(α)anthracene (DMBA)-induced rat mammary carcinomata (Pearson, Molina, Butler, Llerena & Nasr, 1972). Non-steroidal anti-oestrogens retard the growth of DMBA-induced rat mammary carcinoma (Schulz, Haselmayer & Hölzel, 1971; Terenius, 1971) and one such compound nafoxidine (U-11, 100A) has been shown to inhibit oestrogen-stimulated prolactin release in rats (Heuson, Waelbroeck, Legros, Gallez, Robyn & L'Hermite, 1971–72) thereby suggesting a mechanism for antitumour activity which may occur simultaneously with tumour oestrogen receptor blockade (Terenius, 1971). The present investigation was undertaken to determine whether other anti-oestrogens could control oestrogen-stimulated prolactin release.
The non-steroidal anti-oestrogens ICI 46,474 (tamoxifen, trade name Nolvadex, trans 1-(ρ-β-dimethylaminoethoxyphenyl)-1,2-diphenyl but-1-ene) and MER 25 (ethamoxytriphetol,
Search for other papers by Jordan M Willcox in
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Relaxin produces a sustained decrease in total peripheral resistance, but the effects of relaxin on skeletal muscle arterioles, an important contributor to systemic resistance, are unknown. Using the intact, blood-perfused hamster cremaster muscle preparation in situ, we tested the effects of relaxin on skeletal muscle arteriolar microvasculature by applying 10−10 M relaxin to second-, third- and fourth-order arterioles and capillaries. The mechanisms responsible for relaxin-induced dilations were explored by applying 10−10 M relaxin to second-order arterioles in the presence of 10−5 M N(G)-nitro-l-arginine methyl ester (l-NAME, nitric oxide (NO) synthase inhibitor), 10−5 M glibenclamide (GLIB, ATP-dependent potassium (K+) channel inhibitor), 10−3 M tetraethylammonium (TEA) or 10−7 M iberiotoxin (IBTX, calcium-associated K+ channel inhibitor). Relaxin caused second- (peak change in diameter: 8.3±1.7 μm) and third (4.5±1.1 μm)-order arterioles to vasodilate transiently while fourth-order arterioles did not (0.01±0.04 μm). Relaxin-induced vasodilations were significantly inhibited by l-NAME, GLIB, TEA and IBTX. Relaxin stimulated capillaries to induce a vasodilation in upstream fourth-order arterioles (2.1±0.3 μm), indicating that relaxin can induce conducted responses vasodilation that travels through blood vessel walls via gap junctions. We confirmed gap junction involvement by showing that gap junction uncouplers (18-β-glycyrrhetinic acid (40×10−6 M) or 0.07% halothane) inhibited upstream vasodilations to localised relaxin stimulation of second-order arterioles. Therefore, relaxin produces transient NO- and K+ channel-dependent vasodilations in skeletal muscle arterioles and stimulates capillaries to initiate conducted responses. The transient nature of the arteriolar dilation brings into question the role of skeletal muscle vascular beds in generating the sustained systemic haemodynamic effects induced by relaxin.
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
Search for other papers by Jordan S F Chan in
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.
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ABSTRACT
In order to investigate whether the impaired GH secretion associated with hypothyroidism and hyperthyroidism is due to a hypothalamic or a pituitary disorder, we have studied plasma GH responses to GH-releasing factor (1–29) (GRF) in euthyroid, hypothyroid and hyperthyroid rats. Hypothyroid rats showed a significant (P< 0·001) reduction in GH responses to GRF (5 μg/kg) at 5 min (350 ± 35 vs 1950 ±260 μg/l), 10 min (366±66 vs 2320 ± 270 μg/l) and 15 min after GRF injection (395 ± 72 vs 1420 ± 183 μg/l; means ± s.e.m.) compared with euthyroid rats. Hyperthyroid rats showed a significant (P<0·05) decrease in GH responses to 5 μg GRF/kg after 30 min (200±14 vs 325 ± 35 μg/l) but not at other time-points, or after the administration of 1 μg GRF/kg. These data indicate that in hypothyroidism and perhaps hyperthyroidism there is an alteration in the responsiveness of the somatotroph to GRF administration.
J. Endocr (1986) 109, 53–56
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Macrophage migration inhibitory factor (MIF) is an essential regulator of the macrophage responses to endotoxin. MIF also has the ability to override the anti-inflammatory actions of glucocorticoids during an immune response, and is thus an important pro-inflammatory factor. The presence of MIF in cells of the anterior pituitary has been described, and high levels of MIF in other rapidly proliferating tIssues have also been demonstrated. It has been hypothesised that MIF release from these cells is influenced by the hypothalamo-pituitary-adrenal axis, and that ACTH and MIF are released simultaneously to exert counter-regulatory effects on cortisol. However, another intracellular role for MIF has also been suggested as it has been shown that MIF exerts an effect on the inhibitory cell cycle control protein p27 through an interaction with Jab1, a protein implicated in p27 degradation. We studied MIF expression in different normal and adenomatous human pituitary samples using immunohistochemistry and RT-PCR. There was evidence of co-immunoprecipitation of MIF with Jab1, suggesting an interaction of the two proteins. Our results showed that there is increased expression of MIF protein in the nuclei of all pituitary adenomas compared with normal tIssue (P=0.0067), but there was no statistically significant difference in nuclear MIF expression between the different adenoma types. Nuclear MIF expression correlated positively with p27 and its phosphorylated form in normal tIssue (P=0.0028 and P<0.0001); however, this relationship was not seen in the adenoma samples. Cytoplasmic expression of MIF was found to be variable both in normal and adenomatous samples, with no consistent pattern. MIF mRNA was demonstrated to be present in all tumour and normal samples studied. Somatotroph tumours showed higher MIF mRNA expression compared with normal pituitary or other types of adenomas. In conclusion, MIF is expressed in cell nuclei in pituitary adenomas to a greater extent than in normal pituitary tIssue. We speculate that it may play a role in the control of the cell cycle, but whether its higher level in adenomas is a cause or a consequence of the tumorigenic process remains to be clarified.
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
Search for other papers by Jordan S F Chan in
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Research Institute, University of Alberta, Edmonton, Alberta, Canada
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Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide’s ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1 CM−/− mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1 CM−/− mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4. All mice were randomized to treatment with either vehicle control or liraglutide (30 µg/kg) twice daily during the final 2.5 weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1 CM−/− mice with T2D, in the presence of mild weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1 CM−/− mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e′/a′ and E/e′ ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1 CM−/− mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.