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α-Melanocyte-stimulating hormone (α-MSH) has been shown to act directly on the mammalian melanocyte in short-term cultures of hair follicles obtained from the Siberian hamster. Melanogenesis was stimulated through an increase in tyrosinase activity which resulted in an increase in melanin production. The response of hair follicle melanocytes to α-MSH occurred only in follicles taken from moulting animals, implying that they show a discontinuous expression of MSH receptors during the hair follicle growth cycle. Synthetic 1–24 ACTH had no effect on melanogenesis regardless of whether the follicles came from moulting or non-moulting animals. The pineal peptide, [8-arginine]-vasotocin (AVT), inhibited melanin production without a concomitant decrease in tyrosinase activity. In this respect AVT resembled melatonin, although AVT showed a potency ratio of less than half on a molar basis. The action of AVT, like that of melatonin, must ultimately be on some post-tyrosinase step in melanin biosynthesis. In these hair follicle melanocytes AVT seems to bind to specific receptors since neither of the closely related peptides, oxytocin and [8-arginine]-vasopressin, displayed any activity in our culture system.

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P M Pierson, M E Guibbolini and B Lahlou


We analysed the effects of specific neurohypophysial analogues for pharmacological characterization of the type of vasotocin receptor involved in the control of the adrenocorticotrophin hormone (ACTH) release from the perifused pituitary in the rainbow trout, Oncorhynchus mykiss.

Mammalian corticotrophin releasing factor (CRF) and teleostean neurohypophysial peptides (arginine vasotocin (AVT) and isotocin (IT)) stimulated ACTH release. Analysis of concentrations giving half-maximal effects (D50) showed that these peptides affected ACTH release in the following order of potency: CRF (8 × 10−13 m) >AVT (2 × 10−10 m)>IT (10−7 m). Maximal responses (Dmax) were obtained for hormonal concentrations of 10−10 m, 10−8 m and 10−6 m respectively. This suggests that AVT and IT have different roles in the control of ACTH release. The values obtained for AVT and IT were in agreement with the circulating levels we previously found for these peptides.

Specific V1 or V2 agonists or antagonists (with reference to vasopressin in mammals) were used to define the specificity of the neurohypophysial peptide receptor involved in this stimulation. The V1 agonist, [Phe2, Orn8]-oxytocin, stimulated ACTH release while the V2 agonist, [deamino1, Val4, d-Arg8]-vasopressin, had no such effect. Maximal and half-maximal responses were obtained in the presence of the V1 agonist with 10−7 m and 7 × 10−9 m respectively, and were in the range of values obtained with natural peptides. The V1 antagonist, [d(CH2)5 1, O-Me-Tyr2, Arg8]-vasopressin, and the V2 antagonist, [d(CH2)5 1, d-Ile2, Ile4, Arg8, Ala9]-vasopressin, maximally reversed the 10−9 m AVT-stimulated ACTH release by 60% and 25% respectively, for a 5 × 10−10 m concentration of the analogues and a D50 approximately 2 × 10−11 m.

These results demonstrated the presence of only one V1-type receptor in fish pituitary, with some of the structural and functional peculiarities typically displayed by the mammalian V1a-type receptor, but distinct from it. In this sense, the fish pituitary vasotocin receptor may represent a novel type of neurohypophysial hormone receptor, more closely related to the mammalian V1b-type.

Journal of Endocrinology (1996) 149, 109–115

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ME Guibbolini and M Avella

Neurohypophysial hormone receptors were studied in primary cultures of sea bass (Dicentrarchus labrax) gill respiratory-like cells grown on permeable supports. This preparation was previously shown to provide a functional model for investigating the hormonal regulation of Cl- secretion. Under control conditions, the cultured monolayered epithelium had a short-circuit current (ISC) of 3.5+/-1.1 micro A x cm(-2). This current had previously been identified as an active Cl- secretion. The addition of increasing concentrations of the fish neurohypophysial hormones, arginine vasotocin (AVT) or isotocin (IT), elicited a concentration-dependent stimulation of the ISC. Maximal increases of 60.9+/-12.1% and 117.7+/-28.0% above the basal ISC value were obtained for 10(-7) M AVT and IT respectively. Half-maximal effects were obtained for 3.1 x 10(-9) M AVT and for 1.4 x 10(-9) M IT. Mucosal application of 1.0 mM diphenylalamine-2-carboxylic acid (a specific blocker of Cl- channels) after serosal addition of 5 x 10(-8) M AVT or IT inhibited not only the basal but also the stimulated current, revealing a correlation with a hormone-dependent Cl- transport. Specific V1 or V2 receptor analogues of vasopressin (mammalian hormone) were used to characterize the type of neurohypophysial hormone receptors pharmacologically. While the V1 agonist [Phe2,Orn8]-oxytocin stimulated the basal Cl- secretion with a similar profile to that of AVT or IT, the V2 agonist [Deamino1,Val4,d -Arg8]-vasopressin had no effect. The V1 antagonist [d(CH2)5 1,O-Me-Tyr2,Arg8]-vasopressin used at a concentration of 5 x 10(-7) M totally reversed the 10-8 M AVT-stimulated Cl- secretion, whereas the V2 antagonist [d(CH2)5 1,d -Ile2,Ile4,Arg8,Ala9]-vasopressin used at the same concentration had no significant effect. In contrast, similar experiments carried out in the presence of 10(-8) M IT showed that both antagonists significantly reduced the IT-stimulated Cl- secretion, with the efficiency of the V1 receptor antagonist being significantly greater than that of the V2. This study provides evidence for neurohypophysial hormone control of Cl- secretion in fish cultured gill respiratory cells. It suggests that on a physiological basis the hormonal effect is shared by the two peptides present in fish neurohypophysis (AVT and IT), acting by means of two distinct, although pharmacologically similar, V1-type receptors (according to the mammalian classification). These specific receptors are expected to play an important role in controlling ion homeostasis in seawater fish.

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M-W Wang, D L Crombie, J S Hayes and R B Heap


The rapid onset of normal maternal behaviour after parturition in mice, consisting of cleaning, warming, feeding and protection of offspring, is primed by oestrogen, progesterone and oxytocin. Previous studies showed that passive transfer of monoclonal antibodies against progesterone significantly increases the incidence of maternal rejection of pups. To test the hypothesis that aberrant maternal behaviour is due to partial progesterone withdrawal leading to hormonal imbalance during late pregnancy, maternal rejection was assessed following treatment with a progesterone receptor antagonist. Mifepristone (RU486) was given subcutaneously on either day 2 (100 μg) or day 17 (50 μg) of pregnancy, or on the first day of lactation (100 μg). Maternal behaviour was monitored twice daily for the first 6 days of lactation and pup rejection recorded for a further 15 days. Maternal rejection was significantly greater after mifepristone administration on either day 2 or day 17 (28·6% and 38·3%) compared with controls (11·1% and 5·2% respectively). Rejection was negligible in both treated and control groups if mifepristone was given after parturition. When mothers were treated at day 17, the length of the latent period before pups were retrieved and returned to the nest was markedly increased in mifepristone-treated mothers (46·3 s) compared with controls (4·4 s) though the effect was transient. The results indicate that mifepristone interferes with the hormonal priming mechanism(s) necessary for the onset of normal maternal behaviour by a receptor-mediated effect. The similarity of the present results and those obtained with anti-progesterone antibodies implies that receptor antagonism or antibody scavenging of progesterone influence a common central nervous mechanism that is essential for the normal priming process.

Journal of Endocrinology (1995) 145, 371–377

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WX Wu, XH Ma, Q Zhang and PW Nathanielsz

Our objective was to examine the topology-, gestation- and labor-related changes of estrogen receptor (ER)alpha, progesterone receptor (PR), oxytocin receptor (OTR) and thrombospondin-1 (TSP1) mRNA in pregnant baboon myometrium. ER alpha, PR, OTR and TSP1 mRNAs extracted from the lower uterine segment and fundal myometrium of pregnant baboons not in labor between 121 and 180 days of gestational age (n=9) and in established spontaneous labor between 164 and 193 days of gestational age (n=5) were analyzed by Northern blot. There were no topology-, gestation- or labor-related changes of ER alpha and PR mRNA in or between the lower uterine segment or/and the fundus. OTR mRNA was the same in the lower uterine segment and the fundus from baboons not in labor and non-labor fundal, but not lower uterine segment, myometrial OTR mRNA increased with gestation (R(2)=0.81, P<0.05). Fundal OTR mRNA rose significantly compared with the lower uterine segment during spontaneous labor. TSP1 mRNA increased significantly in both the fundus and lower uterine segment during labor. TSP1 mRNA in the lower uterine segment during spontaneous labor was higher than in the fundus during spontaneous labor. In conclusion, fundal and lower uterine segment ER alpha and PR mRNA remained unchanged in late gestation and spontaneous labor. The increased OTR mRNA may serve as a mechanism to increase uterine sensitivity to OT during late gestation. The higher fundal OTR mRNA compared with the lower uterine segment provides polarity which assists fetal expulsion by uterine contractions during labor. The significance of increased TSP1 mRNA during labor may relate to homeostasis and merits further study.

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J. R. Seckl, R. C. Dow, S. C. Low, C. R. W. Edwards and G. Fink


Steroid-metabolizing enzymes modulate the effects of androgens on brain differentiation and function, but no similar enzymatic system has been demonstrated for adrenocorticosteroids which exert feedback control on the hypothalamus. 11β-Hydroxysteroid dehydrogenase (11β-OHSD) rapidly metabolizes physiological glucocorticoids (corticosterone, cortisol) to inactive products, thereby regulating glucocorticoid access to peripheral mineralocorticoid and glucocorticoid receptors in a site-specific manner. Using in-situ hybridization, we found expression of 11β-OHSD mRNA in neurones of the hypothalamic paraventricular nucleus (PVN) where corticotrophinreleasing factor-41 (CRF-41) is synthesized and from where it is released into hypophysial portal blood. Administration of glycyrrhetinic acid (GE), a potent 11β-OHSD inhibitor, decreased CRF-41 release into hypophysial portal blood in the presence of unchanged circulating glucocorticoid levels, suggesting that 11β-OHSD regulates the effective corticosterone feedback signal to CRF-41 neurones. These effects of GE were not observed in adrenalectomized animals, demonstrating dependence on adrenal products. In contrast, GE led to two- to threefold increases in arginine vasopressin and oxytocin release into portal blood, effects also dependent upon intact adrenal glands. These results suggest that 11β-OHSD in the PVN, and possibly other sites, may represent a novel and important control point of corticosteroid feedback on CRF-41 release in vivo.

Journal of Endocrinology (1993) 136, 471–477

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D. J. Flint, R. A. Clegg and C. H. Knight


Milk yield declined significantly between days 22 and 28 of lactation in rats, when lactation was extended by frequent replacement of older litters with younger ones. Corticosterone implants but not cortisol injections or implants prevented this decline. Cortisol, however, appeared to inhibit milk ejection since the mammary glands became engorged with milk and milk yield was improved dramatically by oxytocin injections. In both cases corticosteroid concentrations increased approximately threefold above basal concentrations.

Both corticosteroids increased total mammary gland RNA content and lipoprotein lipase (LPL) activity of the mammary gland but were without effect on insulin binding. They also decreased LPL activity, lipogenesis and the number of insulin receptors on adipose tissue.

Serum prolactin and insulin concentrations were unaffected by any of the treatments.

The results suggest that corticosteroids (1) inhibit milk ejection under certain conditions, (2) may be circulating in lower concentrations, which thereby limit milk production, during prolonged lactation and (3) may improve milk yield during extended lactation in part by suppressing anabolic activity in adipose tissue.

J. Endocr. (1984) 103, 213–218

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A. Lipton, A. Vinijsanun and L. Martin


The non-steroidal antioestrogen tamoxifen (trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene), widely used in the treatment of breast cancer, and its oestrogenic cis-isomer rapidly inhibited contractile responses of isolated rat myometrium to supramaximal concentrations of oxytocin (1·28 × 10−6 mol/l). Both compounds were effective at concentrations comparable with the plasma concentrations of tamoxifen reached in therapy (i.e. 5 × 10−7to 5 × 10−6 mol/l). Inhibition was too rapid in onset ( < 3 min) to involve changes in RNA transcription and protein synthesis, and was not prevented or reversed by the addition of oestradiol to the bath. We conclude that the inhibition did not involve the classical oestrogen receptor pathway. Oestradiol-17β at concentrations above 10−6 mol/l also inhibited the myometrium and potentiated the effects of the antioestrogens. Our experiments suggest that the antioestrogens and oestradiol act via a similar route with tamoxifen having an equilibrium affinity approximately tenfold greater than that of oestradiol.

J. Endocr. (1984) 103, 383–388

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SJ Yankey, BA Hicks, KG Carnahan, AM Assiri, SJ Sinor, K Kodali, JN Stellflug, JN Stellflug and TL Ott

Interferon-tau (IFN tau) acts locally on the endometrium to suppress estrogen and oxytocin receptor expression and block luteolysis in ruminants. Systemic administration of conceptus homogenates or recombinant ovine IFN tau does not block luteolysis or enhance pregnancy rates in sheep or cattle, respectively. However, IFN tau up-regulates expression of the antiviral protein Mx throughout the entire uterine wall during early pregnancy. These studies determined if conceptus-derived IFN tau also up-regulates Mx expression in components of the circulating immune system that migrate through the endometrial wall. In experiment one, peripheral blood mononuclear cells (PBMC) were isolated from ewes at D26 post-artificial insemination (AI) and Mx mRNA levels examined by Northern and slot-blot hybridization. Pregnancy resulted in a two-fold increase in Mx mRNA levels compared to bred, non-pregnant ewes at D26. In experiment two, PBMC were isolated from ewes at AI, and every three days from D9 to D30. Results showed a four-fold increase in Mx mRNA levels in PBMC from pregnant versus bred, non-pregnant ewes at D15. Increased Mx mRNA, which remained elevated through D30, was accompanied by increased levels of Mx protein. These results show that pregnancy recognition signaling rapidly induces Mx gene expression in PBMC, and are the first to suggest that IFN tau activates gene expression in components of the circulating immune system.

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GC Harris and HD Nicholson

Oxytocin (OT) is present in the mammalian testis and has been postulated to play a role in modulation of seminiferous tubule contractility. However, recent evidence suggests that the myoid cells responsible for such contractile activity do not express OT receptors. In this study computer-assisted analysis and time-lapse videomicrography were used to investigate the biological effects of neurohypophysial peptides and their analogues on seminiferous tubule contractility. Adult rat testes were placed in fresh oxygenated Dulbecco's modified Eagle's medium (DMEM) F12 medium, decapsulated and the tubules gently teased apart. A small section of tubule was placed in a microslide chamber and perifused with medium. Seminiferous tubules were treated with OT (2 nM), [Arg8]-vasopressin (AVP, 0.2 nM) or [Thr4,Gly7]-OT (TGOT, 2 nM, 8 nM and 0.2 microM). Specific antagonists were also given simultaneously with OT and AVP treatments. Data were analysed to give arbitrary units of contractility. Both OT and AVP increased tubule contractility, with AVP being at least 10 times more potent than OT. Treatment with the selective OT antagonist, desGly-NH2,d(CH2)5[d-Tyr2,Thr4]-ornithine vasotocin (OTA, 0.2 microM and 2 microM) significantly reduced OT-induced increases in seminiferous tubule contractility but had no effect on AVP-induced responses. In contrast, the AVP antagonist, Phaa-d-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (AVPA) was more potent at reducing AVP-induced increases than OT-induced responses. The selective non-peptide AVPA SR 49059 blocked the response to both peptides in a similar manner, whilst the non-peptide OTA L367,773 did not block OT-induced increases in seminiferous tubule contractility at doses that were slightly inhibitory to AVP-induced responses. The specific OT agonist TGOT did not induce a contractile response. The data in this study demonstrate that in the testis AVP acts via V1a receptors to stimulate contractile activity and suggest that OT may act via a receptor which differs from the classical V1a and uterine-type OT receptor. These findings support a role for OT in the regulation of seminiferous tubule contractility and raise the possibility that AVP may also be important in this process.