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C Rivier

Publications and source records attributed to C Rivier.

At least 91 records · Page 5Linked to original sources
PubMed1995

Activin causes premature superovulation.

In the rat ovary, follicle cells produce and respond to activin, but as yet, the functional significance of the autocrine/paracrine effects of ovarian activin remains equivocal. To assess the effects of activin on folliculogenesis, normal cycling female rats were injected once every 8 h over a 40-h period with recombinant human activin A (120 micrograms/kg) beginning at 1300 h on estrus (day 1 of treatment). A total of 10 rats were injected with activin in 2 separate experiments. On days 3 and 4 of treatment, blood was obtained for hormone measurements, and the ovaries were removed for histology. Follicle counts were performed in 1 ovary from 3 representative animals in each treatment group. All antral (Graafian) follicles 300 microns or more in diameter were measured and classified as healthy or atretic based on the number of pyknotic nuclei in the largest cross-section. On day 3, all rats were in diestrus (diestrous day 2). After 3 days of activin administration, serum levels of estradiol were increased 200%, progesterone levels were decreased 67%, and FSH levels were unchanged compared with those in matched controls. By day 4 (i.e. 1 day after the last injection), no changes in the levels of these hormones were observed. Injection of activin for 3 days did not change the total number of antral follicles per ovary (control, 41.3 +/- 4.9; activin, 43.7 +/- 3.9); however, activin significantly increased the total number of atretic follicles (control, 69%; activin, 92%). Morphometric analysis of the ovaries removed on day 3 showed a marked increase (2-fold) in the number of large follicles, but most (89%) were atretic. Follicle counts suggested that the additional large follicles may have come from the pool of healthy small follicles. Histological studies showed that some of the day 3 activin-treated follicles had initiated ovulation. On day 4, control and activin-treated animals were at proestrus and estrus, respectively. Therefore, activin shortened the estrous cycle by 1 day. Little or n change in the follicle populations was observed in day 4 control ovaries. Interestingly, however, in 2 of the 3 activin-treated animals, 1 set of large follicles had ovulated (12 +/- 1 expanded egg cumulus complexes/oviduct), and another set (13 +/- 2) was just about to rupture. The activin-exposed oocytes (tubal and follicular) appeared arrested in metaphase I. After ovulation, activin-treated follicles developed into typical corpora lutea. No ovulations were found in control animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Activins↗
PubMed1995

Blockade of nitric oxide formation augments adrenocorticotropin released by blood-borne interleukin-1 beta: role of vasopressin, prostaglandins, and alpha 1-adrenergic receptors.

Blockade of nitric oxide (NO) formation with the arginine derivative L-N omega nitro-L-arginine-methylester (L-NAME) produces a dramatic increase in ACTH released by the iv injection of interleukin-1 beta (IL-1 beta). The present work investigated the potential role of three mechanisms in this effect: the activation of adrenergic receptors and/or the release of vasopressin (VP) or prostaglandins (PG). As previously observed, blockade of adrenergic receptors with prazosin and propranolol did not alter the stimulatory effect of IL-1 beta. We show here that this treatment did not significantly interfere with the potentiating influence of L-NAME 30 min after IL-1 injection, but blunted this effect at 60 min. Immunoneutralization of endogenous VP did not consistently decrease the ACTH response to IL-1 beta regardless of whether NO was present. Finally, as expected, blockade of PG synthesis with ibuprofen totally abolished IL-1 beta-induced ACTH secretion; in addition, it prevented the interaction between L-NAME and the pituitary response. In contrast to results obtained after the injection of IL-1 beta, neither the adrenergic antagonists nor ibuprofen significantly altered the ability of L-NAME to potentiate the stimulatory effect of VP. Collectively, these results indicate that the influence of NO on ACTH released by blood-borne IL-1 beta (an effect thought to be primarily exerted on nerve terminals in the median eminence) is not primarily mediated by endogenous VP. The inability of L-NAME to augment the stimulatory effect of the cytokine on ACTH secretion in the presence of ibuprofen suggests that PG play an obligatory role in the response of the hypothalamic-pituitary axis to systemic cytokine administration that cannot be compensated for by removing the restraining influence of NO. Finally, removal of the inhibitory effect of NO either unmasks the participation of adrenergic receptors in modulating the response of the hypothalamic-pituitary axis to IL-1 beta or stimulates catecholamine secretion, which, in turn, acts on CRF nerve terminals and/or synergizes with IL-1 beta-induced CRF release.

Adrenergic alpha-Antagonists↗
PubMed1994

A ketamine mixture anesthetic inhibits neuroendocrine and behavioral consequences of cocaine administration.

Cocaine is known to affect different brain systems, particularly those associated with arousal, motor and motivational functions. In order to identify a possible neurochemical link among these systems, we investigated the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and dissociative anesthetic, ketamine (as a mixture with the sedatives acepromazine and xylazine) on the secretion of pituitary adrenocorticotropin hormone (ACTH) and on the development of behavioral sensitization induced by cocaine. Pretreatment with the ketamine anesthetic mixture (1.6 ml/kg; s.c.) completely blocked the stimulation of ACTH by cocaine (5 mg/kg, i.v.; administered 30 min after the ketamine mixture) without interfering with ACTH secretion induced by exogenous corticotropin-releasing factor (CRF; 5 micrograms/kg; i.v.) or interleukin-1 beta (IL-1 beta; 100 ng/kg; i.v.). Administration of the ketamine mixture prior to each of five repeated cocaine injections (15 mg/kg; i.p.) also completely reversed the behavioral sensitization observed in saline-treated control animals. Administration of the anesthetic mixture did not appear to impair the dopamine (DA) re-uptake blocking properties of cocaine in the nucleus accumbens since substantial increases in extracellular DA were observed in the presence of the ketamine mixture. In addition to the present results, no behavioral sensitization was also observed in rats anesthetized with a different general anesthetic (pentobarbital, 50 mg/kg) under similar conditions to that of the ketamine mixture. Taken together, these results are in accordance with the hypothesis that stimulation of excitatory amino acid receptor function may be just one of the mechanisms whereby cocaine exerts its effects on neuroendocrine and behavioral activating systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Induction of c-fos in rat brain by acute cocaine and fenfluramine exposure: a comparison study.

Although cocaine shares the ability of fenfluramine to inhibit the synaptic reuptake of serotonin, previous observations from our group suggest that the genomic effects of fenfluramine in the rat striatum are primarily mediated by dopaminergic rather than serotonergic mechanisms. To compare and further understand the nerve cell type(s) targeted by psychotropic drugs, we studied, by use of immunocytochemistry and in situ hybridization, changes in c-fos in brain nerve cells of the caudate putamen and hypothalamus following acute cocaine or fenfluramine exposure. Predictably, both drugs (20 mg/kg; i.p.) evoked rapid but transient increases in c-fos in the caudate putamen. In addition, double labeling immunocytochemistry indicated that Fos-like protein was expressed preferentially in striatal neurons containing the protein phosphatase inhibitor, DARPP-32. In contrast, fenfluramine, but not cocaine, elicited c-fos mRNA and Fos-like protein in the neuroendocrine paraventricular nucleus (PVN) of the hypothalamus despite the fact that both drugs are known to be equally capable to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This difference is discussed in terms of serotonergic, dopaminergic and DARPP-32 input to hypothalamic neurons and tanycytes associated with adrenocorticotropin hormone (ACTH) secretion. To further identify the phenotypes of nerve cells expressing c-fos by fenfluramine in the PVN, it was demonstrated that the immediate-early gene was induced in a subpopulation of neurons constitutively expressing nitric oxide synthase (NOS). Taken together, we identified a number of common and disparate actions of cocaine and fenfluramine in striatal and hypothalamic tissue, thereby suggesting that c-fos induction in these two brain structures is differentially regulated by intrinsic events in addition to neuronal phenotype. We propose that the genomic effects produced by these two drugs represent part of a general dopaminergic and glutamateric mechanism by which monoamine reuptake inhibitor drugs affect specific brain nerve cells.

Animals↗
PubMed1994

Conformationally restricted competitive antagonists of human/rat corticotropin-releasing factor.

Corticotropin releasing factor (CRF) is a 41-peptide amide which stimulates the release of ACTH (Vale et al. Science 1981, 213, 1394). CRF has been postulated to assume an alpha-helical conformation upon binding to its pituitary receptor (Hernandez et al. J. Med. Chem. 1993, 36, 2860). We have exploited this hypothesis in the design of a limited series of cyclic analogues and have taken into consideration the effects of side-chain deletion (Alanine scan, Kornreich et al. J. Med. Chem. 1992, 35, 1870) as well as of changes in chirality (Rivier et al. J. Med. Chem. 1993, 36, 2851), with the rationale that side chains necessary for binding could also be replaced by side-chain bridges. In particular, we have used computer modeling to predict likely side chain bridging opportunities and evaluated the effects of such replacements by correlating biological results with those derived from CD spectroscopy. We have synthesized 38 monocyclic peptide amides, competitive antagonists of human/rat CRF, using solid-phase methodology on MBHA resin. After purification by preparative RP-HPLC, the peptides were analyzed by RP-HPLC and capillary zone electrophoresis and characterized by mass spectroscopy and amino acid analysis. CRF antagonists were tested for their ability to interfere with CRF-induced release of ACTH by rat anterior pituitary cells. In most cases, one of the bridge heads was located at a position where substitution by a D-residue was tolerated (i.e., positions 12 and 20). It has become clear that careful optimization of bridge length and chirality is critical. This is best exemplified by the fact that out of the 38 analogues that were synthesized and tested, only two, [cyclo(20-23)[DPhe12,Glu20,Lys23, Nle21,38]h/rCRF12-41 and cyclo(20-23)[DPhe12,Glu20,Orn23,Nle21,38] h/rCRF12-41], were found to be more potent (3 and 2 times, respectively) than [DPhe12,Nle21,38]h/rCRF12-41, the parent compound. Six analogues belonging to two different families were found to be half as potent as the standard, 18 had 2-20% of the potency of the standard, and the others were significantly less potent. CD results of all analogues in 50% TFE (a concentration of TFE that induced nearly maximum helicity of [DPhe12,Nle21,38]h/rCRF12-41) suggest that while helicity may be an important factor for CRF analogue recognition, little correlation is found between percent helicity as determined by spectral deconvolution and biological activity in vitro.

Adrenocorticotropic Hormone↗
PubMed1994

Stimulatory effect of cocaine on ACTH secretion: role of the hypothalamus.

The administration of cocaine to rats causes the release of adrenocorticotropin hormone (ACTH). The observation that immunoneutralization of endogenous corticotropin-releasing factor (CRF) significantly blunts this response has suggested the importance of CRF-dependent pathways in this response. As the paraventricular nucleus (PVN) of the hypothalamus represents a major source of the CRF delivered to the pituitary, the present studies investigated the role of this hypothalamic nucleus in mediating cocaine-induced ACTH secretion. We first observed that one single iv injection of 5 mg cocaine/kg, or two sequential sc injections of 40 mg cocaine/kg, caused a measurable increase in steady-state levels of CRF mRNA. Bilateral lesions of the PVN significantly (P < 0.01) decreased the ability of cocaine to release ACTH measured 15 min later. Though we failed to measure any changes in the levels of the mRNA encoding for vasopressin (VP) following either regimen of drug administration, we noted that rats in which the magnocellular portion of the PVN (which contains VP perikarya) was spared, showed a normal ACTH response to cocaine. We therefore studied the possibility that VP might regulate the activity of the corticotrophs in response to cocaine. However, prior iv injection of polyclonal antibodies against VP did not measurably alter cocaine-induced ACTH secretion, while in the same experiment, immunoneutralization of endogenous CRF completely blocked the stimulatory action of cocaine. Taken together, these results show that CRF of PVN origin represents the major modulator of ACTH released in response to cocaine, while VP does not appear to play an important role.

Adrenocorticotropic Hormone↗
PubMed1994

Interaction between alcohol and interleukin-1 beta on ACTH secretion and the expression of immediate early genes in the hypothalamus.

We have observed that alcohol does not alter adrenocorticotropin (ACTH) released in response to the iv injection of interleukin-1 beta (IL-1 beta). In contrast, prior (-30 to -90 min) administration of moderate doses of alcohol (0.5-2.0 g/kg) significantly blunts ACTH secretion following the intracerebroventricular (icv) injection of the cytokine. We explored two possible mechanisms responsible for this phenomenon: Corticosteroid feedback and alcohol-induced inhibition of hypothalamic neuronal activation (measured through changes in c-fos and NGFI-B mRNA levels). Increasing plasma corticosterone levels by exposing rats to mild electroshocks or injecting them with corticosterone did not alter ACTH released by rats administered with IL-1 beta into the brain ventricles. Alcohol, which by itself did not stimulate c-fos or NGFI-B mRNA levels in the paraventricular nucleus of the hypothalamus, significantly blunted the ability of icv IL-1 beta to increase the expression of these immediate early genes. We conclude that the inhibitory influence exerted by prior alcohol treatment on ACTH released by icv administered IL-1 beta may reflect an interference with the stimulatory influence of the cytokine on hypothalamic neurons involved in the activation of the hypothalamic-pituitary-adrenal axis.

Adrenocorticotropic Hormone↗
PubMed1994

Induction of c-fos and CRF mRNA by MK-801 in the parvocellular paraventricular nucleus of the rat hypothalamus.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) stimulates the secretion of adrenocorticotropin hormone (ACTH). As corticotropin-releasing factor (CRF) represents the primary modulator of this secretion, we tested the hypothesis that the ability of MK-801 to activate the hypothalamic-pituitary-adrenal (HPA) axis was modulated through actions at the hypothalamic level that modulate the secretion of CRF. Induction of the immediate-early gene c-fos, as well as of CRF mRNA within the paraventricular nucleus (PVN) of the rat hypothalamus, was examined following the intraperitoneally administration of MK-801 (1 mg/kg). MK-801 markedly increased the expression of Fos-like protein in parvocellular nerve cells of the PVN within 60 min of systemic treatment, and double labeling immunocytochemistry indicated that Fos was primarily localized in CRF-containing neurons of the PVN. MK-801 also significantly increased CRF biosynthesis as detected by in situ hybridization, thus suggesting that c-fos could be involved in the regulation of CRF genes. Taken together, these results suggest that MK-801 stimulates the rat HPA axis probably through the neuronal gene expression of PVN CRF. The significance of these data is discussed in terms of hypothalamic NMDA receptor blockade and subsequent transcriptional regulation of CRF by immediate-early genes.

Animals↗
PubMed1994

Stress and interleukin-1 beta-induced activation of c-fos, NGFI-B and CRF gene expression in the hypothalamic PVN: comparison between Sprague-Dawley, Fisher-344 and Lewis rats.

Various signals are known to activate the hypothalamic-pituitary-adrenal (HPA) axis, an event largely dependent on the release of corticotropin-releasing factor (CRF) which originates mainly from the parvocellular paraventricular nucleus (PVN) of the hypothalamus. These signals include neurogenic stimuli such as exposure to mild electroshocks, and systemic stimuli like administration of cytokines. The HPA axis activity of Lewis rats has been reported to be hyporesponsive to such stimuli, but the exact mechanisms involved in this phenomenon are poorly understood. The present study investigated the effect of footshock exposure and central injection of interleukin (IL)-1 beta, on CRF neuronal activity and gene expression in the PVN of adult male Sprague-Dawley (SD), Fisher-344 (F344) and Lewis (LEW) rats. The animals were deeply anesthetized and rapidly perfused transcardially with a solution of 4% paraformaldehyde 3 h after the beginning of the footshock session (1.5 mA, 2 s duration, 4/min over 1 h), or the i.c.v. injection of IL-1 beta (100 ng in 10 microliters). mRNA encoding the immediate 'early' genes (IEGs) c-fos and NGFI-B, as well as CRF, were assayed by in situ hybridization histochemistry, while the localization of Fos protein within CRF-immunoreactive (ir) neurons in the PVN was determined using a dual immunostaining protocol. Both stress and IL-1 beta induced robust Fos-ir expression within the parvocellular division of the PVN in all 3 strains. The number of cells immunoreactive for both Fos and CRF proteins in the PVN was similar in SD, F344 and LEW rats following either challenge. While control animals did not display detectable levels of c-fos or NGFI-B mRNA in the PVN, both treatments induced significant expression of these transcripts in this hypothalamic nucleus and no significant differences were observed among SD, F344 and LEW rats. Relative levels of CRF mRNA in the PVN were also significantly and comparably increased following either stress or central IL-1 beta treatment. In contrast, plasma ACTH and corticosterone levels were significantly higher in F344 and SD rats than in LEW animals during the stress session. These results provide further evidence that physical stress and central IL-1 beta can enhance expression of several IEGs, as well as CRF, within the parvocellular division of the PVN. These independent indices of functional activation within parvocellular CRF neurons appear to respond similarly to diverse challenges in adult male SD, F344 and LEW rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Hypophysiotropic role and hypothalamic gene expression of corticotropin-releasing factor and vasopressin in rats injected with interleukin-1 beta systemically or into the brain ventricles.

Intact adult male rats were injected intravenously (i.v., 400 ng/kg), intraperitoneally (i.p., 400 ng/kg) or intracerebroventricularly (i.c.v., 100 ng/kg) with interleukin-1 beta (IL-1 beta) or its vehicle. In comparison with vehicle-treated animals, IL-1 beta induced significant (P < 0.01) increases in plasma ACTH levels measured 30 min later regardless of the route of cytokine administration. These changes were markedly blunted in rats administered specific antibodies directed against corticotropin-releasing factor (CRF). In contrast, vasopressin (VP) antibodies significantly blunted ACTH released by the i.c.v. injection of IL-1 beta, but only modestly altered the effect of the systemic injection of the cytokine. We then used semi-quantitative in situ hybridization analysis to measure changes in steady-state mRNA levels, as they might occur in response to these same doses of IL-1 beta. Following administration of the vehicle, measurement of gene expression in the paraventricular (PVN) portion of the hypothalamus indicated a measurable amount of hybridization signals for both CRF and VP. No detectable changes in either CRF or VP gene expression were observed in rats injected with IL-1 beta i.v. or i.p. 5 h earlier. In contrast, the i.c.v. administration of the cytokine significantly (P < 0.01) increased both CRF and VP mRNA levels measured 5 h later. These results suggest that while endogenous CRF modulates the response of the corticotrophs to this cytokine regardless of the route of administration, the role of VP is more important in rats injected centrally than in those injected peripherally.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Effect of postnatal exposure of female rats to an alcohol diet: influence of age and circulating sex steroids.

We have previously reported that when compared with animals fed ad libitum, adult ovariectomized (OVX) female rats fed an alcohol diet, but not its isocaloric equivalent control, showed a blunted ACTH response to the intravenous injection of interleukin-1 beta (IL-1 beta). The present work was undertaken to determine whether this finding could be extended to intact rats, and whether the stage of sexual maturation and/or circulating sex steroids of ovarian origin modulated the inhibitory influence of alcohol. Intact female rats were exposed to alcohol or pair-fed between postnatal days 25-35 (group I), 35-45 (group II), or 45-55 (group III). Animals of comparable age and fed ad libitum served as controls. All alcohol-exposed animals had similar blood alcohol levels measured during the eighth night of treatment. Group I lost the most weight following exposure to alcohol, but did not show measurable changes in ACTH released in response to 20 or 100 ng IL-1 beta/kg. Both alcohol and pair-feeding caused a modest decrease in IL-1-stimulated ACTH in rats of group II, but only alcohol significantly blunted corticotrophs' activity in group III. Group III, when fed alcohol, also showed lower CRF content in the median eminence compared with absolute controls or the isocaloric diet. No measurable changes, however, were observed in steady-state CRF mRNA levels in the hypothalamus of animals fed any of the diets. When intact and OVX rats were compared at 55 days of age, alcohol feeding caused a decrease in IL-1-induced ACTH secretion which was slightly, though not significantly, larger in intact animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Prenatal alcohol exposure alters the hypothalamic-pituitary-adrenal axis response of immature offspring to interleukin-1: is nitric oxide involved?

We have previously shown that following prenatal alcohol exposure, immature offspring showed blunted ACTH released in response to the peripheral administration of interleukin-1 beta (IL-1 beta). The present studies were conducted to investigate the role of changes in corticosteroid feedback (measured by altered adrenal responses to ACTH), corticotropin-releasing factor (CRF) content of the median eminence (ME), and the influence of endogenous nitric oxide (NO). The injection of several doses of ACTH failed to indicate measurable differences between the corticosterone responses of offspring born to dams fed ad libitum [control (C)], pair-fed (PF), or fed alcohol [ethanol (EtOH) = E]. CRF content in the ME, taken as an index of the amount of releasable peptide, showed a small, but statistically significant, decrease following prenatal alcohol exposure. A comparable change, however, was also noted in PF rats. As expected, the subcutaneous injection of IL-1 beta (0.5 microgram/kg) induced smaller increases in plasma ACTH levels of E than C pups. The response of PF animals was intermediate between that of E and C rats. Finally, we observed that inhibition of NO formation by the administration of the arginine derivative L omega nitro-L-arginine-methylester significantly augmented ACTH secretion in all three experimental groups, and reversed the decreased corticotrophs' response to IL-1 beta caused by prenatal alcohol. Taken together, our results suggest that the ability of prenatal alcohol exposure to alter ACTH released by immature pups in response to blood-borne IL-1 beta is probably not mediated through changes in adrenal responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Lesions of hypothalamic PVN partially attenuate stimulatory action of alcohol on ACTH secretion in rats.

We have previously shown that the ability of alcohol to stimulate adrenocorticotropic hormone (ACTH) secretion was significantly blunted by immunoneutralization of endogenous corticotropin-releasing factor (CRF) and that long-term exposure to alcohol increased CRF mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus. In the present study, we further investigated the participating role of the PVN by studying the effect of bilateral lesions of the PVN on alcohol-induced ACTH release. The acute injection of alcohol (1.5 g/kg ip) induced significant increases in plasma ACTH levels in sham-operated animals. Lesions of the PVN attenuated this response but did not abolish it. Indeed, lesioned rats retained significantly elevated ACTH values despite removal of secretagogues of PVN origin. Because removal of hypothalamic CRF can alter ACTH secretion in response to secretagogues, we studied possible changes in pituitary responsiveness to CRF. The results failed to indicate that hyperresponsiveness of the corticotrophs played a major role in accounting for the residual ACTH release of lesioned rats after alcohol treatment. We conclude that brain regions other than the PVN can modulate ACTH release during acute administration of alcohol.

Adrenocorticotropic Hormone↗
PubMed1994

Stimulatory effect of interleukin-1 beta on the hypothalamic-pituitary-adrenal axis of the rat: influence of age, gender and circulating sex steroids.

The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the hypothalamic-pituitary-adrenal (HPA) axis to the stimulatory influence of interleukins (ILs). It is thus reasonable to assume that inappropriate responses of the HPA axis to ILs might play a role in modulating the onset of pathological conditions such as infections. As part of our programme aimed at investigating the ability of ILs to release pro-opiomelanocortin-like peptides and corticosterone in rats exposed to alcohol, we observed that this stimulatory action appeared to be influenced by the gender of the animals. We therefore examined the ability of IL-1 beta, injected peripherally, to stimulate the HPA axis as a function of stage of sexual maturation and the presence or absence of circulating sex steroids. In immature (21 to 22-day-old) rats, both males and females responded to the i.p. administration of 0.5 or 2.0 micrograms IL-1 beta/kg with statistically comparable increases in plasma ACTH levels. In contrast, females released significantly (P < 0.01) more corticosterone in response to the lower dose of cytokine. Forty-day-old intact animals showed no sexual dimorphism in ACTH secretion, but the females again secreted significantly (P < 0.05-0.01) more corticosterone. Gonadectomy, performed 7-8 days prior to the assay, increased the absolute amount of corticosterone released over a 60-min period. A noticeable dimorphism of the ACTH response to IL-1 beta became apparent in 70-day-old intact rats, with females secreting more ACTH than males.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to interleukin-1 beta, vasopressin, and oxytocin.

Nitric oxide (NO) synthase (NOS), the enzyme responsible for NO formation, is found in hypothalamic neurons containing oxytocin (OT), vasopressin (VP), and to a lesser extent corticotropin-releasing factor (CRF). Because NO is reported to modulate endocrine activity, we have investigated the hypothesis that endogenous NO participates in ACTH released by various secretagogues in the rat. In the adult male rat, the intravenous injection of interleukin-1 beta (IL-1 beta; 0.2-0.3 micrograms/kg), VP (0.3-0.9 micrograms/kg), and OT (30 micrograms/kg) significantly increased plasma ACTH and corticosterone levels. Pretreatment with the L-form, but not the D-form, of N omega nitro-L-arginine-methylester (L-NAME; a specific inhibitor of NOS) markedly augmented the effects of these secretagogues whether it was injected acutely or over a 4 d period. Blockade of NOS activity also caused significant (P < 0.01) extensions of the duration of action of IL-1 beta, VP, and OT. In contrast, L-NAME did not significantly alter the stimulatory action of peripherally injected CRF, or centrally administered IL-1 beta. Administration of L-arginine, but not D-arginine (100 mg/kg), used as a substrate for basal NO synthesis and which did not by itself alter the activity of the hypothalamic-pituitary-adrenal (HPA) axis, blunted IL-1-induced ACTH secretion, and reversed the interaction between L-NAME and IL-1 beta. The stimulatory action of endotoxin, a lipopolysaccharide that releases endogenous cytokines, was also augmented by inhibition of NO formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Single point D-substituted corticotropin-releasing factor analogues: effects on potency and physicochemical characteristics.

In an attempt to determine which conformational parameters are important for the biological activity of ovine corticotropin-releasing factor (oCRF), we have synthesized in significant amounts (50-200 mg) and characterized chemically, structurally (CD), and biologically, oCRF analogues with substitution of each amino acid by its corresponding D-isomer. Out of 37 of these analogues, three were found to be equipotent to, or twice as potent as, oCRF, 13 had potencies in the range from 10 to 60%, 17 had potencies ranging from 1 to 10%, and the four others had potencies less than 0.5%. None of the analogues antagonized oCRF-induced release of ACTH in vitro at concentrations > or = 1000 oCRF. Since antagonists to CRF action can be generated by deletion of the first 8-14 residues, a series of CRF antagonists which exhibit significantly higher in vitro and in vivo biological potency than [Met18,Lys23,Glu27,29,40,Ala32,41,-Leu33,3 6,38] h/rCRF, [alpha-helical-CRF9-41], is also described. [D-Phe12,Nle21,38,Arg36]h/rCRF, in particular, was found to be ca. 15 times more potent than alpha-helical-CRF9-41 in vitro. In the rat, however, this analogue was about as effective as alpha-helical-CRF9-41 in blocking CRF-induced decrease in mean arterial blood pressure and increase in heart rate. Its potency in blocking epinephrine release by CRF was not significantly different from that of alpha-helical-CRF9-41. In the adrenalectomized rat, [Lys36]alpha-helical-CRF(9-41) (1.7 mg/kg) blunted the effect of endogenous CRF over a 90-min period; by comparison, a similar dose of alpha-helical-CRF9-41 was effective for less than 1 h.

Adrenocorticotropic Hormone↗