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Biomedical subjects

C Rivier

Publications and source records attributed to C Rivier.

At least 19 recordsLinked to original sources
PubMed1992

Immunocytochemical and in situ hybridization detection of hypothalamic neuropeptides from postmortem unfixed rat brains.

The effects of postmortem delay on neuropeptide-containing perikarya was studied in the paraventricular nucleus (PVN) of the rat hypothalamus. Serial sections from brains kept in the skull after death for 6 h and immunocytochemically processed for oxytocin (OT), vasopressin (AVP) and corticotropin releasing factor (CRF) or hybridized in situ for CRF resulted in the well preserved phenotypic expression and stability of mRNA of the aforementioned neuropeptides. Furthermore in most cases, AVP and CRF expression was discernibly enhanced relative to prefixed immunopositive tissue. Results of this study suggest that postmortem variables do not significantly alter the neurochemical coding of magnocellular or parvocellular neurosecretory systems, and support the view that rat and human brain topography can be investigated from tissue left in situ after death for a relatively long period of time.

Adrenalectomy↗
PubMed1992

The 5-hydroxytryptamine agonist fenfluramine increases Fos-like immunoreactivity in the brain.

This study was designed to assess the effects of the 5-hydroxytryptamine (5-HT) indirect agonist fenfluramine on the brain distribution of Fos- and corticotropin-releasing factor-like immunoreactivity (F-LI and CRF-LI). A single intraperitoneal injection of either DL-fenfluramine (25 mg/kg) or saline was given to resting Sprague-Dawley rats housed on a 12-12 h light-dark cycle and fed libitum. Sixty min following injections, rats were killed and brains removed and sliced (40 microns thick) in a coronal plane from the anterior olfactory bulb to the brainstem. Brain slices were then stored at -40 degrees C pending the tissue localization of F-LI and CRF-LI. F-LI and CRF-LI were determined by means of a double immunostaining procedure using the peroxidase-avidin:biotin complex (ABC) method. Fenfluramine injection led to a marked increase in F-LI in the caudate-putamen (CPu), the parvocellular division of the hypothalamic paraventricular nucleus (PVN), and the central amygdaloid nucleus (CeA). In the PVN, most of the F-LI was co-localized with CRF-LI. There was no attempt to identify which types of neurons displayed F-LI in CPu and CeA. While F-LI was readily observable in all rats treated with fenfluramine, it was not discernible in the control animals. This study provides evidence for an involvement of the immediate-early genes c-fos in the central action of fenfluramine.

Amygdala↗
PubMed1992

Differential effects of central and peripheral injection of interleukin-1 beta on brain c-fos expression and neuroendocrine functions.

Cytokines such as interleukin-1 beta (IL-1 beta) alter the activity of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in the rat. However, the brain sites at which IL-1 beta exerts these effects have not been well identified. The present study sought to identify some of these sites, using c-fos protein expression as an index of cellular activation. We also attempted to determine possible differences between the effects of peripheral and central injection of IL-1 beta on the activation of specific brain areas. Castrated male rats received intravenous (i.v.) or intracerebroventricular (i.c.v.) injections of IL-1 beta through a jugular catheter or a permanent cannula implanted in the right lateral ventricle, respectively. Blood samples were taken before, as well as 30 and 120 min after i.v. or i.c.v. IL-1 beta infusion in order to measure plasma ACTH and LH levels. Immediately thereafter, the rats were anesthetized with pentobarbital, then perfused. Their brains were removed and postfixed for one hour. Thirty-microns frozen sections were cut and approximately every fourth tissue section was processed for c-fos expression by an avidin-biotin-peroxidase method. Both i.v. (1 microgram) and i.c.v. (100 ng) injection of IL-1 beta significantly increased plasma ACTH levels, but only i.c.v. treatment measurably inhibited LH secretion. I.c.v. infusion of the cytokine markedly augmented c-fos expression in the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the hypothalamus. A large amount of CRF cells in the PVN contained labelled c-fos protein (as measured by a double labelling technique), which indicates that CRF perikarya in this hypothalamic region are activated by the central administration of IL-1 beta. In contrast, i.v. injection of IL-1 beta did not significantly alter c-fos expression in the PVN or the ARC of the hypothalamus. These results suggest that the increased HPA axis activity which follows the peripheral IL-1 beta administration, a phenomenon previously shown to depend on endogenous CRF, does not require immediate activation of hypothalamic CRF perikarya. Thus our results indicate that the stimulatory effect of blood-born cytokine may be exerted at the level of nerve terminals in the median eminence. In contrast, i.c.v.-injected IL-1 beta appears to activate the HPA axis through a stimulation of CRF neurons within the parvocellular part of PVN.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Alanine series of ovine corticotropin releasing factor (oCRF): a structure-activity relationship study.

Previous structure-activity relationship studies of CRF have shown that residues 1-4 were not necessary for receptor binding or transduction, that residues 4-8 were important for activation, and that residues 12-41 were mostly responsible for binding. Finally it was proposed that CRF assumed an alpha-helical structure when interacting with its receptor. By systematic substitution of each residue (except residues 1-4) in ovine CRF (oCRF) by Ala, we have investigated the role played by individual side chains in receptor recognition and activation. Out of 33 analogues (synthesized using SPPS on an MBHA resin, purified by RPHPLC and characterized by amino acid and mass spectral analyses), a significant loss of biological potency (less than 1% potency of native) was observed for 6 analogues ([Ala6], [Ala8], [Ala10], [Ala12], [Ala14], and [Ala38]); 12 analogues had biological potencies ranging from 1% to 60% and ranked as follows: [Ala35] less than [Ala16] less than [Ala9] less than [Ala19] less than [Ala15] less than [Ala13] less than [Ala7] less than [Ala23] less than [Ala11] less than or equal to [Ala21] less than [Ala27] less than or equal to [Ala18]; 8 analogues were found to be equipotent (greater than 60% and less than 150%) ([Ala5], [Ala17], [Ala26], [Ala29], [Ala30], [Ala34], [Ala36], and [Ala37]; and 7 analogues were found to be approximately 2-5 times more potent than native oCRF ([Ala25] = [Ala40] less than or equal to [Ala39] less than or equal to [Ala33] less than [Ala20] less than [Ala22] less than [Ala32], in an in vitro pituitary cell culture assay. In summary, the Ala substitutions which showed the greatest loss of potency (less than 1% of native oCRF) were those replacing hydrophobic residues while those showing the greatest increase in potency were replacing hydrophilic residues. Of the 22 Ala-containing analogues in the C-terminal half of the molecule, 17 analogues have equal or greater potencies than native oCRF. Substitution of Ala in the N-terminal region (residues 5-19) on the other hand is generally detrimental to biological activity. These results suggest that the side chains of residues 5-19 are very important for receptor binding and activation while, in the C-terminal region, the amino acid side chains may be more responsible for structural conservation than for functional expression.

Adrenocorticotropic Hormone↗
PubMed1992

Differential effects of intermittent or continuous exposure to cocaine on the hypothalamic-pituitary-adrenal axis and c-fos expression.

Accumulating evidence indicates that acute administration of cocaine alters neuroendocrine functions. In order to ascertain the long-term effects of cocaine on the male rat's hypothalamic-pituitary-adrenal (HPA) axis, a series of experiments were performed utilizing two different paradigms of cocaine administration for 6 days. In the first paradigm, rats received daily intravenous injections of cocaine (5 mg/kg), while in the second, they were continuously exposed to the drug (5 or 100 mg/kg/day) via osmotic pumps. We measured plasma adrenocorticotropin hormone (ACTH) and corticosterone levels, as well as the brain pattern of the proto-oncogene c-fos expression in response to either mode of drug administration. Repeated, intermittent injections of cocaine caused consistent increases in ACTH and corticosterone secretion over a 30-min sampling period on days 2, 4 and 6. This paradigm of drug administration also induced considerable, short-lasting and reversible c-fos expression in the caudate putamen but not in hypothalamic regions associated with endocrine function. In contrast, we consistently failed to observe any measurable increases in ACTH or corticosterone secretion at any time during continuous exposure to the drug. Administration of cocaine by osmotic pumps also had no effect on c-fos expression in the caudate putamen, indicating that c-fos expression as well as activation of the HPA axis are dependent upon the mode and frequency in which cocaine is administered. We conclude that continuous exposure to cocaine does not appear to activate the HPA axis, while intermittent injections of the drug induce repeated increases in plasma ACTH and corticosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Cocaine-induced stimulation of the rat hypothalamic-pituitary-adrenal axis is progressively attenuated following hourly-interval regimens of the drug.

The role of multiple (iv) injections of cocaine on the rat hypothalamic-pituitary-adrenal (HPA) axis was examined using four different temporal regimens of drug exposure. In intact rats, cocaine (5 mg/kg) consistently stimulated the secretion of adrenocorticotropin hormone (ACTH) and corticosterone over a 6 hr interval regimen. In all experimental groups, administration of the vehicle alone failed to measurably alter the secretion of the aforementioned hormones. When rats where exposed to the drug over a 4 hr interval regimen, a modest attenuation of ACTH, but not corticosterone, secretion was observed following the third and last cocaine injection. To test whether the attenuation of ACTH secretion to cocaine administration was caused by corticosterone-mediated negative feedback, the response of intact and adrenalectomized (ADX) rats over 2 hr and 1 hr interval regimens was compared. In intact rats, both drug interval regimens resulted in a significant attenuation of ACTH secretion following, the second and third injections of the drug. ADX rats, on the other hand, exhibited significant increases in ACTH levels following either interval regimens, though we observed a modest blunting of pituitary responsiveness to the 1 hr regimen. From these results we conclude that in intact rats the activity of the HPA axis is significantly attenuated in response to multiple, acute cocaine injections, and that this decreased response may be at least in part caused by a negative corticoid feedback mechanism.

Adrenalectomy↗
PubMed1992

Cocaine-induced ACTH secretion: dependence of plasma levels of the drug and mode of exposure.

To determine whether changes in pituitary responsiveness might account for the lack of corticotropin (ACTH) stimulation following 6 consecutive days of continuous cocaine administration (5 or 25 mg/kg/day, via osmotic minipumps), the hormonal response of vehicle- or cocaine-pretreated male rats was compared. Intravenous injections of synthetic corticotropin-releasing factor (CRF) (0.2, 1, or 5 micrograms/kg) elicited dose-dependent increases in ACTH secretion irrespective of whether rats had been previously exposed to cocaine or not. Similarly, in both vehicle- and cocaine-pretreated rats ACTH response to acute injections of the drug was identical, indicating that pituitary corticotrophs remained responsive following continuous administration of cocaine. To determine and compare plasma concentrations of cocaine and its metabolites after continuous or acute administration of the drug, pharmacokinetics analysis of concentration vs. time was ascertained. Circulating concentrations of cocaine from rats continuously exposed to the drug were relatively low throughout the 6 days of exposure. In contrast, intravenous injections of cocaine produced peak concentrations of the drug that were significantly higher than those measured during continuous cocaine infusion. Such peak concentrations in cocaine correlated with marked increases in plasma ACTH levels. Plasma concentrations of the metabolites benzoylecgonine and methyl ester ecgonine followed a pharmacokinetic clearance similar to that of the parent compound, with low concentrations detected during continuous exposure whereas high concentrations were observed following intravenous injections of the drug. Our results suggest two nonmutually exclusive conclusions. First, there may be a critical threshold of cocaine plasma concentrations (as indicated by our results as being over 800 ng/ml) that are necessary for activation of the hypothalamic-pituitary-adrenal axis to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Alcohol-induced inhibition of LH secretion in intact and gonadectomized male and female rats: possible mechanisms.

Alcohol (EtOH) is reported to decrease gonadotropin secretion, but the mechanisms mediating these changes are not fully understood. The present study examined the ability of acutely or chronically administered EtOH to alter plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in both male and female rats, and correlated these changes with blood EtOH levels (BALs); investigated possible changes in the pituitary responsiveness of animals exposed to EtOH; and probed the role of the paraventricular nucleus (PVN) of the hypothalamus in mediating alcohol-induced decreases in plasma LH levels. The injection of 0.5 g EtOH/kg was accompanied by significantly higher BALs in females compared with males. This dose of alcohol did not alter rectal temperature, and only significantly (p < or = 0.01) decreased plasma LH levels in female rats. These findings were not altered by removal of gonadal steroids. Administration of 2.0 g EtOH/kg was followed by BALs that were comparable in both groups of rats at the 1- and 2-hr time-points, but were significantly (p < or = 0.01) higher in females 3 hr after treatment. Rectal T measurably decreased in all rats injected with 2 g EtOH/kg, though intact females showed the greatest change. This alcohol treatment also significantly (p < or = 0.01) inhibited immunoreactive LH release in both sexes, but there were no measurable changes in FSH values at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMed1992

Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood-brain barrier.

Melanin-concentrating hormone (MCH) is a peptide reported to inhibit ACTH and cortisol secretion in teleost fish. Its ability to modify the activity of rat corticotrophs, however, remains controversial. We report here that while the peripheral injection of rat (r) MCH failed to alter plasma ACTH levels of conscious rats with an intact blood-brain barrier (BBB), it significantly activated the hypothalamic-pituitary-adrenocortical axis of rats with increased BBB permeability induced by protamine sulfate administration into the internal carotid artery. Similarly, the intracerebroventricular injection of this peptide into rats with intact BBB measurably released ACTH. The ACTH response to rMCH was markedly, but not totally, inhibited by passive immunoneutralization of CRF. These results indicate that rMCH acts within the central nervous system to stimulate the hypothalamic-pituitary-adrenocortical axis of rats, and that the site of action of the peptide is located in brain structures protected by the BBB. Activation of CRF-secreting neurons represents an important final pathway, although other regulatory factors also seem to be involved.

Adrenocorticotropic Hormone↗
PubMed1991

Gonadotropin releasing hormone antagonists: novel structures incorporating N omega-cyano modified guanidine moieties.

A series of GnRH antagonists with substitutions at positions 1, 2, 3, 5 and 6 that included the recently reported homoArg-N omega-cyano-N omega'-alkyl- or Lysine-N epsilon-5'-(3-amino-1H-1,2,4-triazole) [Lys(atz)] amino acid derivatives was synthesized, characterized and tested for antiovulatory and anaphylactoid activities and binding affinity. Overall, these analogs were found to be considerably more soluble at neutral pH than their homologs Nal-Glu or Antide. The decapeptides with these substitutions in positions 5 and/or 6 retained high in vivo potency while those with similar substitutions at positions 1, 2 and 3 were significantly less potent than Nal-Glu or Antide. Of the 16 new analogs reported here, Azaline (Ac-DNal1, DCpa2, DPal3, Lys5(atz),DLys6(atz), ILys8,DA1a10]-GnRH) showed the most promising physico-chemical and biological properties [Lys(atz) = N epsilon-5'-(3-amino-1H-1,2,4-triazole) lysine]. Azaline is readily soluble in dilute buffers at pH 7.0, completely inhibits ovulation at 2.0 to 3.0 micrograms per rat, is equipotent to GnRH in releasing histamine in the rat and has a weaker anaphylactoid response in the rat than other analogs such as Nal-Glu or even Antide.

Amino Acid Sequence↗
PubMed1991

Novel gonadotropin-releasing hormone antagonists: peptides incorporating modified N omega-cyanoguanidino moieties.

In order to minimize the deleterious effects of histamine release resulting from the administration to rats and humans of some potent gonadotropin-releasing hormone (GnRH) antagonists, various arginine residues were replaced with the less basic N omega-cyano-N omega-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and N omega-triazolyllysine, -ornithine or -p-aminophenylalanine residues in active analogues. These novel analogues were synthesized on a solid-phase support via a two-step modification of the N omega-NH2 of lysine, ornithine, or p-aminophenylalanine residues in otherwise protected resin bound peptides. Most analogues were tested in the rat antiovulatory assay (AOA) and three in vitro assays; a pituitary cell culture assay, a binding assay to pituitary cell membranes, and a histamine release assay. Introduction of the cyanoguanidino and N omega-triazolyl moieties into GnRH analogues yielded several water-soluble antagonists which showed a desirable therapeutic ratio (low histamine release activity to high in vivo potency). Among them, "Azaline" (10, [Ac-DNal1,DCpa2,DPal3,Lys5(atz), DLys6(atz),ILys8,DAla10]GnRH), inhibited ovulation in the rat by 90% at 2 micrograms/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.

Animals↗
PubMed1991

Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis: peripheral and central mechanisms.

This article reviews the mechanisms believed to mediate stress-induced inhibition of reproductive functions and the anatomical sites at which these effects take place. Particular emphasis is placed on the potential modulating role of hormones or neurotransmitters released during stress. At the level of the gonads, adrenal corticoids, pro-opiomelanocortin (POMC)-like peptides, and corticotropin-releasing factor (CRF) are reported to interfere with the stimulatory action of gonadotropins on sex steroid-producing cells. Increased circulating corticosteroid levels may also decrease pituitary responsiveness to GnRH. There is, however, increasing evidence that these mechanisms are primarily involved in mediating the effects of prolonged stress, but not those of an acute stimulus. In contrast, a variety of hormones or neurotransmitters, including CRF, POMC peptides, and biogenic amines act within the brain to mediate the inhibitory influence of both acute and prolonged stresses on reproductive function.

Adrenal Cortex Hormones↗
PubMed1991

Effect of recombinant inhibin on luteinizing hormone and follicle-stimulating hormone secretion in the rat.

We investigated the effect of the iv injection of recombinant human (rh) inhibin on FSH and LH secretion in the female rat under various experimental circumstances. Rh inhibin caused dose-related decreases in mean plasma FSH, but not LH, levels in ovariectomized female rats 14 days old and older. The duration of this inhibition was proportional to the dose of rh inhibin, but no consistent changes in FSH secretion were observed until 4 h after treatment. Maximum suppression of FSH release was observed at about 15 micrograms rh inhibin/kg BW and lasted 8-10 h. Measurement of the area under the curve from 4-12 h after injection of inhibin indicated a dose-related decrease in total FSH secreted. When blood samples were withdrawn every 10 min to evaluate pulsatile gonadotropin release, analysis of FSH pulse parameters indicated that rh inhibin (25 micrograms/kg) interfered with pulse frequency, amplitude, and peak levels in both intact and ovariectomized rats. In contrast, pulsatile LH secretion was not measurably altered. These results demonstrate that rh inhibin acts primarily at the level of the pituitary to inhibit all parameters of FSH secretion and suggest that this effect is at least not entirely mediated by changes in GnRH receptors.

Aging↗
PubMed1991

An inhibitory effects of interleukin-1a on basal gonadotropin release in the ovariectomized rhesus monkey: reversal by a corticotropin-releasing factor antagonist.

Interleukin-1 (IL-1), an important component of the immune system, has recently been shown to influence the release of several hormones in the rodent. In this paper, the effectiveness of IL-1a in modulating basal gonadotropin secretion as well as cortisol release in the primate has been investigated. Eight adult ovariectomized rhesus monkeys were given a 30-min intracerebroventricular infusion of physiological saline (n = 5), various doses of IL-1a (17 micrograms n = 5; 8.5 micrograms; n = 3; 4.2 micrograms n = 5; and 2.1 micrograms n = 4) or IL-1a plus a CRF antagonist (n = 5). LH and FSH concentrations were measured at 15-min intervals during the 3-h preinfusion baseline control and the 5-h postinfusion period, while cortisol concentrations were determined at 45-min intervals. While LH concentrations remained unchanged in the monkeys receiving saline only, they decreased significantly after the 30-min IL-1a infusion. By hour 5 after IL-1a administration, mean (+/- SE) hourly areas under the LH curves (expressed as a percentage of preinfusion baseline) were 27.7% +/- 7.3 (17 micrograms IL-1a), 31.9% +/- 8.4 (8.5 micrograms), 33.3% +/- 5.5 (4.2 micrograms), and 39% +/- 4.0 (2.1 micrograms) (P less than 0.05 vs. morning control). FSH concentrations were also significantly decreased after IL-1a, 17 micrograms: by hour 5, they were 67.4% +/- 5.0 of baseline control. While cortisol concentrations decreased thoughout the experiment in the animals receiving saline, they increased with all IL-1a doses: overall mean (+/- SE) postinfusion concentrations were 21.8 +/- 1.1 (saline), 49.5 +/- 2.2 (IL-1a, 17 micrograms), 35.1 +/- 1.9 (8.5 micrograms), 45.7 +/- 1.5 (4.2 micrograms), and 39.5 +/- 1.5 (2.1 micrograms) micrograms/dl (P less than 0.05 IL-1a vs. saline). Concomitant infusion of the CRF antagonist, [D-Phe12, NLE 21,38caMe LEU37] CRF (12-41), (120-360 micrograms), prevented the IL-1a induced LH inhibition. By hour 5, areas under LH curves were 33.5% +/- 1.7 for IL-1a alone and 99.2% +/- 4.2 (NS vs. saline) for IL-1a + CRF antagonist. The CRF antagonist also blocked the ability of IL-1a to increase cortisol secretion: mean cortisol concentrations were 28.6 +/- 1.4 micrograms/dl (NS vs. saline). The results clearly indicate that the cytokine IL-1a inhibits pulsatile LH and FSH secretion in the ovariectomized rhesus monkey and demonstrate that this inhibition is causally related to the activation of CRF by this cytokine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Effect of recombinant inhibin on gonadotropin secretion during proestrus and estrus in the rat.

This work investigated the ability of recombinant human (rh) inhibin A or the GnRH antagonist [Ac-D2Nal1, delta Cpa2, delta 3Pal3, Arg5 delta 5-(p-methoxyphenyl)5-oxo-2-aminopentanoic acid6, delta Ala10]GnRH to alter plasma immunoreactive LH and FSH levels in cycling female rats. In a first series of experiments, rh inhibin A (25 micrograms/kg) was injected iv between 0800 and 0830 h, or at 0800 and 1200 h, on proestrus, and plasma hormone levels were measured from 1200-1900 h. Both regimens of administration significantly (P less than or equal to 0.01) lowered mean plasma FSH levels but did not mask the primary FSH surge. This treatment also lowered the overall amount of LH released, although the difference between control and inhibin-treated rats only reached statistical significance (P less than or equal to 0.05) after two injections of the protein. Measurement of the number of tubal ova shed on the next estrus showed no difference between rats injected with the vehicle or inhibin at 0830 h. Finally, it was shown that administration of the GnRH antagonist (100 micrograms/kg) at 1200 h interfered with the primary surges of both LH and FSH. In a second series of experiments, rh inhibin A (25 micrograms/kg) was injected once at 2000 h on proestrus. In these animals, inhibin significantly (P less than or equal to 0.01) decreased mean plasma FSH levels between 2000 h on proestrus and 0500 h on estrus and totally suppressed the secondary FSH surge. LH secretion remained low in control animals, and no measurable changes were observed after inhibin treatment. Flushing of the ova 5 days later (i.e. during estrus of the subsequent cycle) showed no difference between control and inhibin-treated rats. Injection of the GnRH antagonist (100 micrograms/kg) at 2000 h on proestrus decreased the total amount of FSH secreted during late proestrus and early estrus. However, FSH secretion showed an increase at between 0100 and 0400 h of estrus despite blockade of GnRH receptors. These results indicate that administration of rh inhibin A interferes with both the primary and secondary FSH surges. In contrast to its inability to alter LH release by ovariectomized rats, inhibin also blunted LH secretion during the afternoon of proestrus. Whether these results represent differential effects of inhibin on LH secreted by intact and gonadectomized animals, or whether the documented changes in pituitary responsiveness to GnRH during proestrus are accompanied by an increased sensitivity to inhibin, needs further investigation.

Animals↗
PubMed1991

Stimulatory effect of interleukin-1 on adrenocorticotropin secretion in the rat: is it modulated by prostaglandins?

The in vivo release of ACTH by interleukin-1 alpha (II-1 alpha) is reportedly blocked by acute treatment with indomethacin (indo), suggesting an involvement of endogenous prostaglandins in the effect of cytokines on the hypothalamic-pituitary-adrenal axis. However, indo also increases plasma corticosterone levels, raising the possibility that inhibition of ACTH release is due to suppressive effects of hypercorticolemia rather than to blockade of the stimulatory effects of II-1 alpha. We observed that the iv administration of indo (10 mg/kg) 15 min before II-1 alpha completely abolished the rise in plasma ACTH levels caused by the peripheral injection of this lymphokine to intact rats. At the time of II-1 alpha injection, plasma corticosterone levels were 39 +/- 12 ng/ml in controls and 121 +/- 22 ng/ml in indo-treated animals (P less than or equal to 0.01). In contrast, implantation of intact rats with indo pellets (which delivered 30 micrograms drug/h) 28 h before II-1 only partially interfered with II-1-induced ACTH secretion. In these rats plasma corticosterone levels before II-1 alpha injection were 29 +/- 14 ng/ml in controls and 66 +/- 18 ng/ml in rats implanted with indo pellets (P less than or equal to 0.05). To determine whether the effect of indo was due to corticosteroid feedback or represented a modulating action of prostaglandins themselves, a similar series of experiments was carried out in adrenalectomized rats. In the absence of corticoid replacement therapy, acute treatment with indo did not measurably interfere with the stimulatory effect of II-1 alpha. In contrast, indo blunted, but did not abolish, the effect of II-1a in ADX rats pretreated with corticosterone or dexamethasone to normalize basal ACTH levels. We conclude that the acute ability of indomethacin to totally block II-1-induced ACTH secretion by intact rats appears to be primarily mediated through corticosteroid feedback. However, results obtained when a similar experiment was carried out in adrenalectomized/corticosteroid-treated rats suggest, although they do not prove, that the ability of II-1 alpha to activate the hypothalamic-pituitary-adrenal axis may be partially dependent on the release of prostaglandins.

Adrenalectomy↗
PubMed1991

Differential antagonist activity of alpha-helical corticotropin-releasing factor9-41 in three bioassay systems.

Studies were performed in conscious unrestrained rats to compare the ability of the CRF receptor antagonist, alpha-helical CRF9-41, to inhibit the actions of CRF in three in vivo bioassay systems. When both peptides were administered intracerebroventricularly, an antagonist:agonist ratio between 6:1-12:1 was required to abolish CRF-induced elevations of plasma catecholamine levels. When both peptides were administered iv, CRF-induced hypotension and tachycardia were completely prevented by an antagonist:agonist ratio of 6:1, whereas total blockade of CRF-induced elevations of plasma ACTH and beta-endorphin levels required an antagonist:agonist ratio of 3000:1. These results demonstrate marked differences in the ability of alpha-helical CRF9-41 to antagonize various biological actions of CRF and support the existence of multiple CRF receptor subtypes.

Adrenocorticotropic Hormone↗