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Biomedical subjects

J Rivier

Publications and source records attributed to J Rivier.

At least 199 records · Page 11Linked to original sources
PubMed1986

Hormonal regulation of granulosa cell inhibin biosynthesis.

The hormonal regulation of inhibin production by cultured granulosa cells from immature hypophysectomized, estrogen-treated rats was examined using a specific RIA which detects the N-terminal portion of the inhibin alpha-chain. The RIA measured bioactive inhibin of Mr about 32,000 in granulosa cell conditioned media fractionated by fast protein liquid chromatography. In the presence of 10(-7) M androstenedione, FSH stimulated inhibin production in a dose-dependent manner during a 2-day culture. Inclusion of a phosphodiesterase inhibitor decreased the EC50 for FSH from 2.6 to 0.8 ng/ml (n = 3). The stimulatory effect of FSH could be mimicked with forskolin (an adenyl cyclase activator) and with a cAMP analog, (Bu)2cAMP, consistent with FSH action mediated through a cAMP dependent pathway. Intracellular levels of inhibin were unmeasureable, suggesting that inhibin is not stored to any great extent by the granulosa cells. This finding was consistent with in vivo studies which showed that whereas FSH treatment for 2 days doubled serum inhibin levels when compared with basal levels, there was no increase in the concentration of extractable inhibin in ovarian tissue. Granulosa cells which had been exposed to 20 ng/ml FSH for 2 days to induce LH receptors produced inhibin in response to both LH and human CG during the subsequent 2-day culture, with the levels of inhibin equalling the amount inducible by FSH. In contrast, neither PRL nor terbutaline, a beta 2-adrenergic agonist, had any effect on inhibin production even though receptors for these hormones are also induced by FSH. GnRH was found to inhibit the FSH-stimulated production of inhibin (IC50, 10(-7) M), consistent with previous observations that GnRH can act at the ovarian level to inhibit granulosa cell differentiation. This inhibition by GnRH could be reversed by inclusion of a specific GnRH antagonist. On the other hand, another regulatory peptide, vasoactive intestinal peptide, slightly stimulated inhibin production. The effect of several growth factors was also tested. Insulin-like growth factor I raised not only FSH-stimulated inhibin levels, but basal levels as well. Insulin was also effective, but only at 100-fold higher concentration. Epidermal growth factor inhibited FSH-stimulated inhibin production (IC50 = 0.1 ng/ml), whereas fibroblast growth factor had no effect. Thus, granulosa cell inhibin secretion is regulated by FSH and LH but not by PRL, presumably via a cAMP-mediated pathway.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Dual effects of growth hormone (GH)-releasing hormone infusion in normal men: somatotroph desensitization and increase in releasable GH.

Continuous infusion of human GH-releasing hormone (GHRH) stimulates GH secretion in normal subjects, but a single supramaximal iv dose of GHRH thereafter elicits a diminished serum GH response compared to that after a saline infusion; the response to the single dose challenge is inversely related to the dose of GHRH previously infused. To determine if this attenuated GH response is a result of depletion of available GH or desensitization of the somatotroph, a 6-h infusion of saline or GHRH (10 ng/kg . min) was administered to 10 normal men, and an iv bolus dose of either GHRH (3.3 micrograms/kg) or regular insulin (0.15 U/kg) was given after 5.5 h of infusion. On both days of GHRH infusion, there was significant stimulation of GH secretion compared to that after saline infusion. The GH response to the supramaximal dose of GHRH was greater after saline infusion than after GHRH infusion, and the GH response to insulin-induced hypoglycemia was significantly greater after GHRH infusion compared with the responses on the other 3 study days. The greatest GH secretion occurred during GHRH infusion followed by insulin administration; therefore, pituitary reserve was not decreased by prior exposure to GHRH. These studies suggest that somatotrophs become partially refractory to GHRH stimulation over time, but remain responsive to an alternate stimulus of GH secretion. We suggest that the hypoglycemia-induced GH response occurs via a reduction in hypothalamic somatostatin secretion, and the attenuated GH response to the supramaximal GHRH dose after GHRH infusion probably represents either partial desensitization or down-regulation of the GHRH receptor.

Adult↗
PubMed1986

The dependency of folliculogenesis and corpus luteum function on pulsatile gonadotropin secretion in cycling women using a gonadotropin-releasing hormone antagonist as a probe.

A potent GnRH antagonist, [Ac-delta 3-Pro1,p-F-D-Phe2,D-Trp3,6]GnRH (4F-Antag), was used as a probe to determine the relative dependency of ovarian cyclicity on pulsatile gonadotropin secretion. 4F-Antag was administered in a dose of 80 micrograms/kg sc twice a day for 3 consecutive days during different phases of the menstrual cycle. This treatment resulted in a prompt attenuation of pulsatile gonadotropin secretion in all women studied. Maximal suppression of gonadotropin levels, expressed as percent change from baseline, averaged 48% for LH and 22% for FSH. The reduced pulsatile gonadotropin release induced by 4F-Antag administration during the early follicular phase resulted in a significant decrease in serum estradiol levels during the period of treatment and was followed by a prolongation of follicular phase (2.4 days) and cycle length (3.5 days), but no alteration of subsequent cyclic ovarian steroid profiles compared to control cycles. Treatment initiated during the midfollicular phase 4-6 days before the expected LH surge resulted in a more dramatic decline in serum estradiol levels and prolongation of follicular phase length by 5-6 days compared to control cycles. Normal luteal function was preserved. These alterations were compatible with induction of the demise of the dominant follicle followed by the reinitiation of follicular recruitment. Administration of 4F-Antag during the midluteal phase resulted in rapid falls in serum estradiol and progesterone levels and the onset of menstrual bleeding in all women. The luteolytic effect of 4F-Antag was completely negated by the administration of hCG. These data indicate that 4F-Antag interferes with ongoing cyclic ovarian function by reducing pulsatile gonadotropin stimulation, which disrupts folliculogenic processes and induces the demise of the corpus luteum. From these findings we infer that the functional integrity of ovarian cyclicity is remarkably sensitive to brief (3 days) and partial reduction in pulsatile gonadotropin secretion.

Adult↗
PubMed1986

Single subcutaneous doses of a luteinizing hormone-releasing hormone antagonist suppress serum gonadotropin and testosterone levels in normal men.

The ability of single doses of a LHRH antagonist [Ac-delta 3Pro1, 4F-D-Phe2, D-Trp3,6]LHRH (4F-antagonist) to suppress serum gonadotropin and testosterone levels was studied in six normal men. The 4F-antagonist was given sc at four doses: 40, 80, 160, and 320 micrograms/kg body weight. Serum immunoreactive LH, FSH, and testosterone and bioactive LH were measured at intervals for the subsequent 18 h. Serum LH decreased rapidly by (mean +/- SE) 39.7 +/- 2.7%, 41.6 +/- 5.4%, 45.5 +/- 4.7%, and 45.3 +/- 5.4% after each of the four doses. The mean number of LH pulses and their amplitude decreased after each dose and remained suppressed for at least 6 h. After each of the four doses, mean serum FSH levels decreased by 20.0 +/- 4.1%, 33.8 +/- 6.8%, 25.8 +/- 3.6%, and 33.3 +/- 5.7%, and mean serum testosterone levels decreased by 47.7 +/- 7.3%, 55.6 +/- 10.5%, 58.2 +/- 10.8%, and 76.0 +/- 6.0%. Serum testosterone remained low for at least 18 h after the two higher doses. LH bioactivity and the ratio of bioactive LH to immunoreactive LH decreased in all subjects, especially after higher doses of the 4F-antagonist. No side effects or adverse reactions occurred after 4F-antagonist administration, and toxicology studies were negative. These results demonstrate that a single sc injection of this potent LHRH antagonist inhibits the pituitary-gonadal axis in normal men.

Adult↗
PubMed1986

Growth hormone releasing factor and somatomedin C production: extrahypothalamic localization and possible functional significance.

Growth hormone-releasing factor (GRF) is found in the highest concentration (albeit lower compared to other hypothalamic regulatory hormones) in the hypothalamus. There is mounting evidence that GRF-like immunoreactivity is found in other sites in the CNS and in the periphery. The role of GRF, other than to stimulate growth hormone secretion by the somatotroph, is unknown. In addition generation of IGF-1 in response to GRF appears to be dependent on an intact pituitary.

Animals↗
PubMed1986

Stimulation of in-vivo growth hormone secretion in young chickens by rat hypothalamic growth hormone-releasing factor and synthetic analogues.

Rat hypothalamic GH-releasing factor (rhGRF), at doses between 0.1 and 10 micrograms/kg, increased plasma GH concentrations in immature domestic fowl 5-10 min after i.v. injection. Sodium pentobarbitone anaesthesia blunted the GH responses to rhGRF, although in both conscious and anaesthetized chicks the maximal responses were induced by a dose of 1 microgram rhGRF/kg. The stimulatory effect of rhGRF on in-vivo GH secretion was less than that provoked by corresponding doses of human pancreatic GRF, but greater than that elicited by two rhGRF analogues, (Nle27)-rhGRF(1-32) and (Nle27)-rhGRF(1-29). These results demonstrate that the chicken pituitary is responsive to mammalian GRF and provide evidence of structure-activity relationships of GRF in the domestic fowl.

Animals↗
PubMed1986

Modulation of brain NMDA receptors: common mechanism of sigma/PCP receptors and their exogenous and endogenous ligands.

Quantitative autoradiographic distribution patterns of sigma/PCP and NMDA receptors show striking similarities but not in all brain areas. We have identified an endogenous ligand of brain PCP receptors which noncompetitively antagonizes NMDA-induced neurotransmitter release from brain slices. These data support the concept that the sigma/PCP receptor ligands may exert their unique behavioral effects by indirect modulation of NMDA-mediated transmission.

Acetylcholine↗
PubMed1986

Inhibition of estradiol-induced gonadotropin release in ovariectomized rhesus macaques by a gonadotropin-releasing hormone antagonist.

Six adult ovariectomized rhesus macaques were given a gonadotropin-releasing hormone (GnRH) antagonist [Ac-beta-(2)DNAL,pFDPhe,DTrp,DArg]-GnRH, by intravenous infusion for 3 to 3.5 days to determine whether the positive feedback action of estradiol benzoate (E2B) on pituitary luteinizing hormone (LH) secretion could be inhibited by blockage of GnRH binding to pituitary gonadotropes. The LH release was suppressed when the antagonist was given either as a bolus injection every 6 hours or as a constant infusion, beginning 24 hours after the E2B was administered. Both LH release and follicle-stimulating hormone release were suppressed if the GnRH antagonist infusion began when the E2B was administered. The results suggest that continued hypothalamic GnRH stimulation of the pituitary is necessary for the full expression of the preovulatory-like gonadotropin surge that occurs in ovariectomized macaques in response to E2.

Animals↗
PubMed1985

Peptide neurotoxins from fish-hunting cone snails.

To paralyze their more agile prey, the venomous fish-hunting cone snails (Conus) have developed a potent biochemical strategy. They produce several classes of toxic peptides (conotoxins) that attack a series of successive physiological targets in the neuromuscular system of the fish. The peptides include presynaptic omega-conotoxins that prevent the voltage-activated entry of calcium into the nerve terminal and release of acetylcholine, postsynaptic alpha-conotoxins that inhibit the acetylcholine receptor, and muscle sodium channel inhibitors, the mu-conotoxins, which directly abolish muscle action potentials. These distinct peptide toxins share several common features: they are relatively small (13 to 29 amino acids), are highly cross-linked by disulfide bonds, and strongly basic. The fact that they inhibit sequential steps in neuromuscular transmission suggests that their action is synergistic rather than additive. Five new omega-conotoxins that block presynaptic calcium channels are described. They vary in their activity against different vertebrate classes, and also in their actions against different synapses from the same animal. There are susceptible forms of the target molecule in peripheral synapses of fish and amphibians, but those of mice are resistant. However, the mammalian central nervous system is clearly affected, and these toxins are thus of potential significance for investigating the presynaptic calcium channels.

Amino Acid Sequence↗
PubMed1985

Purification and partial characterization of inhibin from porcine follicular fluid.

Inhibin, a protein of gonadal origin that suppresses the basal secretion of follicle stimulating hormone by anterior pituitary cells has been purified from porcine follicular fluid. Using several RP-HPLC steps and gel filtration under denaturing conditions, we obtained a fraction approximately ten thousand fold purified which showed one band on SDS PAGE and in the same experiment two bands after reduction (MW ca 14K and ca 18K) suggesting a molecular weight of 32K for inhibin. Edman degradation of isolated inhibin and carboxymethylated chain A indicated that the first 6 residues were H-Ser-Thr-Ala-Pro-Leu-Pro-; by subtraction, the first 3 residues of chain B could be deduced to be H-Gly-Leu-Glu-. EC50 was ca 0.3 ng/ml or 10 pM in our in vitro pituitary cell culture assay. Antibodies to residues 1-6 were raised which could immunoneutralize purified inhibin activity in an in vitro assay.

Amino Acid Sequence↗
PubMed1985

Binding sites for calcitonin gene-related peptide in distinct areas of rat brain.

Calcitonin gene-related peptide (CGRP) binding sites were localized in rat brain and spinal cord by an in vitro labeling light microscopic technique using [125I]rCGRP as radioligand. Specific rCGRP binding with a dissociation constant (Kd) of 0.53 nM to membrane preparations from rat brain cortex was characterized. The presence and the selective distribution of specific high affinity CGRP binding sites in the central nervous system suggest a role for this recently predicted peptide as a neurotransmitter.

Animals↗
PubMed1985

Reproductive/endocrine and anaphylactoid properties of an LHRH-antagonist, ORF 18260 [Ac-DNAL1(2), 4FDPhe2,D-Trp3,D-Arg6]-GnRH.

It has been demonstrated in a variety of experiments that ORF 18260 inhibits (ED100) spontaneous and LHRH-induced ovulation in rats (10 micrograms/kg s.c.; 10 mg/kg i.g.) and hamsters (100 micrograms/kg s.c. and 100 mg/kg i.g.). Inhibition of LHRH induced ovulation appears to be competitive in nature. In normally cycling animals, efficacy varies with time of administration. In the spontaneously ovulating rat, the most effective time is 15.00 hr of proestrus; in the hamster it is 10.00 hr. Continuous administration inhibits ovulation in rats, and ORF 18260 has contragestational activity in rats and hamsters but not in guinea pigs and mice. Prostate growth in rats is inhibited at a dose of 100 micrograms/kg (s.c.). Our studies also suggest that ORF 18260 can also induce cutaneous anaphylactoid-like reactions in rats. When compound is administered intradermally in rats, ORF 18260 causes a dose-related whealing response, noticeable from the 0.01 micrograms/rat dose level.

Administration, Oral↗
PubMed1985

The distribution of growth-hormone-releasing factor (GRF) immunoreactivity in the central nervous system of the rat: an immunohistochemical study using antisera directed against rat hypothalamic GRF.

Immunohistochemical methods have been used to chart the distribution of rat hypothalamic growth-hormone-releasing factor (rhGRF) immunoreactivity in the brains of normal and colchicine-treated adult albino rats. The results suggest the existence of at least two distinct rhGRF-containing systems: one responsible for delivery of the peptide to portal vessels in the median eminence, and one whose relationship, if any, to hypophysiotropic function is less direct. A dense plexus of rhGRF-stained fibers was found throughout the external lamina of the median eminence that is the route by which the peptide is delivered to the anterior pituitary. This projection appears to arise primarily from a group of rhGRF-immunoreactive neurons centered in the arcuate nucleus. Some 1,000-1,500 rhGRF-positive neurons were counted on each side of the brain in rats pretreated with colchicine. Colocalization studies, using a sequential double staining technique, indicated that a subset of rhGRF-immunoreactive neurons in the arcuate region contain neurotensin immunoreactivity. No evidence was obtained for colocalization of rhGRF with either of two pro-opiomelanocortin-derived peptides (alpha-melanocyte-stimulating hormone, adrenocorticotropic hormone (1-24)) in individual neurons in the arcuate nucleus. Much smaller groups of neurons were localized in the parvicellular division of the paraventricular nucleus of the hypothalamus and in the dorsomedial nucleus, and it is unclear whether they contribute to the plexus of rhGRF-stained fibers in the median eminence. The only other region in the rat brain in which rhGRF-stained cells were found reliably was in the area that roughly encapsulates the caudal aspect of the ventromedial nucleus of the hypothalamus. Because cells in this region are not known to project to the median eminence, they may be assumed to contribute to the extrahypophysiotropic rhGRF-stained projections outlined below. From the level of the arcuate and ventromedial nuclei, rhGRF-immunoreactive fibers could be traced along the base of the brain and through the periventricular system to discrete terminal fields limited almost exclusively to the hypothalamus and adjoining parts of the basal telencephalon. All parts of the periventricular region of the hypothalamus receive an input, including the preoptic and anterior parts in which somatostatin-containing neurons that project to the median eminence are clustered. Other prominent terminal fields were localized in discrete parts of the dorsomedial, paraventricular, suprachiasmatic, and premammillary nuclei, and in the medial preoptic and lateral hypothalamic areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Differential regulation of corticotropin-releasing factor receptors in anterior and intermediate lobes of pituitary and in brain following adrenalectomy in rats.

The effects of adrenalectomy on corticotropin-releasing factor (CRF) receptors in anterior and intermediate lobes of rat pituitary and in forebrain were examined using in vitro autoradiography with the radioiodinated analogue of ovine CRF, Nle21, [125I]Tyr32-CRF. The concentration of CRF receptors in the anterior pituitary was significantly reduced at 4 days and remained decreased at 9 weeks after adrenalectomy. In contrast, adrenalectomy did not alter CRF receptors in the intermediate lobe or in a variety of forebrain regions. The adrenalectomy-induced change in CRF receptors in the anterior pituitary was completely reversed by glucocorticoid replacement with dexamethasone. These data indicate that endogenous CRF is capable of modulating its receptor density in the anterior pituitary and suggest that different sources of CRF or other factors may be important in regulating intermediate lobe hormone secretion and neuronal activity in brain.

Adrenal Glands↗
PubMed1985

Acceleration of growth in two children treated with human growth hormone-releasing factor.

Two growth hormone-deficient children were treated with growth hormone-releasing factor for six months. The pattern of administration--1 to 3 micrograms per kilogram of body weight, given subcutaneously over one minute every three hours by infusion pump--was chosen to simulate growth hormone secretion in normal children. During the first week of therapy, both children had evidence of the metabolic effects of increased growth hormone secretion--i.e., nitrogen retention, demonstrated by decreased nitrogen excretion (P less than 0.05), and increased urinary calcium excretion (P less than 0.01). Growth hormone secretion was increased after pulses of growth hormone-releasing factor during the entire six-month period, and growth was accelerated. One child grew at a rate of 7.1 cm per year, as compared with 4.6 cm per year before therapy; the other grew at a rate of 13.7 cm per year, as compared with 2.1 cm per year before therapy, and had increased serum levels of somatomedin C. Growth hormone--releasing factor can restore growth hormone secretion and its biologic effects, including an increase in nitrogen retention, an increase in serum somatomedin C, and acceleration of linear growth in children with growth hormone deficiency. It is premature to speculate how useful this agent will prove to be in the treatment of children with growth hormone deficiency.

Calcium↗
PubMed1985

Chlordiazepoxide attenuates response suppression induced by corticotropin-releasing factor in the conflict test.

The role of corticotropin-releasing factor (CRF) in mediating the stress response was studied using a behavioral test in which anxiety or conflict influence performance. Rats implanted with intraventricular cannulae were tested in a Geller-Seifter conflict test modified for incremental shock. CRF produced a dose-dependent attenuation of punished and nonpunished responding in the conflict test. Chlordiazepoxide increased punished, but not unpunished, responding and produced a dose-dependent reversal of CRF-induced response suppression. CRF had no effect on tail flick or hot-plate analgesia tests. The results support the hypothesis that CRF produces behavioral effects consistent with "anxiety" or an increased responsiveness to stress.

Analgesics↗