Biomedical subjects

J Rivier

Publications and source records attributed to J Rivier.

At least 235 records · Page 13Linked to original sources

PubMed1985

Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study.

Corticotropin-releasing factor (CRF) receptor-binding sites have been localized and quantified in the rat central nervous system (CNS) by autoradiography with an iodine-125-labeled analogue of ovine CRF substituted with norleucine and tyrosine at amino acid residues 21 and 32, respectively. High affinity and pharmacologically specific receptor-binding sites for CRF were found in discrete areas within the rat CNS. CRF receptors were highly concentrated in laminae 1 and 4 throughout the neocortex, the external plexiform layer of the olfactory bulb, the external layer of the median eminence, several cranial nerve nuclei in the brainstem including the facial, oculomotor, trochlear, vestibulocochlear, and trigeminal nuclei, the deep cerebellar nuclei, and the cerebellar cortex. Moderate concentrations of CRF receptors were present in the olfactory tubercle, caudate-putamen, claustrum, nucleus accumbens, nucleus of the diagonal band, basolateral nucleus of the amygdala, paraventricular nucleus of the hypothalamus, mammillary peduncle, inferior and superior olives, medullary reticular formation, inferior colliculus, and brainstem nuclei including tegmental, parabrachial, hypoglossal, pontine, cuneate, and gracilis nuclei, and in spinal cord. Lower densities of CRF binding were found in the bed nucleus of the stria terminalis, central and medial amygdaloid nuclei, and regions of the thalamus, hypothalamus, hippocampus, and brainstem. The distribution of CRF-binding sites generally correlates with the immunocytochemical distribution of CRF pathways and with the pharmacological sites of action of CRF. These data strongly support a physiological role for endogenous CRF in regulating and integrating functions in the CNS.

Animals↗

PubMed1985

Effect of a luteinizing hormone releasing hormone agonist given during combination chemotherapy on posttherapy fertility in male patients with lymphoma: preliminary observations.

Six men undergoing potentially curative chemotherapy for advanced lymphomas received daily injections (50 micrograms) of an analogue of luteinizing hormone releasing hormone (LH-RHa) in an attempt to protect posttreatment gonadal function. The median duration of combined LH-RHa-chemotherapy administration was 25 weeks (range, 14 to 31 weeks). During the simultaneous administration of LH-RHa and chemotherapy, plasma testosterone levels decreased to subnormal levels, while both follicle-stimulating hormone (FSH) and luteinizing hormone levels declined to the lower limit of normal. All subjects became oligospermic or azoospermic within eight weeks of starting treatment. Following discontinuation of chemotherapy and LH-RHa, both plasma testosterone and LH promptly increased and stabilized within the normal range. FSH progressively increased to a level well above the normal range. Only one patient has recovered evidence of active spermatogenesis at 84 weeks postcessation of chemotherapy. No untoward side effects due to LH-RHa were experienced. Although LH-RHa can be administered safely during combination chemotherapy, no improvement in posttreatment fertility has yet been demonstrated.

Adolescent↗

PubMed1984

Impaired growth hormone responses to growth hormone-releasing factor in obesity. A pituitary defect reversed with weight reduction.

To investigate whether the impaired growth hormone secretion associated with obesity is a result of a hypothalamic or a pituitary disorder and whether it is a cause or a consequence of obesity, we studied plasma growth hormone responses to growth hormone-releasing factor in morbidly obese patients before gastrointestinal surgical therapy, in formerly obese subjects who had lost considerable weight postoperatively, and in non-obese controls. Growth hormone secretion was also assessed in response to insulin-induced hypoglycemia (in seven patients preoperatively and four postoperatively). In patients studied preoperatively, growth hormone responses to growth hormone-releasing factor were markedly impaired (P less than 0.001 as compared with controls), whereas in patients studied postoperatively they were partially restored to normal (P less than 0.05 as compared with those studied preoperatively). Growth hormone responses to insulin-induced hypoglycemia were similarly diminished in obese patients studied before operation (P less than 0.02). The growth hormone response to growth hormone-releasing factor was inversely correlated with the percentage of ideal body weight (P less than 0.01) and directly correlated with the growth hormone response to insulin (P less than 0.01). The impaired responsiveness to growth hormone-releasing factor suggests that the diminished response to insulin hypoglycemia is mediated by an impaired pituitary response to endogenous growth hormone-releasing factor. The reversibility of the defect after weight reduction suggests that it is a consequence rather than a cause of obesity.

Adolescent↗

PubMed1984

Response of superfused goldfish pituitary fragments to mammalian and salmon gonadotropin-releasing hormones.

Salmon and mammalian gonadotropin-releasing hormones (sGnRH, mGnRH) were tested for their ability to stimulate in vitro gonadotropin (GtH) release from superfused goldfish pituitary fragments. A two minute exposure to either peptide was sufficient to stimulate a dose-dependent increase in GtH release which reached maximum levels in 15 minutes and returned to baseline within one hour. Both peptides were approximately equipotent in stimulating GtH release, as was a superactive analog of mGnRH. These results demonstrate that sGnRH is capable of directly stimulating GtH release from teleost pituitary tissue, and that structural differences between the three peptides tested do not result in significant differences in in vitro bioactivity.

Animals↗

PubMed1984

Effect of a potent gonadotropin releasing hormone antagonist on pulsatile testosterone and gonadotropin secretion in the male nonhuman primate.

A potent gonadotropin releasing hormone (GnRH) antagonist [Ac-delta 3Pro1, pFDPhe2, DTrp3,6]-GnRH was given to adult male monkeys to determine the acute effect on pulsatile testosterone and gonadotropin secretion. Blood was drawn at 30 min intervals over 54 h without anesthesia using a mobile vest and tether assembly to support an indwelling catheter. After a 6 h control period, 0.1, 1.0, 2.0, 4.0 mg GnRH antagonist/kg bw in 1 ml corn oil sc, was given to intact adult male monkeys. The highest dose of GnRH antagonist decreased circulating testosterone within 6 h and for approximately 24-36 h duration. These data demonstrate that this GnRH antagonist can reduce serum testosterone both acutely and for intervals greater than 24 h and that the effective dose in intact animals is several-fold (up to 20 times) greater than in castrate animals.

Animals↗

PubMed1984

Growth hormone-releasing factor stimulates pancreatic enzyme secretion.

Growth hormone-releasing factors (GRF's) from two human pancreatic tumors (hpGRF's) that caused acromegaly and from the rat hypothalamus ( rhGRF ) were recently isolated and characterized. Although these peptides are potent growth hormone secretagogues, they have not until now been described to have actions outside the pituitary. These GRF's were shown to stimulate digestive enzyme secretion from an exocrine pancreatic preparation in vitro, rhGRF being more than 100 times as potent as hpGRF. Adenosine 3',5'-monophosphate mediates this action of the GRF's.

Amylases↗

PubMed1984

Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study.

Corticotropin-releasing factor, a hypophyseo-tropic hormone that stimulates adrenocorticotropic hormone (ACTH) secretion, has recently been isolated, characterized, and synthesized in the sheep and rat. We report on a patient with metastatic carcinoma of the prostate presenting with anterior and posterior pituitary hormone deficiency together with ACTH-dependent Cushing's syndrome. At postmortem examination, large areas of the median eminence and pituitary stalk were replaced by tumor, but the corticotrophs were markedly hyperplastic. Immunostaining of tumor cells was positive for corticotropin-releasing factor and was negative for ACTH and a wide range of other hormones. Radioimmunoassay and bioassays showed that tumor extracts and further purified fractions were active in corticotropin-releasing factor, and the tumor material coeluted with corticotropin-releasing factor on high-pressure liquid chromatography. These studies demonstrate that ectopic secretion of corticotropin-releasing factor is a cause of Cushing's syndrome in human beings. The features of this syndrome include hypercortisolism, pituitary corticotroph hyperplasia, elevation of circulating ACTH levels, and failure to suppress the pituitary-adrenal axis with exogenous glucocorticoids.

ACTH Syndrome, Ectopic↗

PubMed1984

Corticotropin-releasing factor receptors in rat forebrain: autoradiographic identification.

Corticotropin-releasing factor (CRF) receptors were identified in rat forebrain by autoradiography with an iodine-125-labeled analog of ovine CRF substituted with norleucine and tyrosine at amino acid residues 21 and 32, respectively. High-affinity receptors for CRF were found in discrete areas of rat forebrain, including laminae I and IV of the neocortex, the external layer of the medium eminence, the lateral nucleus of the amygdala, and the striatum. These results are consistent with earlier findings on the immunohistochemical distribution of CRF and suggest that endogenous CRF has a physiological role in regulating activity of the central nervous system.

Amygdala↗

PubMed1984

A comparison of the behavioral effects of CRF, sauvagine and urotensin I.

The 41 amino acid peptide, corticotropin-releasing factor (CRF), isolated from ovine hypothalami has been shown to have sequence homologies with two other peptides, sauvagine (SA) and urotensin I (UT). All 3 of these peptides share some common biological properties in their ability to stimulate the release of ACTH from pituitary cells and cause vasodilation in defined vascular beds. CRF administered into the cerebral ventricles (i.c.v.) has previously been shown to have the additional property of being able to elicit behavior in the rat which has elements resembling the behavioral response to the stress of environmental novelty. The structurally related peptides SA and UT are shown here to have behavioral effects similar to those of CRF. When administered in doses of 0.5-2.0 micrograms i.c.v. 60 min prior to testing in a novel open-field environment, all 3 peptides cause a decrease in the amount of food consumed in the open field and a decrease in the mean amount eaten per approach to the food pedestal. They also decrease rearing and increase grooming. In addition, the 3 peptides caused the occurrence of a 'ballistic tail' phenomenon and a high frequency tremor in the forelimbs of several animals. The order of potency of the peptides in producing these effects was SA greater than or equal to CRF greater than UT. This order of potency differs from that previously reported for effects on vasodilation or on release of pituitary ACTH. The free acid C-terminus deaminated form of CRF (CRF-OH) failed to produce the profile of effects seen with the other peptides.

Amphibian Proteins↗

PubMed1984

Oxytocin potentiates the ACTH-releasing activity of CRF(41) but not vasopressin.

The effects of CRF(41), oxytocin (OT), and arginine vasopressin (AVP) on ACTH secretion were studied alone and in combination in an in vitro system of superfused rat hemipituitaries. CRF(41) (10(-9)M) and AVP (10(-8)M) alone produced a significant increase in ACTH secretion while OT (10(-8)M) alone had no effect. However the same concentration of OT markedly potentiated the ACTH response to CRF(41) while having no effect on the ACTH response to AVP. The data support a physiologic role for OT in the regulation of ACTH secretion.

Adrenocorticotropic Hormone↗

PubMed1984

Synthetic competitive antagonists of corticotropin-releasing factor: effect on ACTH secretion in the rat.

Polypeptide analogs of the known members of the corticotropin-releasing factor (CRF) family were synthesized and tested in vitro and in vivo for enhanced potency or competitive antagonism. Predictive methods and physicochemical measurements had suggested an internal secondary alpha-helical conformation spanning about 25 residues for at least three members of the CRF family. Maximization of alpha-helix-forming potential by amino acid substitutions from the native known sequences (rat/human and ovine CRF, sauvagine, and carp and sucker urotensin 1) led to the synthesis of an analog that was found to be more than twice as potent as either of the parent peptides in vitro. In contrast, certain amino-terminally shortened fragments, such as alpha-helical CRF or ovine CRF residues 8 to 41, 9 to 41, and 10 to 41, were found to be competitive inhibitors in vitro. Selected antagonists were examined and also found to be active in vivo.

Adrenocorticotropic Hormone↗

PubMed1984

Reversed-phase high-performance liquid chromatography: preparative purification of synthetic peptides.

Biologically active peptides synthesized by the solid phase methodology of Merrifield were purified by reversed-phase high-performance liquid chromatography using newly developed preparative radially compressed cartridges fitting Waters Assoc . Prep LC 500 liquid chromatograph. Cartridges were handpacked with Vydac C18, C4 or diphenyl derivatized silicas (pore size 300 A) of different particle sizes (10-20 micron). Large scale purification of gram amounts of gonadotropin releasing hormone analogs (agonist and antagonist) as well as amidated human pancreatic tumor growth hormone releasing factor (a 40-peptide) illustrate the resolutive power of this technique applied to the isolation of more than 300 synthetic peptides in our laboratory over the last two years. Difficult separations were achieved by changing supports (C18, C4, diphenyl) as well as mobile phase composition: (triethylammonium phosphate pH 2.25 or 6.5, 0.1% trifluoroacetic acid, ammonium acetate pH 6.5 and acetonitrile). Protected amino acids and peptides amenable to normal-phase chromatography on Vydac spherical underivatized silica were purified economically by the reversed-phase mode. It is understood that this general, convenient and versatile strategy may be applicable to the preparative scale isolation of any other class of compounds usually separated on reversed-phase high-performance liquid chromatography.

Chromatography, High Pressure Liquid↗

PubMed1984

Corticotropin-releasing factor receptors in rat pituitary gland: autoradiographic localization.

Corticotropin-releasing factor (CRF) receptors were localized in rat pituitary gland by an in vitro labeling light microscopic autoradiographic technique using the radioiodinate ovine CRF analog, [Nle21,125I-Tyr32]-CRF. Our data confirms the existence of CRF receptors in anterior pituitary and demonstrates the presence of specific CRF binding sites in the intermediate lobe of rat pituitary. The distribution of CRF binding sites closely resembles the clustering of corticotrophs in anterior lobe and the uniform distribution of opiomelanocortin-producing cells in the intermediate pituitary. These results suggest that endogenous CRF plays a physiological role in regulating secretion of pro-opiomelanocortin-derived peptides from both anterior and intermediate lobes of rat pituitary.

Animals↗

PubMed1984

Synthetic human pancreatic growth hormone releasing factor (GRF) stimulates growth hormone secretion in the domestic fowl (Gallus domesticus).

Synthetic human pancreatic Growth Hormone-Releasing Factor (hpGRF) elevated the plasma concentration of growth hormone (GH) in young and adult domestic fowl. This in vivo effect of hpGRF appeared to be largely similar for both the 32 amino-acid (hpGRF 1-32) or 40 amino-acid (hpGRF 1-40) polypeptide, although the effect of hpGRF 1-32 was more prolonged than that of hpGRF 1-40 in adult domestic fowl. The increase in plasma GH concentrations following hpGRF administration (10 micrograms/kg) was somewhat greater in young than adult chickens (the increase in plasma concentration of GH being 230 ng/ml at 1 week old, 282 ng/ml at 6 week old, 241 ng/ml at 10 weeks and 150 ng/ml in adults). In the adult domestic fowl hpGRF stimulated a greater increase in the plasma concentration of GH than did thyrotropin-releasing hormone (TRH). However in the young chicks TRH was more active. The in vitro release of GH from dispersed chicken pituitary cells was elevated by hpGRF (1-32) and hpGRF (1-40).

Animals↗

PubMed1984

Species differences in the sensitivity to the antitesticular effects of [Ac-D-NAL(2)1, 4FD-Phe2, D-Trp3,D-Arg6]-LHRH, a potent LHRH antagonist.

The antigonadal effects of [Ac-D-NAL(2)1, 4FD-Phe2, D-TRP3, D-Arg6]-LHRH (LHRH-A), a potent antagonist of LHRH, were investigated in rats and rabbits. Rats and rabbits were given LHRH-A (1250 micrograms/kg) daily for 15 days. Some animals were killed on day 16 (24 h after the last treatment) while others were mated. In the male rats serum LH and testosterone levels as well as the weights of sexual organs were significantly reduced. Mating behavior and fertility that were suppressed by the end of treatment returned to normal by 7 weeks after last treatment. In contrast to rats, the testicular function and fertility of rabbits appeared unaffected by LHRH-A treatment. The difference in the response between rats and rabbits led us to compare the response of rats and mice. Male rats and mice were given LHRH-A (1450 micrograms/kg) daily for 5 days and killed on day 6. In rats LHRH-A caused a 93% decrease in serum T and 88% decrease in in vitro testicular T production. In mice, however, the Leydig cell function remained unaffected when examined 24 h after the last dose of LHRH-A. To explain the differences between the effects of LHRH-A on rats, rabbits and mice, the acute effect of this peptide on serum T levels was investigated in these species. Administration of a single dose of LHRH-A (1250 micrograms/kg) led to a rapid decrease in serum T that was sustained for 24 h in rats. In rabbits and mice, however, the same dose of LHRH-A caused only a transient decrease in serum T. Male rhesus monkeys treated with LHRH-A (1000 micrograms/kg) also showed a transient decrease in serum T concentrations. It is concluded that there are considerable species differences in the sensitivity to the antigonadal effects of LHRH-A.

Animals↗

PubMed1984

Synthesis of potent heptapeptide analogues of cholecystokinin.

Nine new analogues of acetyl-CCK-heptapeptide (Ac-Tyr(SO3H)2-Met3-Gly4-Trp5-Met6-Asp7-Phe8-NH2 ) were synthesized by solid-phase methodology. In a first series, the Asp7 residue was replaced by hydroxy amino acid sulfate esters. In another series, Gly4 was substituted by D-Ala, while Trp5 and Met6 were replaced by their D enantiomer. The introduction of the sulfate ester was performed with a new, mild, crystalline, and stable reagent, pyridinium acetyl sulfate. Each analogue that contained Tyr(SO3H)2 and a hydroxy amino acid sulfate ester [Ser(SO3H), Thr(SO3H), or Hyp(SO3H)] in position 7 proved to be more potent (1.9, 1.7, and 3.0 times, respectively) than CCK-8 in vitro (isolated gallbladder strips). While devoid of gastrin-like activity in vivo, these analogues had potent anticonvulsive activity. The analogues containing a D-amino acid residue were less potent than the parent compound in vitro. The D-Ala4 replacement, however, yielded a compound that was 40% as potent as CCK-8 in the in vitro test but showed prolonged duration of action on sphincter Oddi. While the 7-substituted Ac-CCK heptapeptides are among the most potent CCK analogues reported so far, the D-Ala4 replacement resulted, for the first time, in prolonged activity in vivo.

Amino Acid Sequence↗

PubMed1984

Differential suppression of FSH and LH secretion by follicular fluid in the presence or absence of GnRH.

The differential role of porcine follicular fluid (pFF) in regulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release in vivo in situations of different gonadotropin releasing hormone (GnRH) backgrounds was studied. In experiment 1, 2-week ovariectomized rats injected intravenously with 4, 16 or 64 mg of protein from pFF, showed a dose-dependent suppression of FSH over time, with a maximal suppression to 40% of control values by 10 h. LH levels were slightly, but significantly, elevated by the two lower doses, but not by the highest dose of pFF. In experiment 2, 64 mg pFF was superimposed (i.v. injection) in ovariectomized rats injected subcutaneously with a high dose of GnRH antagonist (500 micrograms) 24 h earlier. The pFF suppressed FSH 35% below the level achieved in the absence of GnRH stimulation, with no effect on LH. In experiment 3, the rise in FSH secretion in acutely ovariectomized rats was shown to be inhibited by 8 or 32 mg pFF administered intravenously 3.5 h after surgery. Injection of GnRH (250 or 1,000 ng) 4.5 h after pFF could not overcome the inhibitory action of pFF on FSH, although non-pFF-treated controls responded in a dose-dependent fashion to GnRH stimulation. The expected LH response to GnRH was not affected by pFF, except in the group receiving 1,000 ng GnRH and 8 mg pFF. In these rats, LH was enhanced in one trial, but suppressed in a replicate trial, illustrating the inconsistent effects of pFF on LH under conditions of high GnRH stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Effects of alpha-flupenthixol and naloxone on CRF-induced locomotor activation.

Corticotropin-releasing factor injected intracerebroventricularly in a dose of 1 microgram produced a prolonged locomotor activation (3 h) in rats previously habituated to the test cage environment. This activation was reversed by alpha-flupenthixol (intraperitoneally), a dopamine receptor antagonist, only at cataleptic doses and not at all by naloxone (subcutaneously) in doses of 0.02-5.0 mg/kg. The effective dose 50% (ED50) for the alpha-flupenthixol reversal of locomotor activity induced by corticotropin-releasing factor was 0.13 mg/kg; similar to the 0.14 mg/kg ED50 needed to reverse the locomotor activation produced by caffeine (10 mg/kg s.c.). The ED50 necessary to reverse amphetamine (0.75 mg/kg s.c.) locomotion with this drug was 0.07 mg/kg. The results suggest that the corticotropin-releasing factor acts independently of direct activation of the dopamine or opioid peptide systems.

Animals↗