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J Rivier

Publications and source records attributed to J Rivier.

At least 163 records · Page 9Linked to original sources
PubMed1987

Neuronal calcium channel inhibitors. Synthesis of omega-conotoxin GVIA and effects on 45Ca uptake by synaptosomes.

We previously described a 27-amino acid peptide neurotoxin from the venom of Conus geographus, omega-conotoxin GVIA, which inhibits neuronal voltage-activated calcium channels. In this paper we describe the total synthesis of omega-conotoxin GVIA and demonstrate that it efficiently blocks voltage-activated uptake of 45Ca by standard synaptosomal preparations from chick brain. Dihydropyridines do not block 45Ca uptake under these conditions. Thus, the omega-conotoxin-sensitive, but dihydropyridine-insensitive uptake of 45Ca2+ by chick brain synaptosomes serves as a functional assay for a Ca channel target of omega-conotoxin. The use of synthetic GVIA should rapidly accelerate our understanding of the molecular biology of Ca2+ channels and their role in neuronal function.

Animals↗
PubMed1987

Exogenous GnRH overrides the endogenous annual reproductive rhythm in green iguanas, Iguana iguana.

Female green iguanas, Iguana iguana, were caught in Belize, Central America (17 degrees N), in December, at the onset of seasonal gonadal activity. The animals were immediately transferred to San Diego (32 degrees N). Ovarian follicular development continued, with peak plasma hormone levels measured in January and February; 200 pg/ml for progesterone (P) and 800 pg/ml for total estrogens (Et = estradiol [E2] + estrone [E1]). E2 was the predominant estrogen throughout the cycle. Follicular atrophy was indicated in April with circulating progesterone and estrogen levels decreasing to baseline (refractory phase) levels (P = 20 pg/ml; Et = 50 pg/ml). Approximately midway through the refractory phase of their annual reproductive cycle (late May), either the D-Arg6 analog of Chicken II or mammalian GnRH was administered via intraperitoneal osmotic pumps for 14 days to nine females. The analog of chicken II induced a fivefold increase in total circulating estrogens within 3-4 days after implantation. Both continuous and pulsatile delivery of the chicken II analog produced a similar pattern of steroidogenic response. A radical sham control animal showed no increase in steroidogenesis. Mammalian GnRH produced a pattern of similar duration, although the magnitude of the steroidogenic response was only half that produced by the chicken II analog. Estrogen titers approached baseline levels in all treatment groups two days after treatment ceased. Progesterone levels increased in all treatment groups during the delivery of exogenous GnRH, although the increases were not consistent. Untreated male cagemates housed with treated females exhibited increased territoriality, courtship behavior, and mating, which began on day 4 or 5 of the treatment period. The control female was not courted by its male cagemate.

Animals↗
PubMed1987

Growth hormone and prolactin responses to bolus and sustained infusions of GRH-1-40-OH in man.

To determine whether GRH stimulates PRL secretion we studied the effects of iv bolus injections and prolonged infusions of GRH 1-40-OH on PRL and GH serum levels in normal volunteers. Eight patients with acromegaly, two of whom had elevated basal levels of PRL, were also tested with single bolus injections. Six normal subjects given 3.3 micrograms/kg bolus injections of GRH showed a mean increment of GH of 22.0 +/- 1.7 ng/ml (mean +/- SE). A small rise in PRL was noted in 5 of the 6 subjects (mean peak level of 6.4 +/- 1.9 ng/ml vs basal level of 3.3 +/- 0.4 ng/ml, p less than 0.05). During the continuous intusion of GRH (10 ng/kg/min), GH levels rose gradually from a mean baseline of 1.1 +/- 0.1 ng/ml to a mean peak of 30.0 +/- 7.2 ng/ml at about 2 h and then slowly declined to a nadir of 4.2 +/- 0.4 ng/ml at 330 min. PRL levels did not rise significantly during the infusion. To determine whether the decline in GH levels in the face of continued infusion was due to loss of GH responsiveness, a 3.3 micrograms/kg bolus of GRH was given during the nadir at 330 min; this GH increment was significantly less than that obtained by the GRH bolus injection without the infusion (12.9 +/- 3.5 ng/ml vs 22.0 +/- 1.7 ng/ml, p less than 0.05). The PRL response to the GRH bolus was the same during the infusion of GRH as before. In each of 8 acromegalic patients (including two who had initially elevated basal PRL levels) GRH led to an increase in both GH and PRL levels. PRL and GH levels spontaneously fluctuated in parallel in 4 acromegalic cases studied with repeated samples over 6 h during placebo administration. These experiments show that GRH has significant, though weak, PRF effect in normals and that it is more potent PRF in acromegalic patients. Furthermore, the effects on GH and PRL of a sustained infusion of GRH for 5 1/2 h are both qualitatively and quantitatively different. These results suggest that the GRH effect is exerted either on different pituitary receptors for GH and PRL regulation, or that the releasable pools of the two hormones have different sizes and/or turnover times.

Acromegaly↗
PubMed1987

Corticotropin-releasing factor antagonist blocks stress-induced fighting in rats.

Corticotropin-releasing factor (CRF) has been shown to have potent central nervous system-activating effects when administered intracerebroventricularly (i.c.v.). In the present experiment, this activating effect was exaggerated by use of a stress-motivated behavioral paradigm. Low doses of CRF (0.01 and 0.1 micrograms/rat) administered i.c.v. facilitated stress-induced fighting. More importantly, alpha-helical CRF-(9-41), a CRF antagonist, blocked stress-induced fighting produced by higher levels of stress. These results suggest that CRF in the central nervous system may have a role in mediating behavioral responses to stress.

Aggression↗
PubMed1987

Inhibition of CRF- and urotensin I-stimulated ACTH release from goldfish pituitary cell columns by the CRF analogue alpha-helical CRF-(9-41).

alpha-Helical CRF-(9-41) is an analogue of corticotropin-releasing factor (CRF) that antagonizes CRF-stimulated ACTH release in rats. In the present study, alpha-helical CRF-(9-41) was tested to determine whether it would antagonize the ACTH-releasing activity of CRF or urotensin I (UI) observed with superfused, dispersed goldfish anterior pituitary cells. At a concentration of 4 microM, alpha-helical CRF-(9-41) completely blocked the ACTH-releasing activity of 100 nM CRF or 100 nM UI. The inhibitor by itself showed little intrinsic ACTH-releasing activity. This investigation reveals similarities in the CRF-antagonism of alpha-helical CRF-(9-41) in the teleost and mammalian pituitary in vitro. It also provides are similar and suggests that alpha-helical CRF-(9-41) may be useful as a tool to investigate the effects of CRF-like and UI-like peptides in teleost fishes.

Adrenocorticotropic Hormone↗
PubMed1987

Pituitary responses to synthetic corticotropin-releasing hormone: absence of modulatory effects by estrogen and progestin.

To determine if the activity of the adrenocorticotropic hormonal-adrenal axis is modulated in part by estrogens and progestins, we have compared pituitary and adrenal responses to corticotrophin-releasing hormone in normal women during the early follicular, late follicular, and midluteal phases of the menstrual cycle and in four women undergoing ovariectomy who received estradiol (E2) implants alone or in combination with oral medroxyprogesterone acetate administration. Basal adrenocorticotropic hormone and cortisol levels (9:00 AM) and responses to ovine CRH were unaffected by variations in E2 and progesterone during each phase of the menstrual cycle. In women undergoing ovariectomy who received E2 replacement therapy, basal concentrations of adrenocorticotropic hormone and cortisol (9:00 AM) and the responses to human corticotrophin-releasing hormone were not altered by administration of E2 alone or E2 with medroxyprogesterone acetate. Under these experimental conditions, our findings suggest that physiologic changes in E2 and progesterone levels during the menstrual cycle and replacement doses of estrogen and progestin commonly used clinically do not significantly influence basal adrenocorticotropic hormone and cortisol levels or responsiveness to corticotrophin-releasing hormone.

Adrenocorticotropic Hormone↗
PubMed1987

Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis.

Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an alpha beta heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the alpha beta heterodimer, the beta beta homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrating the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, we have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the alpha beta heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the beta beta homodimer suppresses androgen production. Furthermore, similar modulatory actions of inhibin-related proteins were found in cultured ovarian theca-interstitial cells and theca explants treated with LH. In contrast, treatment with the inhibin-related proteins alone did not affect gonadal steroidogenesis. Our data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops.

Androgens↗
PubMed1987

Synthesis, resolution and characterization of ring substituted phenylalanines and tryptophans.

Experimental protocols have been developed for the synthesis and resolution of numerous ring substituted phenylalanines and tryptophans in half mole quantities. Physical constants on these amino acids are given and their behavior on ion exchange supports (amino acid analyzer and post column ortho-phthalaldehyde derivatization) as well as that of some selected N-methylated amino acids is described. Those amino acids were then derivatized (N alpha-protection with the t-butyloxycarbonyl group) for solid phase peptide synthesis.

Indicators and Reagents↗
PubMed1987

Contraction of major artery segments of rat by fish neuropeptide urotensin II.

Urotensin II (U II) caused marked concentration-dependent contractions of helical strips from several major arteries of the rat. The thoracic aorta was most sensitive; the apparent concentration of U II producing half-maximal contraction was 6.8 X 10(-10) M. Papaverine, dibutyryl cyclic AMP, forskolin, and nitroprusside antagonized the contractile responses to U II at the apparent concentrations producing 50% inhibition (IC50) of 7.6 X 10(-6), 2.1 X 10(-4), 2.5 X 10(-6), and 1.5 X 10(-8) M, respectively. Verapamil, a calcium channel-blocking agent, partially inhibited the contractile response to U II at IC50 = 6.5 X 10(-6) M. Maximal relaxation, i.e., a complete inhibition, could not be obtained even at a concentration of 3 X 10(-5) M verapamil. Cyproheptadine reduced the U II-induced contraction at higher concentrations. Phentolamine (10(-5) M), propranolol (10(-5) M), atropine (10(-4) M), tetrodotoxin (10(-6) M), burimamide (10(-5) M), and indomethacin (10(-5) M) did not change the U II-induced contraction. At higher concentration, U II (10(-8) M) induced a small contraction of aortic strips in Ca2+-free Krebs Henseleit solution similar to that of norepinephrine, but the U II-induced contraction was not inhibited by phentolamine or propranolol. The action of U II did not require the presence of endothelial cells. It is concluded that U II acts on vascular smooth muscle and induces the contraction partly through intracellular Ca2+ mobilization but mainly by stimulating the influx of extracellular Ca2+ via potential dependent and potential independent calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Studies of the inhibin family of hormones: a review.

While the concept of a nonsteroidal entity of gonadal origin, which specifically regulates FSH secretion, was proposed over 50 years ago, problems linked to the assay, isolation and characterization of this protein have only recently been solved. The structure of inhibin from follicular fluid origin has been established as a heterodimer consisting of two subunits (alpha and beta) linked by disulfide bridges. The development of antisera specifically directed against the N-terminus part of the alpha-chain of inhibin has allowed the measurement of plasma levels of inhibin, as well as the evaluation of the biological effect of removal of endogenous inhibin. These studies have demonstrated age-related changes in the circulating levels of inhibin in the female rat and support the hypothesis that inhibin represents an important modulator of FSH secretion in this species.

Amino Acid Sequence↗
PubMed1987

A new cytotoxin specific for the target cells of corticotropin-releasing factor.

To develop a cytotoxic agent selective for pituitary corticotropes, an analog of CRF, [Nle21,38,Arg36]rat (r) CRF, was conjugated to the plant toxin gelonin using glutaraldehyde as a cross-linking agent. In a two-step synthesis, glutaraldehyde was first coupled to the amino-terminal of the CRF analog. This was then reacted with gelonin to form a product, which contained 20 mol [Nle21,38,Arg36]rCRF/mol gelonin, as indicated by amino acid analysis. Efficacy and specificity of the gelonin-[Nle21,38,Arg36]rCRF conjugate were assessed in cultured rat anterior pituitary cells 3 days after a 12-h exposure to the cytotoxic conjugate, CRF, or gelonin. While pretreatment with the cytotoxic gelonin-[Nle21,38,Arg36]rCRF conjugate decreased cellular ACTH content by 74%, pretreatment with appropriate concentrations of CRF had no significant effect on cellular ACTH content. The ACTH secretory response to 2.5 nM CRF was completely eliminated by pretreatment with the gelonin-[Nle21,38,Arg36]rCRF conjugate; in contrast, pretreatment with identical doses of CRF had minimal effect. Neither pretreatment with CRF nor pretreatment with the gelonin-[Nle21,38,Arg36] rCRF conjugate had any effect on the content of LH or the LH secretory response to GnRH. These results indicate the efficacy and specificity of the conjugate of [Nle21,38,Arg36]rCRF to gelonin in eliminating CRF target cells.

Adrenocorticotropic Hormone↗
PubMed1987

Gonadotropins and testosterone escape from suppression during prolonged luteinizing hormone-releasing hormone antagonist administration in normal men.

The ability of prolonged administration 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 normal men. The 4F-antagonist was given either as a continuous 13.3 micrograms/kg X h sc infusion for 72 h or as intermittent sc injections of 100 micrograms/kg every 6 h for 7 days. Serum FSH, LH, and testosterone levels decreased in the period immediately following initiation of 4F-antagonist administration. However, an escape toward baseline levels for each of these hormones occurred during prolonged antagonist administration. When men receiving the continuous infusion were challenged with iv bolus doses of 50 micrograms LHRH, the response of LH after the first 12 h of 4F-antagonist administration was similar to that before its administration. This gonadotropin and testosterone escape suggests that, at the doses used, the inhibitory action of the antagonist on gonadotropin secretion is progressively lost. The initial decrease in androgen levels could serve to augment endogenous LHRH release, which, in turn, overcomes the pituitary effects of the antagonist, or to augment endogenous LH secretion directly. These results demonstrate that the pituitary can escape from the suppressive effects of prolonged LHRH antagonist administration and partially restore serum gonadotropin and testosterone levels to normal in man.

Adult↗
PubMed1987

Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone-stimulated GH secretion in normal man.

The role of the dopaminergic system and its interaction with GH-releasing hormone (GHRH) in the regulation of GH secretion was investigated in normal men in two complementary studies. The men were given continuous iv infusions of 0.15 M saline (5 h), dopamine (4 micrograms/kg X min; 1 h), GHRH (2 ng/kg X min; 2 h), and GHRH (2 ng/kg X min; 2 h) plus dopamine (4 micrograms/kg X min; 1 h) on four separate occasions, and serum GH responses were measured. In a second study, on separate days, placebo or bromocriptine (2.5 mg/dose) was administered, and GH and PRL responses to a single iv GHRH dose were measured. A continuous infusion of dopamine and GHRH on separate days stimulated GH secretion in all subjects. The mean integrated GH secretion was 13.2 +/- 3.1 (+/- SEM) ng/mL X h during the dopamine infusion and 14.7 +/- 4.6 during GHRH, compared with 1.7 +/- 0.4 during the saline infusion. The combination of GHRH and dopamine resulted in the greatest stimulation of GH secretion (29.8 +/- 5.7 ng/ml X h; P less than 0.05 vs. 3 other study days). The oral dopamine agonist bromocriptine also augmented GHRH-stimulated GH secretion. Integrated GH secretion after a single iv injection of GHRH following two doses of bromocriptine was 160 +/- 29.5 ng/ml X h compared with 81.3 +/- 22.2 after placebo (P = 0.04). We suggest that these findings are compatible with the hypothesis that dopamine inhibits hypothalamic somatostatin secretion, which then allows for a greater stimulatory effect of GHRH.

Adult↗
PubMed1987

Transmitter release from presynaptic terminals of electric organ: inhibition by the calcium channel antagonist omega Conus toxin.

Cholinergic synaptosomes from electroplax of the ray Ommata discopyge release both ATP and ACh when depolarized with high K+ concentration in the presence of Ca2+. Others have shown that the ATP and ACh are released in the molar ratio found in isolated synaptic vesicles. Thus, it is assumed that the release of ATP reflects exocytosis of synaptic vesicles, and that transmitter release can be indirectly monitored by assaying ATP release. We present further evidence for this assumption and examine the effects of presynaptic neurotoxins on this ATP release. As expected for transmitter release, we find that depolarization-evoked ATP release is supported by Sr2+ and Ba2+ and is inhibited by the Ca channel antagonists Co2+ and Mn2+. Likewise, the presynaptic toxins omega-CmTX and omega-CgTX, omega peptides from the venom of the marine snails Conus magus and Conus geographus, respectively, inhibit 80% of the depolarization-evoked ATP release. Half-maximal inhibition of ATP release occurs with approximately 0.5 microM of either toxin. The toxins' effects are reversible, and when toxin is washed away, the time dependence of recovery of release is approximately first order and half complete within 40 min with omega-CmTX and 15 min with omega-CgTX. The Ca2+ ionophore A23187 induces Ca2+-dependent ATP release from resting synaptosomes. As would be expected of a Ca channel antagonist, omega-CmTX does not affect this ionophore-induced release. Leptinotarsin-d (LPTd), a putative Ca channel agonist from the Colorado potato beetle, evokes Ca2+-dependent ATP release from resting synaptosomes. omega-CmTX does not block LPTd-evoked release of ATP, which suggests that omega-CmTX and LPTd act at different sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Ovulation induction in anestrous bitches by pulsatile administration of gonadotropin-releasing hormone.

Preliminary studies in anestrous Beagle bitches demonstrated that a single injection of gonadotropin-releasing hormone (150 micrograms) produced a rapid, physiological rise in serum estradiol lasting 1-3 days while progesterone remained below 1 ng/ml, whereas serial injections of FSH rapidly produced greater elevations in estradiol and a rapid rise in progesterone over 2 ng/ml. Consequently, attempts to induce fertile ovulation by means of pulsatile intravenous administration of GnRH (1 pulse/1.5 hours for 6-12 days; 0.04-0.43 micrograms/kg body weight/pulse) were conducted in eight anestrous bitches. Willingness to mate, serum progesterone levels and results of mating were monitored. In six of the eight bitches, vulval and vaginal signs of proestrus occurred by Day 2-4 after initiation of treatment (Day 0); but, two bitches showed negligible responses. In five of the six bitches in which proestrus was induced, behavioral (n = 4) and vaginal (n = 5) correlates of early estrus occurred by Day 5-7 of treatment and breedings occurred over a period of 4-12 days. Following onset of estrus, four of the five bitches had increases in serum progesterone levels between Days 14 and 18 after initiation of treatment (and 4-11 days after cessation of treatment); three of them became pregnant and whelped normal litters (ranging from 9 to 11 pups). The fifth bitch did not have elevated progesterone during the induced estrus, and upon return to estrus one month later was successfully bred and whelped a normal litter of 10 pups.(ABSTRACT TRUNCATED AT 250 WORDS)

Anestrus↗