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Biomedical subjects

W Vale

Publications and source records attributed to W Vale.

At least 361 records · Page 20Linked to original sources
PubMed1983

Influence of the frequency of ovine corticotropin-releasing factor administration on adrenocorticotropin and corticosterone secretion in the rat.

We have examined the pattern of ACTH secretion in rats receiving two or more injections of synthetic ovine corticotropin-releasing factor (CRF). A first exposure of cannulated intact rats to CRF caused a blunting of the ACTH response when CRF was again injected 0.5-6 h later. Since plasma corticosterone levels stayed elevated for only 2 h after the first injection of CRF, the diminished pituitary responsiveness persisted at a time when plasma corticosterone levels had returned to control values. When cannulated adrenalectomized animals were subjected to a similar treatment, the blunting of the ACTH release due to the second injection of CRF, though present, was of significantly shorter duration. Duplication of the corticosterone levels that follow one CRF injection by exogenous administration of the steroid inhibited the subsequent ACTH response to CRF for a maximum of 2 h. Finally, CRF infused into intact rats for 14 days consistently caused elevation of both ACTH and corticosterone secretion. We conclude that CRF administered in a repeated or continuous manner to intact rats, while causing some pituitary desensitization, still elicits a significant degree of ACTH secretion despite the presence of elevated corticosterone release. This observation as well as the fact that CRF-injected adrenalectomized animals exhibit some blunting of their ACTH responses suggest that steroid feedback, while participating in the diminished ability of CRF to repeatedly stimulate ACTH release, does not represent the sole modulator of pituitary responsiveness.

Adrenalectomy↗
PubMed1983

Effect of GnRH antagonist, [Ac-delta 3Pro1, pFDPhe2, DTrp3,6] GnRH, on pulsatile gonadotrop in secretion in the castrate male primate.

Three different doses of a potent antagonist to GnRH, [Ac-delta 3Pro1, pFDPhe2, DTrp3,6], GnRH were compared in adult male monkeys to determine the acute effect on pulsatile gonadotropin secretion. In accomplishing these studies, blood was drawn at 15 min intervals over 24-30 h without anesthesia using a mobile vest and tether assembly to support an indwelling cannula. After a 3 to 6 h control period, 2.0, 0.2 or 0.02 mg GnRH antagonist/kg bw in 1 ml corn oil sc, was given to castrate adult monkeys. The highest dose decreased circulating LH (by radioimmunoassay and bioassay) and FSH whereas the intermediate dose decreased LH only. The higher dose produced both a more prolonged and greater reduction in circulating gonadotropins. These data demonstrate that this GnRH antagonist can reduce serum gonadotropins both acutely and for intervals greater than 24 h.

Animals↗
PubMed1983

Induction of hot flashes in premenopausal women treated with a long-acting GnRH agonist.

To examine the relationship between the occurrence of menopausal hot flashes and the pulsatile release of LH, we have investigated the serum hormone levels and the occurrence of hot flashes by objective recordings in five women with endometriosis given daily injections of a long-acting GnRH agonist (GnRH-a) for 28 days. Results were compared to the findings made in 25 young women 6-8 weeks after bilateral oophorectomy. Serum levels of estrone and estradiol were similar in the subjects given GnRH-a and the women who underwent a surgical castration. In comparison with values before GnRH-a administration, the mean FSH level was lower whereas the mean LH concentration was significantly higher (P less than 0.01) on the last day of therapy. The coefficients of variations of both gonadotropins measured during 4-h sampling periods at 20-min intervals before and at the end of GnRH-a administration were significantly reduced (P less than 0.01) with therapy. During the total of 20 h of frequent sampling in the 5 subjects, 15 pulses (20% rise from nadir) of LH and 12 pulses of FSH were detected before GnRH-a, whereas only 2 and 8 pulses, respectively, were observed on day 28 of treatment. Hot flashes were observed in both groups of patients. The proportion of women experiencing hot flashes, the rate of occurrence/h and the characteristics of the physiological changes were similar in the 2 groups of women. These data indicate that hot flashes can occur in the absence of prominent LH pulses, suggesting the pulsatile release of this hormone is merely associated with the hot flash rather than being etiological.

Castration↗
PubMed1983

The dynamics of gonadotropin inhibition in women induced by an antagonistic analog of gonadotropin-releasing hormone.

The inhibitory effect of a GnRH antagonist, [AC-delta 2-Pro1, p-F-D-Phe 2, D-Trp3,6]GnRH (4F-Antag), on gonadotropin secretion was determined by four sequential studies in five hypergonadotropic postmenopausal women. In response to an iv (80 micrograms/kg) dose of 4F-Antag, a progressive decline in basal gonadotropin levels with a marked attenuation of pulse amplitude was observed. Mean serum LH and FSH concentrations were maximally reduced by 46% and 26%, respectively, 4 and 9 h after the iv bolus. A similar pattern of suppression was found with sc and im routes of administration, with maximal effects occurring at 6.0 h for LH and 8.5 h for FSH. This was followed by the resumption of pulsatile release and a return to basal levels between 10 and 24 h for both gonadotropins. When 4F-Antag was superimposed during an iv infusion of GnRH (0.2 micrograms/min) at the time (2 h) of maximal LH release (231% above basal values), a 47.1% decrease in GnRH-stimulated LH levels and a 15.8% decrease in FSH values occurred at 1.75 h. A positive linear correlation was found between basal and exogenous GnRH-stimulated LH and FSH concentrations and the inhibitory effect of the 4F-antagonist. The dynamics of the antagonistic effect demonstrated by this analog provide an important reference for future investigations of endogenous GnRH control of gonadotropin secretion as well as for exploring contraceptive potential.

Estradiol↗
PubMed1983

Effect of synthetic ovine corticotropin-releasing factor: prolonged duration of action and biphasic response of plasma adrenocorticotropin and cortisol.

The duration of the response to synthetic ovine corticotropin-releasing factor (CRF) was studied in 13 healthy male volunteer subjects. Placebo or CRF (0.3, 3, or 30 micrograms/kg BW) was administered as an iv bolus or, in the case of the largest dose, a 30-sec infusion in single blind fashion in the late afternoon. Basal plasma immunoreactive ACTH (IR-ACTH) and IR-cortisol were 10.8 +/- 7.7 pg/ml and 5.0 +/- 1.8 micrograms/dl (mean +/- SD), respectively. IR-ACTH rose rapidly after CRF, reached an initial peak at 15 min, fell rapidly until 1.5 h after CRF, and then either fell more slowly (after the lowest dose) or rose to a second major peak at 2-3 h before falling back to baseline. After 0.3, 3, and 30 micrograms/kg CRF, IR-ACTH remained elevated for 4, 7, and 8 h, respectively. The effect on plasma IR-cortisol was similar, but more prolonged. The magnitude of both peaks of IR-ACTH, the duration of the response, and the area under the curve all appeared dose dependent. The same was true for IR-cortisol, except that the first peak height was similar after all three doses. The duration of CRF's action is probably due to its long circulating half-life. The biphasic response curve may reflect initial secretion of a readily releasable pool of ACTH, followed by later secretion of a second pool of newly synthesized and/or matured peptide. The next morning's normal circadian rise in both IR-ACTH and IR-cortisol was delayed and diminished after 3 micrograms/kg CRF; there was no increase in IR-ACTH after 30 micrograms/kg CRF, and the IR-cortisol level was diminished. Inhibition of the normal circadian rise may reflect inhibition of ACTH secretion by the sustained high plasma cortisol levels.

Adrenocorticotropic Hormone↗
PubMed1983

Intranasal administration of human pancreatic tumor GH-releasing factor-40 stimulates GH release in normal men.

Human pancreatic tumor GH releasing factor-40 (hpGRF-40) selectively stimulates GH secretion in normal men and in some adult patients with GH deficiency. As the latter finding suggests that some children with GH deficiency may benefit from therapy with hpGRF-40 or an analogue, we investigated the effect of hpGRF-40 administered intranasally on GH release. Six normal men were given hpGRF-40 (30 ug/kg; test day) or an equivalent volume of vehicle alone (control day) at 0900 h. Immunoreactive GH was measured in serum obtained at intervals between 0800-1200 h. Mean (+/- SEM) integrated serum levels of GH (ng/ml/h) prior to and following administration of vehicle were not different (1.27 +/- 0.57 vs 0.87 +/- 0.28; p = 0.54). However, following hpGRF-40 administration, GH levels increased significantly (0.53 +/- 0.03 vs 2.88 +/- 0.75; p = 0.022). Peak levels of serum GH were detected within 30 min following hpGRF-40. Except for mild burning of the nasal mucosa reported by one subject, no side effects were noted. We conclude that, if hpGRF-40 or an analogue is shown to be useful in the treatment of some children with GH deficiency, the intranasal route of administration may be utilized and will be more acceptable for chronic therapy than intravenous, intramuscular, or subcutaneous injection.

Administration, Intranasal↗
PubMed1983

Augmentation of ACTH-releasing activity of synthetic corticotropin releasing factor (CRF) by vasopressin in women.

In order to study the interaction between vasopressin (VP) and hypothalamic corticotropin releasing factor (CRF) on the release of ACTH, VP and CRF were administered separately and in combination to normal cycling women. The combined hormones raised plasma ACTH levels higher than the sum of the separate responses and 5 times more than CRF alone. This study reveals for the first time synergism between VP and CRF in their ACTH releasing effects in humans.

Adrenocorticotropic Hormone↗
PubMed1983

Plasma distribution, disappearance half-time, metabolic clearance rate, and degradation of synthetic ovine corticotropin-releasing factor in man.

The plasma distribution, disappearance half-time, MCR, and degradation of corticotropin-releasing factor (CRF) were studied in normal men who received a pulse injection of synthetic ovine CRF (oCRF). Graded iv doses of oCRF produced a linear increase in plasma immunoreactive oCRF (IR-oCRF). The calculated total plasma content of IR-oCRF 2 min after injection represented 41.7 +/- 2.5% (mean +/- SE) of the injected dose. The disappearance of IR-oCRF from plasma was characterized by a biexponential decay curve, with initial distribution and subsequent metabolic t 1/2 values of 6.1 +/- 0.5 and 55 +/- 3.8 min (mean +/- SE), respectively. In two subjects who were studied for 14-16 h after being given the largest dose of oCRF, there was third phase of disappearance, with a t 1/2 of 198 +/- 54 min. The MCR of IR-oCRF was 2.4 +/- 0.2 ml/min . kg (146 +/- 12 l/m2 . day) and was relatively constant over a 3000-fold dose range. The volume of distribution of IR-oCRF was 6.2 +/- 0.6 liters. The plasma IR-oCRF component, examined at increasing intervals after injection, was indistinguishable from the injected oCRF in that its apparent molecular size had not been altered, nor had its biological activity been attenuated. The continued circulation of apparently intact, biologically active oCRF for at least 90 min after injection was associated with sustained release of ACTH into the plasma. Thus, the clearance of oCRF from circulating human plasma is prolonged and appears to be responsible for the sustained release of ACTH that occurs after injection of this hormone-releasing factor.

Adrenocorticotropic Hormone↗
PubMed1983

Hormonal effects of danazol and medical oophorectomy in endometriosis.

The hormonal effects of danazol and of a long-acting gonadotropin-releasing hormone analogue (GnRH-a) were studied in women with endometriosis and those with oophorectomy. During danazol treatment, total serum concentrations of estrone and estradiol, and free, dialyzable estradiol were reduced to the low follicular phase range for premenopausal women. Corresponding estrogen levels were suppressed to a significantly greater degree (P less than .02) at the end of GnRH-a administration, to concentrations which were twofold to fourfold lower than with danazol therapy and similar to values in the oophorectomized women. Sex hormone binding globulin was markedly suppressed (P less than .001) throughout danazol treatment, resulting in a threefold elevation (P less than .01) of free testosterone. These data suggest that danazol may affect endometriosis by mechanisms other than by inducing a pseudomenopause. The increased tissue availability of testosterone may be responsible for acne and hirsutism observed in some women during danazol treatment and may inhibit proliferation of the ectopic endometrium. Medical oophorectomy using GnRH-a may have improved effects on endometriosis without the androgenic side effects of danazol.

Castration↗
PubMed1982

Sequence analysis of a growth hormone releasing factor from a human pancreatic islet tumor.

A growth hormone releasing factor of a human pancreatic islet tumor (hpGRF) of an acromegalic patient was purified and subjected to Edman degradation in a spinning cup sequencer. Approximately 0.7-1.2 nmol of peptide was applied to the cup without any pretreatment, after coupling to 3-sulfophenyl isothiocyanate or after cleavage with cyanogen bromide, staphylococcal protease, or trypsin. On the basis of the analytical data, the N-terminal sequence of 39 residues is established to be H-Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn- Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys- Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser- Asn-Gln-Glu-Arg-Gly-. It is proposed that alanine is residue 40 and represents (as free acid) the C terminus of hpGRF. Synthetic hpGRF(1-40)-OH is highly potent in stimulating GH secretion from the rat anterior pituitary in vitro and in vivo. The C-terminal sequence of hpGRF does not appear to contribute significantly to the biologic intrinsic activity and potency of hpGRF, as demonstrated by the fact that the natural product and the synthetic peptides hpGRF(1-40)-OH, hpGRF(1-40)-NH2, and hpGRF(1-29)-NH2 show equivalent in vitro activities. On the basis of sequence homologies, hpGRF is closely related to members of the glucagon secretin family, especially to the porcine gut peptide PHI.

Adenoma, Islet Cell↗
PubMed1982

Inhibition of adrenocorticotropic hormone secretion in the rat by immunoneutralization of corticotropin-releasing factor.

Intravenous administration of rabbit antiserum to ovine corticotropin-releasing factor (CRF) markedly reduced the CRF-induced rise of plasma adrenocorticotropic hormone (ACTH) in intact nonstressed adult male rats while blocking more than 75 percent of the ACTH release observed in rats exposed to ether stress. Furthermore, antiserum to CRF significantly lowered ACTH levels in adrenalectomized animals. These results suggest that endogenous CRF plays a physiological role in regulating ACTH secretion.

Adrenalectomy↗
PubMed1982

Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty.

Corticotropin-releasing factor was administered into the lateral cerebral ventricles of rats. Sixty minutes later, animals were tested in an open field conflict test or in their home cages for a variety of behaviors which have been shown to be related to the degree of responsiveness to novelty. CRF, in a dose related fashion, altered the frequency of those behaviors which are normally expressed in response to the novel environment. Specifically, CRF caused an increase in grooming and decreases in the amount of rearing, the number of approaches to a food pellet placed in the center of the open field, the amount of food eaten in both the open field and the home cage and a decrease in the mean amount of food eaten per approach to the food pedestal.

Animals↗
PubMed1982

In vivo and in vitro effects of tetrahydroisoquinolines and other alkaloids on rat pituitary function.

Several tetrahydroisoquinolines (TIQs) were tested for their in vitro and in vivo capacities to modulate prolactin (PRl) and beta-endorphin (beta-end) secretion by the rat pituitary and for their abilities to displace [3H]spiroperidol and [3H]naloxone binding from pituitary and hypothalamic membranes. Receptor binding studies showed that TIQs could be classified as having (a) higher affinity for opiate receptors (tetrahydropapaverine, papaverine, 6-methylsalolinol, 1-carboxysalsolinol and 3',4'-deoxy-norlaudanosolinecarboxylic acid), (b) higher affinity for the dopamine receptor (salsolinol and 7-methylsalsolinol), or (c) approximately equal affinity for the two binding sites (6,7-dimethylsalsolinol and tetrahydropapaveroline, THP). In freely moving male rats, THP produced a several-fold increase in plasma PRL levels. This effect was not altered by co-administration of naloxone but was attenuated by dopamine. In vitro several TIQs reversed the inhibitory effect of dopamine on PRL secretion by cultured anterior pituitary cells. The order of potencies of the TIQs in this system paralleled their order of potencies in the dopamine receptor assay. THP, the most potent dopamine antagonist, also blocked dopamine-mediated inhibition of beta-endorphin secretion from neurointermediate lobe cells in culture. These data demonstrate that THP and some other TIQs can act as dopamine antagonists in radioreceptor assays, in cell culture and in vivo.

Animals↗
PubMed1982

Calcitonin COOH-terminal cleavage peptide as a model for identification of novel neuropeptides predicted by recombinant DNA analysis.

A strategy is presented for identification of putative neurohormones that were predicted by sequence analysis of recombinant cDNa molecules. The nucleotide sequence of a cloned calcitonin cDNA insert predicts that the proteolytic excision of calcitonin from a 136-amino acid precursor should generate two additional peptides derived from regions flanking the calcitonin sequence on the NH2 and carboxyl termini. The predicted 16-amino acid COOH-terminal cleavage peptide (NH2-Asp-Met-Ala-Lys-Asp-Leu-Glu-Thr-Asn-His-His-Pro-Thr-Phe-Gly-Asn-COOH) was chemically synthesized using solid phase procedures. Antibodies against this synthetic hexadecapeptide detect immunologically cross-reactive material in tissue extracts from normal thyroid glands and calcitonin-producing medullary thyroid carcinomas. Each of the four calcitonin mRNA-directed cell-free translation products contain the immunological determinants for both calcitonin and the COOH-terminal cleavage peptide.

Amino Acid Sequence↗