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Biomedical subjects

W Vale

Publications and source records attributed to W Vale.

At least 415 records · Page 23Linked to original sources
PubMed1981

Somatostatin, gastrointestinal peptides, and the carcinoid syndrome.

During a control infusion noradrenaline and alcohol each provoked carcinoid flushing in four of five patients and pentagastrin in two of five patients. When tetradecapeptide somatostatin was infused on another day no patient flushed at any time, even when 16 microgram of either noradrenaline or pentagastrin were administered. Carcinoid flushing was not associated with release of gastrin or any of the other vasoactive or postprandially released gut regulatory peptides measured. In a sixth patient with severe prolonged carcinoid flushing, subcutaneous Des AA1, 2, 4, 5, 12D Trp8 somatostatin markedly reduced the incidence and severity of flushing for two days. Somatostatin is thus a potent inhibitor of carcinoid flushing, but no evidence has been found for the gut hormones measured to be mediators of flushing.

Aged↗
PubMed1981

Antireproductive effects of a potent GnRH antagonist in the female rat.

The administration of the potent gonadotropin-releasing hormone antagonist [Ac-dehydro-Pro1,pCl-D-Phe2,D-Trp3,6,N alpha MeLeu7]GnRH (Antag) to female rats results in disruption of the estrous cycle and gestation. Daily doses of 200 microgram Antag are completely effective in blocking regular cycles, which resume 6-9 days after cessation of treatment. When administered to mated female rats, Antag seems to be less effective in terminating pregnancy during the earlier (1-7 days) than later (7-12 days) days of gestation. This may reflect the inability of Antag to lower the secretion of PRL (the luteotropic hormone of early pregnancy) as compared to the Antag-induced inhibition of LH production (the luteotropic hormone of midpregnancy). As a result, administration of Antag 7-12 days after mating is accompanied by a decrease in plasma progesterone levels incompatible with the survival of the embryos. These data provide further evidence that the neutralization of the function of endogenous gonadotropin-releasing hormone is deleterious to reproductive integrity.

Animals↗
PubMed1981

Effect of a potent GnRH antagonist and testosterone propionate on mating behavior and fertility in the male rat.

Daily treatment with 1 mg of the GnRH antagonist [Ac-delta 3-Pro1,pC1-D-Phe2,D-Trp3,6,N alpha MeLeu7]-GnRH abolished mating behavior and disrupted spermatogenesis in male rats within 2 weeks. This was accompanied by a sharp decrease in plasma testosterone (T) levels as well as sexual organ weights while body weight remained normal. Following cessation of treatment, T levels returned to control values within 5 days, while sexual organ weights were still slightly depressed after 6 weeks. In rats having been treated for either 2 weeks or 4 months, mating behavior and fertility were restored between the 4th and 8th week after the last injection. Antagonist-treated animals who concomitantly received high doses of exogenous testosterone were sexually active as well as fertile, while lower doses of testosterone maintained sexual activity but not fertility. These data indicate that GnRH antagonists may be used to control male fertility.

Animals↗
PubMed1981

Somatostatin-28: selective action on the pancreatic beta-cell and brain.

Somatostatin-28 (SS-28) is 380 times as potent as somatostatin-14 (SS-14) to inhibit acutely insulin secretion induced by arginine in vivo; SS-28 is only 3 times as potent as SS-14 to inhibit glucagon secretion induced by arginine. D-Trp substitution in position 28 of SS-28 increase potency to 2600 times that of SS-14 for inhibition of arginine induced insulin secretion. SS-28 in 10 and [D-Trp22]-SS-28 is 100 times as potent as SS-14 to act within the central nervous system to inhibit bombesin induced hyperglycemia. SS-28 compared to SS-14 shows pancreatic beta-cell and brain selectivity of action.

Animals↗
PubMed1981

Characterization of human anti-luteinizing hormone-releasing hormone (LRH) antibodies in the serum of a patient with isolated gonadotropin deficiency treated with synthetic LRH.

In this report we describe the characteristics of human anti-LRH antibodies detected in the serum of a male patient with isolated gonadotropin deficiency. He had received 90 days of therapy with LRH (1 mg, sc, three times daily) and was then placed on three cycles of intermittent therapy (3 weeks of LRH daily, followed by hCG every 3 days for 15 days). At the start of the fourth cycle of therapy with LRH, he developed urticaria at the site of injection, at sites of previous LRH injections, and at distant sites. Upon direct skin testing, the patient reacted positively to 0.02 ng LRH intradermally. A positive intradermal reaction was induced in a normal adult male by preparing his skin with 0.1 ml of the patient's serum and, 24 h later, injecting 0.2 microgram LRH at that site. A binding factor for LRH was detected in the patient's serum by incubation with [125I]LRH. The serum bound 33% of tracer compared to 6% in control serum. We have detected both immunoglobulin G and immunoglobulin E antibodies against LRH in the patient's serum. We have compared displacement of tracer by synthetic LRH with displacement achieved by a series of analogs. Displacements of tracer by LRH, [Lys8]LRH, [D-Trp6,Pro9-NEt]LRH, [des-Gly10]LRH, and [Phe2]LRH were similar, whereas the potencies of Ac-LRH5-10 and AcLRH2-10 were 0.1% or less.

Adult↗
PubMed1981

Therapeutic use of pituitary desensitization with a long-acting lhrh agonist: a potential new treatment for idiopathic precocious puberty.

A two year girl with idiopathic true precocious puberty was treated with a long-acting LHRH agonist, D-Trp6-Pro9-NEt-LHRH (LHRHa). Prior to therapy, the patient demonstrated pulsatile gonadotropin secretion during both night and day, a pubertal response to exogenous LHRH, and an elevated plasma estradiol level. After eight weeks of therapy (4 microgram/kg daily), a mean gonadotropin levels fell to the prepubertal range, there was no evidence of pulsatile discharge of gonadotropins nor any response to exogenous LHRH, and plasma estradiol levels became undetectable. No adverse drug reactions were encountered and all effects of therapy were reversed following cessation of treatment for two months. LHRH analogs may offer a new approach to the therapy of idiopathic precocious puberty and merit further study.

Child, Preschool↗
PubMed1981

The effect of somatostatin analogs on secretion of growth, pancreatic, and gastrointestinal hormones in man.

The potency and specificity of somatostatin (SS) and four of its analogs were compared in seven patients with pancreatic endocrine tumors. The analogs tested were [D-Trp8]-SS, [D-Trp8, D-Cys14]-SS, Des-Asn5-[D-Trp8, D-Ser13]-SS, and Des (AA)1,2,4,5,12,13, [D-Trp8]-SS, and they did not show selective effects on the suppression of basal concentrations of GH, insulin, glucagon, pancreatic polypeptide, gastrin, gastric inhibitory peptide, motilin, enteroglucagon, or neurotensin. The observation that the potency of these analogs is similar to that of the parent molecule throws considerable light on the structure/activity relationship of the somatostatin molecule. Des-AA1,2,4,5,12,13, [D-Trp8]-Ss has been reported to have a prolonged action when administered sc. When administered iv, however, this octapeptide analog ws not long acting, suggesting that the prolonged action seen in the previous study was a result of delayed uptake from the injection site. An increment in plasma SS concentrations of 19 +/- 3 pmol/liter suppressed basal concentrations of GH, insulin, glucagon, and several gastrointestinal hormones by more than 50%, suggesting that even small changes in plasma SS levels may be physiologically important.

Adult↗
PubMed1981

Central nervous system inhibition of gastric secretion in the rat by gastrin-releasing peptide, a mammalian bombesin.

Gastrin-releasing peptide is a 27-amino acid peptide recently isolated from porcine gut. It shares a common C-terminal decapeptide homology with bombesin (except for a His/Gln interchange at residue 8 from C-terminus). Synthetic porcine gastrin-releasing peptide was shown to release gastrin 5 min after intravenous injection in rats. Given intracisternally (0.3--3 microgram), but not intravenously (1--10 micrograms), gastrin-releasing peptide caused a dose-dependent reduction in gastric secretion (volume and acidity) and elevation in plasma gastrin levels measured 2 h after peptide injection and pylorus ligation in rats. Gastrin-releasing peptide given intracisternally had long acting, reversible, and specific inhibitory effects. Gastrin-releasing peptide blocked the secretion of acid evoked by 2-deoxy-D-glucose or TRH given intracisternally or by histamine given subcutaneously. The acetylated C-terminal octapeptide fragment of gastrin-releasing peptide inhibited gastric acid secretion as effectively as gastrin-releasing peptide. Acetylated C-terminal heptapeptide did not. These results demonstrated that gastrin-releasing peptide has the capability to act in the brain to inhibit basal and stimulated gastric secretion and its antisecretory effect does not depend on a decrease in gastrin release. The presence of bombesin immunoactivity in rat brain and its ability to act through the brain to inhibit gastric acid secretion suggest that bombesinlike peptides may be chemical messengers involved in central nervous regulation of gastric secretion.

Animals↗
PubMed1980

Antireproductive effects of a potent gonadotropin-releasing hormone antagonist in the male rat.

Administration of a potent antagonist of gondadotropin-releasing hormone (GnRH) antagonist [Ac-dehydro-Pro1, pCl-D-Phe2, D-Trp3,6]-N alpha-MeLeu7-GnRH to adult male rats for 2 weeks resulted in decreased testosterone production and sexual organ weights and in disrupted spermatogenesis. The results demonstrate the essential role of gonadotropin-releasing hormone in the maintenance of reproductive functions and have implications for the regulation of male fertility.

Animals↗
PubMed1980

Thyrotropin-releasing hormone--CNS action to stimulate gastric acid secretion.

Much physiological and pharmacological evidence has accumulated to suggest that the autonomic nervous system has an important role in the peripheral modulation of gastric secretion, although the neurochemical mediators in the brain which initiate or modulate autonomic input are poorly understood. Recently, the demonstration that some oligopeptides present in mammalian brain act in the central nervous system (CNS) to influence profoundly glucoregulation, thermoregulation, blood pressure, sympathetic outflow, muscular activity of gut and stress-induced gastric haemorrhagic lesions have led us to examine a possible role for some of these endogenous brain oligopeptides as chemical messengers involved in the CNS modulation of gastric secretion. We report here that thyrotropin-releasing hormone (TRH) acts within the CNS to elicit a vagus-dependent stimulation of gastric acid secretion.

Animals↗
PubMed1980

The biologic activity of a potent analogue of gonadotropin-releasing hormone in normal and hypogonadotropic men.

We studied the biologic activity of a long-acting analogue of luteinizing hormone-releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), in five normal men and four hypogonadotropic men previously unresponsive to natural LHRH. All subjects responded to LHRAa, but there were quantitative and qualitative differences between the normal and hypogonadotropic men. Normal men showed a linear dose-response relation, endogenous gonadal steroid secretion, and an adult pattern of gonadotropin secretion characterized by a high ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH). Hypogonadotropic men had improving pituitary responses to each dose of LHRHa (priming response), no demonstrable gonadal steroid secretion, and a prepubertal pattern of gonadotropin release characterized by reversal of the normal ratio of LH to FSH. When compared with native LHRH, LHRHa had an augmented ability to discharge gonadotropins acutely and to sustain their release in normal and hypogonadotropic men.

Adolescent↗
PubMed1980

Brain regulation of gastric secretion: influence of neuropeptides.

Several neuropeptides injected intracisternally were assessed for their effects on gastric secretion in rats. Bombesin (1 microgram) completely suppressed gastric acid secretion, produced the volume of gastric secretion, and partially blocked insulin- or 2-deoxy-D-glucose-induced stimulation of gastric acid output. The inhibitory effect of this peptide is dose-dependent, long-acting, reversible, and specific. Bombesin response appears to be central nervous system-mediated; its expression is not dependent on the vagus nerve or the adrenal glands, and does not rely on a decrease in gastrin secretion. Among seven other peptides tested, only beta-endorphin and a potent gonadotropin releasing-factor (gonadoliberin) agonist significantly reduced gastric acid secretion, with an activity ca. 100 times less than that of bombesin. The presence of bombesin-like material in rat brain and the high potency of bombesin to inhibit gastric secretion suggest that this peptide may be of physiologic significance as a chemical messenger involved in brain modulation of gastric secretion.

Adrenalectomy↗
PubMed1980

Effect of chronic treatment with thyrotropin-releasing hormone (TRH) or an analog of TRH (linear beta-alanine TRH) on the hypothalamic-pituitary-thyroid axis.

The effects of treatment for 5 or 9 days with varying doses of thyrotropin-releasing hormone (TRH) or the linear beta-alanine TRH congener (pGlu-His-Pro-beta-Ala-NH2) on serum levels of TSH, T3, and T4 were studied in mice and rats. At low doses in rats treatment with TRH for 9 days significantly increased serum levels of T3 but not serum T4 whereas a higher dose of TRH (10 mg/kg) reduced serum T3 levels. beta-Ala TRH (0.1--10 mg/kg IP) treatment for 9 days in rats significantly reduced serum T4 levels whereas serum T3 levels were only depressed at higher doses (1--10 mg/kg IP) of the peptide. In mice treatment for 5 days with TRH (1 and 10 mg/kg IP) significantly reduced serum levels of T3 and T4. In addition, TRH (0.1--10 mg/kg IP) or beta-Ala TRH treatment (1.0--10 mg/kg IP) for 9 days significantly reduced serum TSH levels in rats. TRH (10 mg/kg IP for 9 days) also significantly reduced serum GH levels in rats. No alteration in hypothalamic content of TRH and LHRH was observed after chronic TRH treatment. Some, but not all, of our findings support the hypothesis that treatment with high doses of TRH reduce pituitary-thyroid axis functions by a direct effect on hypophysial TRH receptors.

Animals↗
PubMed1979

Suppression of pancreatic endocrine tumour secretion by long-acting somatostatin analogue.

A new long-acting octapeptide analogue of somatostatin, Des AA1,2,4,5,12,13 D Try8 somatostatin, has been tested in 8 patients with pancreatic endocrine tumours. The analogue given subcutaneously suppressed the tumour-derived hormones in patients with insulinomas, glucagonomas, and gastrinomas for up to 24 h. The prolonged action appeared to be the result of slow release from the injection site. No side-effects were observed. Studies of long-term administration of this new peptide are now warranted.

Adult↗