Serotonin Antagonists Cyproheptadine Research Articles

Somatostatin release from rat hypothalamus in vitro: effects of melatonin and serotonin.

The release of immunoreactive somatostatin (SRIF) from explants of rat medial basal hypothalamus, which were maintained in culture for 24 h, was quantitated by a sensitive RIA. Validity of the specific SRIF assay has been previously established by chromatographic criteria using gel and high pressure systems and by the demonstration of immunological parallelism. After 24 h of culture in medium containing heat-inactivated fetal calf serum, hypothalamic fragments were incubated in serum-free medium, and the release of immunoreactive SRIF was quantitated. Melatonin at concentrations of 10(--8) and 10(--7) M stimulated SRIF release, and no significant increases were observed at concentrations of 10(--9) M or less or at concentrations of 10(--6) M or greater. Serotonin oxalate at concentrations of 10(--8)--10(--5) M significantly inhibited SRIF release. The serotonin antagonist cyproheptadine at a concentration of 10(--5)M had no effect on basal SRIF release but abolished the inhibitory effect of 10(--7) M serotonin. Finally, when hypothalami were incubated with melatonin and serotonin, each at 10(--7) M, SRIF release was unchanged compared to control values. The results suggest that the brain indoleamines, melatonin and serotonin, may modulate GH secretion by effects on SRIF release at a hypothalamic level.

Corticosteroidogenesis by isolated human adrenal cells: Effect of serotonin and serotonin antagonists

The direct effect of serotonin and antiserotonin agents on adrenal steroid biosynthesis was studied in isolated adrenal cells derived from patients with Cushing's syndrome. The results indicate that serotonin increases corticosterone production, while the serotonin antagonists cyproheptadine and methysergide depress adrenal steroid - particularly cortisol and aldosterone - biosynthesis.

On the central anti-serotoninergic actions of cyproheptadine and methysergide

The peripheral administration of serotonin antagonists cyproheptadine and methysergide did not result in any changes in brain 5-hydroxyindole levels up to 2 hr after administration, despite a rise in brain tryptophan noted after higher doses of cyproheptadine. Both cyproheptadine and methysergide are hypothermie at room temperature, but exposure of animals to elevated temperature (36 C) results in a rise in colonie temperature equal to that seen in untreated animals exposed to this same temperature. Exposure to elevated ambient temperature results in a similar rise in brain 5-hydroxyindoles in both saline and cyproheptadine-treated animals. Methysergide blocks the rise of 5HIAA that occurs upon exposure to heat. Neither cyproheptadine nor methysergide prevent the decrease in brain 5HIAA levels that follows injection of a 5HT receptor agonist (quipazine). These results suggest that neither cyproheptadine nor methysergide act as central serotonin receptor antagonists, or that they act upon 5HT receptors which do not mediate compensatory feedback responses.

Passive Local Anaphylaxis: Demonstration of Antitumor Activity and Complementation of Intratumor BCG2

When an extracellular dye, Lissamine green, or 51Cr-labeled spleen cells were injected iv into C3H mice bearing small, partially necrotic 3-methylcholanthrene-induced transplantable fibrosarcomas (McC3), the tumor content of these circulating elements per unit weight was substantially lower than that of other selected organs. The level of these blood-borne materials was, however, significantly augmented by the intratumor induction of passive local anaphylaxis (PLA). The PLA-induced augmentation was inhibited by administration of the histamine and serotonin antagonist cyproheptadine; comparable increases were also induced by the intratumor injection of a histamine and serotonin mixture or BCG. The weekly intratumor induction of PLA in McC3 tumors resulted in the complete regression of a significant number of the tumors, and this therapeutic effect was eliminated by cyproheptadine treatment. The intratumor injection of BCG induced the regression of approximately 50% of injected tumors, and the combination of this immunostimulant treatment with the generation of PLA was more therapeutically effective than either treatment alone. PLA in the vicinity of solid tumors may, by increasing vascular permeability, potentiate antitumor effector mechanisms, particularly when these are BCG-stimulated. Despite this demonstration of a possible role of anaphylactic reactions in tumor immunity, no definitive evidence was found that active reagin-mediated local anaphylaxis occurred in C3H mice bearing the McC3 tumor, whether or not they were treated with immunostimulants.

Neurogenic hypercholesterolemia Influence of autonomic drugs

Eleven substances capable of either augmenting or depleting the α- and β-adrenergic capacities of the autonomic nervous system were administered to rats exhibiting hypothalamic hypercholesterolemia and to normal controls. Only the β-adrenergic blocking agents propranolol and possibly 6-OH dopamine were observed to alter (raise) the serum cholesterol concentration, and this occurred in both experimental and control animals. Neither atropine, nor the serotonin-depleting agent, p-chlorophenylalanine, nor the serotonin-antagonist cyproheptadine, were observed to alter serum cholesterol level. Such absence of effect was also noted with metaraminol, phenoxybenzamine, isoproterenol, epinephrine, reserpine, and a-methyl tyrosine.

INHIBITORY EFFECT OF SEROTONIN ANTAGONISTS ON GROWTH HORMONE RELEASE IN ACROMEGALIC PATIENTS

We evaluated the effect of the serotonin antagonists cyproheptadine (Cypro) and methysergide (Methy) on growth hormone secretion in six patients with acromegaly. Two days administration of Cypro decreased the plasma GH concentration during oral glucose tolerance tests in four of the six patients evaluated; 2 days administration of Methy reduced the plasma GH levels of only one of the four patients evaluated. The one patient whose plasma GH concentration was lowered by Methy, did not have a decrease in plasma GH concentration after Cypro administration. Acromegalic patients have normal serum serotonin concentration and normal 5-hydroxyindoleacetic acid excretion. If Cypro lowers plasma GH by antagonizing serotonin, our data would suggest that serotoninergic neuronal pathways are important in the regulation of pituitary GH secretion in some patients with acromegaly.

Glucose intolerance in the carcinoid syndrome.

We assayed glucose tolerance and insulin secretion in ten patients with metastatic carcinoid tumors and the carcinoid syndrome ("active tumors") and in seven patients with metastatic carcinoid tumors without the carcinoid syndrome ("inactive tumors"). The patients with "active tumors" had elevated serum serotonin levels while the patients with "inactive tumors" had normal serum serotonin levels. Of the ten patients with "active tumors," five had diabetic and three had borderline intravenous glucose disposal rate constants (KG = 0.88 +/- 0.07, M. +/- S.E.M.). Their KG was significantly lower (p less than 0.01) than a group of age-matched normals. All of the patients with "inactive tumors" had normal KG values (KG = 1.67 +/- 0.24). Their KG did not differ from that of age-matched normal subjects. Both groups of carcinoid patients had a comparable decrease in their insulinogenic index. Two days' administration of the serotonin antagonist cyproheptadine (Cypro) to eight of the patients with "active tumors" resulted in a significant increase in the "insulinogenic index" (50%) but a nonsignificant increase in the KG (12%). Administration of p-chlorophenylalanine, a compound that blocks serotonin synthesis, resulted in an increase in both the KG (60%) and the "insulinogenic index" (55%). The insulin half-life (t1/2) of patients with "active tumors" (6.1 +/- 0.4 min.) did not differ from the t1/2 of normal subjects (6.6 +/- 0.4 min.), suggesting that the decreased plasma insulin levels following intravenous glucose were due to impaired insulin secretion rather than accelerated insulin destruction. Seven of the patients received treatment with the antitumor agent streptozotocin (Strepto). The patients received cumulative doses of from 70 to 300 mg. of Strepto per kilogram body weight with no impairment in glucose tolerance or insulin secretion. We conclude that there is high incidence of glucose intolerance (80%) and impaired insulin secretion in patients with the carcinoid syndrome and that serotonin plays a role in producing these alterations.

The role of cortisol and growth hormone in the counter-regulation of insulin-induced hypoglycemia.

Four normal volunteers underwent a control insulin tolerance test (ITT) and an insulin tolerance test (ITT) after two days administration of the serotonin antagonist cyproheptadine (Cypro). Cypro administration resulted in an 81 +/- 11.4% (M +/- SEM) reduction in cortisol secretion and a 73 +/- 15.1% reduction in growth hormone (GH) secretion. Despite the reduction in hypoglycemia-induced cortisol and GH secretion, there was a similar decline and recovery of plasma glucose in the control ITT and the ITT after Cypro administration. Although previous studies indicate that normal basal levels of cortisol and growth hormone are needed for normal counter-regulation after insulin-induced hypoglycemia, augmented secretion of these hormones is probably not essential for this response. Hypoglycemia-induced increases in epinephrine and glucagon, secretion may contribute to the restoration of the normal plasma glucose concentration after insulin-induced hypoglycemia.

Inhibition of hypoglycemia-induced cortisol secretion by the serotonin antagonist cyproheptadine.

ABSTRACT Cortisol secretion is provoked by hypoglycemia. Since insulin-induced hypoglycemia is associated with an increase in hypothalamic serotonin, and since animal studies have related serotoninergic mechanisms to control of cortisol secretion, the role of hypothalamic serotonin in cortisol secretion was investigated in man. In normal volunteers, hypoglycemia-induced cortisol secretion was studied during a control period and after 2 days of administration of serotonin antagonists methysergide and cyproheptadine. Plasma cortisol was estimated by the competitive binding assay, and total cortisol secretion was expressed as the area under the cortisol curve from 0 to 120 min. Cyproheptadine administration resulted in a 31% reduction in the area under the cortisol curve, but methysergide administration did not result in a significant change. The plasma glucose levels in control insulin tolerance tests and the posttreatment tests indicated a comparable stimulus for cortisol secretion. If cyproheptadine acts ...

Neurotransmitting substances and endotoxin respone in relation to hepatic enzyme induction.

Since neurotransmission and selected enzymes of the serotonin/adrenalin pathway are altered during endotoxicosis, a variety of neurophilic drugs, some active on defined loci in the tryptophan-serotonin pathway, were evaluated for their ability to modify endotoxin lethality. Among the various putative neurotransmitters, only leucine had some sensitizing effect on endotoxin toxicity. If given prior, and not subsequent, to challenge, <i>p</i>-chlorophenyl-alanine (but not the other analogues) consistently lowered the LD<sub>50</sub> of endotoxin in mice and impaired cortisone proctection against endotoxic death. This effect could not be related to the possible increase in endogenous concentrations of tryptophan, as a result of inhibition of tryptophan hydroxylase by <i>p</i>-chlorophenylalanine (PCPA). Additionally, the endotoxin toxicity in normal mice could not be modified by the serotonin antagonists cyproheptadine and LSD-25. The inorganic mercurial HgCl<sub>2</sub> (but not its organic analoge <i>p</i>-chloromercuribenzoate), behaved like PCPA in its ability to modify the endotoxin lethality. These results are discussed in relation to hepatic enzyme induction and a common receptor-effector system possibly coordinating a variety of inter- and intra-cellular responses.

Inhibition of hypoglycemia-induced growth hormone secretion by the serotonin antagonists cyproheptadine and methysergide.

Abstract Growth hormone secretion is provoked by hypoglycemia. Since hypothalamic serotonin content increases during insulin-induced hypoglycemia, the role of hypothalamic serotonin in growth hormone secretion in man was examined. Hypoglycemia-induced growth hormone release in normal volunteers was studied during a control period and after two days of administration of serotonin antagonists, cyproheptadine and methysergide. Plasma growth hormone was measured by radioimmunoassay, and total growth hormone secretion was expressed as the area under the growth hormone curve from 0 to 120 minutes. Cyproheptadine administration resulted in a 59 per cent reduction (p<0.01), and methysergide in a 35 per cent reduction (p<0.05) in growth hormone secretion. The decrease in plasma glucose during the control and treatment periods indicated a comparable stimulus for growth hormone release in both study groups. If these drugs act by antagonizing serotonin, as assumed, this study suggests that serotonin is involved in hy...