Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver

Endo, Yasuo

doi:10.1111/j.1476-5381.1987.tb16836.x

Cited by 8 publications

(7 citation statements)

References 18 publications

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“…Unlike histamine, the increase in 5-HT appears to be relatively specific for the liver and does not occur in other tissues such as the lung, spleen, intestine or kidney (Endo, 1983a). In addition, the accumulation of 5-HT is not attributable to an enhancement of its synthesis (Endo, 1987), which suggests this amine is transported into the liver from the surrounding tissues.…”

Section: Introductionmentioning

confidence: 90%

The effect of lipopolysaccharide, interleukin‐1 and tumour necrosis factor on the hepatic accumulation of 5‐hydroxytryptamine and platelets in the mouse

Endo

Nakamura

1992

British J Pharmacology

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Injection of lipopolysaccharide (LPS; 0.5–500 μg kg−1) into mice induced a dose‐dependent, slowly developing increase in hepatic content of 5‐hydroxytryptamine (5‐HT). This sustained increase could not be attributed to an LPS‐induced alteration of the pharmacokinetic handling of 5‐HT by stimulation of its uptake or inhibition of its degradation. Regional differences were apparent in the tissue content of histamine and 5‐HT between mast cell‐deficient (W/Wv) and normal (+/ +) mice. LPS administration (0.5 mg kg−1) gave comparable increases in the hepatic level of 5‐HT in mast cell‐deficient and normal mice. Reserpine pretreatment (1 mg kg−1) selectively reduced 5‐HT levels in the blood, spleen, liver, brain and lung of normal mice. Prior treatment with this agent also abolished the LPS (0.5 mg kg−1)‐induced hepatic accumulation of 5‐HT. Accumulation of 5‐HT in the liver by LPS (0.1 mg kg−1) was temporally associated with both a fall in the levels of circulating platelets, and a reduction in the concentration of 5‐HT in the blood. The LPS dose‐dependent (0.5–500 μg kg−1) increase in hepatic 5‐HT content was associated with a similar dose‐dependent reduction in the circulating levels of 5‐HT. Interleukin‐1, α and β (10 μg kg−1) and tumour necrosis factor α (TNFα) (1 mg kg−1) significantly enhanced the accumulation of 5‐HT within the liver. Administration of TNFα (10 μg kg−1) potentiated the increase in hepatic 5‐HT content seen with IL‐1β (10 μg kg−1). Electron microscopy revealed numerous platelets in the sinusoidal and perisinusoidal Disse spaces within the liver, in animals pretreated with LPS (0.1 mg kg−1). The platelets retained their intact structure and showed no evidence of degranulation. These data suggest that the LPS and cytokine‐induced mobilization of 5‐HT in the liver is associated with the hepatic translocation of platelets. This migration appears to be independent of platelet aggregation.

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Section: Introductionmentioning

confidence: 90%

The effect of lipopolysaccharide, interleukin‐1 and tumour necrosis factor on the hepatic accumulation of 5‐hydroxytryptamine and platelets in the mouse

Endo

Nakamura

1992

British J Pharmacology

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“…Intraperitoneal administration of 5-hydroxytryptophan (5-HTP), the immediate precursor of 5-HT, has a hypoglycemic effect in mice that is apparently related to intrahepatic accumulation of 5-HT (8). We have demonstrated that intraportal infusion of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, which prolongs the action of endogenous 5-HT, stimulates NHGU (27).…”

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confidence: 97%

Portal 5-hydroxytryptophan infusion enhances glucose disposal in conscious dogs

Moore¹,

Kimura²,

Shibata³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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Intraportal serotonin infusion enhances net hepatic glucose uptake (NHGU) during glucose infusion but blunts nonhepatic glucose uptake and can cause gastrointestinal discomfort and diarrhea at high doses. Whether the serotonin precursor 5-hydroxytryptophan (5-HTP) could enhance NHGU without gastrointestinal side effects during glucose infusion was examined in conscious 42-h-fasted dogs, using arteriovenous difference and tracer ([3-3H]glucose) techniques. Experiments consisted of equilibration (-120 to -30 min), basal (-30 to 0 min), and experimental (EXP; 0-270 min) periods. During EXP, somatostatin, fourfold basal intraportal insulin, basal intraportal glucagon, and peripheral glucose (to double the hepatic glucose load) were infused. In one group of dogs (HTP, n = 6), saline was infused intraportally from 0 to 90 min (P1), and 5-HTP was infused intraportally at 10, 20, and 40 microg x kg(-1) x min(-1) from 90 to 150 (P2), 150 to 210 (P3), and 210 to 270 (P4) min, respectively. In the other group (SAL, n = 7), saline was infused intraportally from 0 to 270 min. NHGU in SAL was 14.8 +/- 1.9, 18.5 +/- 2.3, 16.3 +/- 1.4, and 19.7 +/- 1.6 micromol x kg(-1) x min(-1) in P1-P4, whereas NHGU in 5-HTP averaged 16.4 +/- 2.6, 18.5 +/- 1.4, 20.8 +/- 2.0, and 27.6 +/- 2.6 micromol x kg(-1) x min(-1) (P < 0.05 vs. SAL). Nonhepatic glucose uptake (micromol x kg(-1) x min(-1)) in SAL was 30.2 +/- 4.3, 36.8 +/- 5.8, 44.3 +/- 5.8, and 54.6 +/- 11.8 during P1-P4, respectively, whereas in HTP the corresponding values were 26.3 +/- 6.8, 44.9 +/- 10.1, 47.5 +/- 11.7, and 51.4 +/- 13.2 (not significant between groups). Intraportal 5-HTP enhances NHGU without significantly altering nonhepatic glucose uptake or causing gastrointestinal side effects, raising the possibility that a related agent might have a role in reducing postprandial hyperglycemia.

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“…In addition to its role as a neurotransmitter, 5-HT has a range of functions that include control of vascular tone, exocrine secretion by the pancreas [4], liver regeneration [5] and glucose homeostasis [6][7][8]. Studies in vivo have shown either hypoglycaemia [6,7] or hyperglycaemia [8] after administration of 5-HT.…”

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confidence: 99%

“…Studies in vivo have shown either hypoglycaemia [6,7] or hyperglycaemia [8] after administration of 5-HT. The latter is attributed to release of epinephrine from the adrenal glands or to vasoconstrictor effects.…”

mentioning

confidence: 99%

“…The latter is attributed to release of epinephrine from the adrenal glands or to vasoconstrictor effects. However, the mechanisms that account for hypoglycaemia [6,7] or improved glucose tolerance in diabetes after treatment with selective 5-HT reuptake inhibitors [9] are not fully understood. In skeletal muscle 5-HT has been found to either stimulate or to have no effect on glucose uptake [10,11].…”

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confidence: 99%

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Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

2007

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Aims/hypothesis Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. Materials and methods Rat hepatocytes were studied in short-term primary culture. Results Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation. Conclusions/interpretation This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

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Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver

Cited by 8 publications

References 18 publications

The effect of lipopolysaccharide, interleukin‐1 and tumour necrosis factor on the hepatic accumulation of 5‐hydroxytryptamine and platelets in the mouse

The effect of lipopolysaccharide, interleukin‐1 and tumour necrosis factor on the hepatic accumulation of 5‐hydroxytryptamine and platelets in the mouse

Portal 5-hydroxytryptophan infusion enhances glucose disposal in conscious dogs

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

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