RESUMO
The aim of this study was to determine the effective waist circumference (WC) reduction rate in avoiding the development of type 2 diabetes mellitus (T2DM) in <55 years and ≥55 years Japanese men with abdominal obesity. The study subjects were 795 men with WC ≥85 cm, fasting plasma glucose <126 mg/dL, 2-hr plasma glucose on 75 g of oral glucose tolerance test <200 mg/dL, and HbA1c 5.6-6.4 % (38-40 mmol/mol) at baseline who underwent general health checkups more than twice between April 2007 and May 2015. They were divided into 5 groups based on the change in WC during the observation period (WC gain group, and four groups stratified according the rate of WC loss). The subjects were also divided into the <55 years and ≥55 years (at baseline) subgroups. The cumulative incidence rate of T2DM was analyzed and compared among the groups. The cumulative incidence rates of the largest WC loss quartile (≥5.45 %) in all age, of the largest WC loss quartile (≥5.60 %) and second largest WC loss quartile (3.44-5.59 %) in the <55 years subgroup, and of the largest WC loss quartile (≥5.37 %) in the ≥55 years subgroup were significantly lower than that of the gain group (p<0.001, p=0.009, 0.012, and 0.012, respectively). WC reduction rate of at least about 3 % in the younger (<55 years) and at least about 5 % in the older (≥55 years) non-diabetic Japanese men with abdominal obesity can effectively reduce the chance of development of T2DM.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Obesidade Abdominal/complicações , Circunferência da Cintura/fisiologia , Redução de Peso/fisiologia , Idoso , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/fisiopatologia , Progressão da Doença , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/fisiopatologia , Fatores de RiscoRESUMO
In this study, we identify the bidirectional organic cation transporter 3 (OCT3/Slc22a3) as the molecule responsible for histamine uptake by murine basophils. We demonstrate that OCT3 participates in the control of basophil functions because exogenous histamine can inhibit its own synthesis--and that of interleukin (IL)-4, IL-6, and IL-13--through this means of transport. Furthermore, ligands of H3/H4 histamine receptors or OCT3 inhibit histamine uptake, and outward transport of newly synthesized histamine. By doing so, they increase the histamine content of basophils, which explains why they mimic the effect of exogenous histamine. These drugs were no longer effective in histamine-free histidine decarboxylase (HDC)-deficient mice, in contrast with histamine itself. Histamine was not taken up and lost its inhibitory effect in mice deficient for OCT3, which proved its specific involvement. Intracellular histamine levels were increased strongly in IL-3-induced OCT3-/- bone marrow basophils, and explained why they generated fewer cytokines than their wild-type counterpart. Their production was enhanced when histamine synthesis was blocked by the specific HDC inhibitor alpha-fluoro-methyl histidine, and underscored the determinant role of histamine in the inhibitory effect. We postulate that pharmacologic modulation of histamine transport might become instrumental in the control of basophil functions during allergic diseases.
Assuntos
Basófilos/metabolismo , Liberação de Histamina/fisiologia , Histamina/metabolismo , Histidina Descarboxilase/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Basófilos/citologia , Transporte Biológico Ativo/genética , Transporte Biológico Ativo/fisiologia , Citocinas/metabolismo , Liberação de Histamina/genética , Histidina Descarboxilase/genética , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Camundongos , Camundongos Knockout , Proteínas de Transporte de Cátions Orgânicos/genética , Receptores Histamínicos H3/metabolismoRESUMO
We have analyzed the role of histamine in the angiogenesis of the granulation tissue in histidine decarboxylase-deficient (HDC(-/-)) mice, mast cell-deficient mice (WBB6F1-W/W(V)), and their corresponding wild-type mice (HDC(+/+) and WBB6F(1)(+/+)). In HDC(+/+) mice, subcutaneous implantation of a cotton thread in the dorsum induced granulation tissue formation with angiogenesis, while the topical injection of anti-vascular endothelial growth factor (VEGF) IgG strongly suppressed them. In HDC(-/-) mice which showed lower VEGF levels in the granulation tissue, there was notably less angiogenesis and granulation tissue formation than in HDC(+/+) mice. The topical injection of histamine or the H(2) agonist dimaprit rescued the defective angiogenesis and granulation tissue formation in HDC(-/-) mice. There was no significant difference in the granulation tissue formation and angiogenesis between WBB6F1-W/W(V) and WBB6F1(+/+) mice. In addition, macrophages in the granulation tissue were found to express HDC. Our findings indicate that histamine derived from non-mast cells plays a significant role in the angiogenesis of the inflammatory granulation tissue.
Assuntos
Histamina/imunologia , Histidina Descarboxilase/imunologia , Mastócitos/imunologia , Neovascularização Patológica/imunologia , Animais , Dimaprit/farmacologia , Fatores de Crescimento Endotelial/biossíntese , Gossypium , Tecido de Granulação/imunologia , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Histidina Descarboxilase/genética , Linfocinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. The increased binding of remnant HDL was not mediated by the low-density lipoprotein receptor or scavenger receptor class B type I (SR-BI), because enhanced remnant HDL binding was observed in low-density lipoprotein receptor-deficient cells with or without SR-BI overexpression. Disruption of cell surface heparan sulfate proteoglycans or blockage of apolipoprotein E-mediated lipoprotein binding also did not abolish the enhanced remnant HDL binding. Our observations indicate that remodeling of triglyceride-enriched HDL by hepatic lipase may result in enhanced binding, internalization, and degradation in tissues involved in HDL catabolism, contributing to rapid clearance and overall lowering of plasma HDL cholesterol in insulin resistance and hypertriglyceridemia.
Assuntos
HDL-Colesterol/metabolismo , Hipertrigliceridemia/metabolismo , Resistência à Insulina/fisiologia , Rim/metabolismo , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismo , Anticoagulantes/farmacologia , Apolipoproteína A-I/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , VLDL-Colesterol/metabolismo , Heparina/farmacologia , Humanos , Hipertrigliceridemia/patologia , Rim/citologia , Rim/efeitos dos fármacos , Lipase/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Receptores Depuradores Classe B/metabolismoRESUMO
Sleep deprivation induces several negative effects on behavior, emotion, attention, and learning ability. Sleep appears to be particularly important during adolescent brain development. In the present study, we examined the effects of sleep deprivation on behavior and hypothalamic neurotransmission including histamine and orexin neurons in adolescent rats using the treadmill method. Adolescent male rats were divided into three groups: treadmill sleep-deprived, treadmill control, and cage control groups. Energy expenditure, anxiety-like behavior, and locomotor activity were examined among the three groups. Histamine concentration in the cortex and diencephalon and the number of c-Fos-positive neurons in the hypothalamus were also examined. In addition, histamine and orexin neurons in the hypothalamus were simultaneously identified using rat histidine decarboxylase and orexin-A immunohistochemistry, respectively. Both energy expenditure and anxiety-related behavior significantly increased by the experimental 3-day sleep deprivation, while exploratory locomotor activity significantly decreased. Histamine contents did not change in the cortex, but significantly decreased in the diencephalon of sleep-deprived rats. Increased expression of c-Fos-positive neurons, including subgroup histamine and orexin neurons, was observed in the hypothalamus. These findings indicate that sleep deprivation increases energy expenditure and anxiety in adolescent rats and provide evidence for the pivotal role of hypothalamus subgroup histamine and orexin neurons in the behavioral response to sleep deprivation.
Assuntos
Ansiedade , Histamina/fisiologia , Hipotálamo/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neurônios/fisiologia , Neuropeptídeos/fisiologia , Privação do Sono/psicologia , Transmissão Sináptica/fisiologia , Animais , Metabolismo Energético , Histamina/metabolismo , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Atividade Motora , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Orexinas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Privação do Sono/metabolismoRESUMO
STUDY OBJECTIVE: To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1. METHODS: Patients meeting the ICSD-2 criteria for narcolepsy with and without cataplexy and who had CSF hypocretin-1 results available were selected from the Stanford Narcolepsy Database on the basis of CSF availability and adequate age and sex matching across 3 groups: narcolepsy with low CSF hypocretin-1 (n=34, 100% with cataplexy), narcolepsy without low CSF hypocretin-1 (n=24, 75% with cataplexy), and normal controls (n=23). Low CSF hypocretin-1 was defined as CSF < or =110 pg/mL (1/3 of mean control values). Six of 34 patients with low CSF hypocretin-1, six of 24 subjects with normal CSF hypocretin-1, and all controls were unmedicated at the time of CSF collection. CSF histamine was measured in all samples using a fluorometric HPLC system. RESULTS: Mean CSF histamine levels were: 133.2 +/- 20.1 pg/mL in narcoleptic subjects with low CSF hypocretin-1, 233.3 +/- 46.5 pg/mL in patients with normal CSF hypocretin-1 (204.9 +/- 89.7 pg/mL if only patients without cataplexy are included), and 300.5 +/- 49.7 pg/mL in controls, reaching statistically significant differences between the 3 groups. CONCLUSION: CSF histamine levels are reduced in human narcolepsy. The reduction of CSF histamine levels was more evident in the cases with low CSF hypocretin-1, and levels were intermediate in other narcolepsy cases. As histamine is a wake-promoting amine known to decrease during sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.
Assuntos
Cataplexia/líquido cefalorraquidiano , Histamina/líquido cefalorraquidiano , Histamina/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/líquido cefalorraquidiano , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Narcolepsia/líquido cefalorraquidiano , Neuropeptídeos/líquido cefalorraquidiano , Neuropeptídeos/deficiência , Adulto , Cataplexia/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Narcolepsia/diagnóstico , Orexinas , Polissonografia , Valores de Referência , VigíliaRESUMO
Histamine H2 receptor (H2R) is a member of G protein-coupled receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the receptor, activation of extracellular signal-regulated kinases ERK1/2, and receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself.
Assuntos
Dinaminas/metabolismo , Endocitose/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H2/efeitos dos fármacos , Receptores Histamínicos H2/metabolismo , Animais , Células COS , Chlorocebus aethiops , AMP Cíclico/biossíntese , Dimaprit/farmacologia , Endocitose/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Humanos , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estrutura Terciária de Proteína/fisiologia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Receptores Histamínicos H2/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
CONTEXT: Low serum adiponectin (Ad) level is an important risk factor for the development of type 2 diabetes mellitus (T2DM). OBJECTIVE: To determine whether the changes in Ad in subjects with low baseline serum Ad levels can reduce the rate of development of T2DM. DESIGN/SETTING/PARTICIPANTS: We performed a large-scale longitudinal study of 7052 healthy Japanese men who underwent general health checkups more than twice between April 2007 and May 2015 at the Physical Check up Center, Sumitomo Hospital. The participants were divided into quartile groups according to baseline Ad level. Subjects of the lowest baseline Ad group (≤5.2 µg/mL) were subdivided into quartile subgroups according to the percent change in Ad (%ΔAd) and into two subgroups according to endpoint Ad (>5.2 and ≤5.2 µg/mL). MAIN OUTCOME MEASURES: The cumulative incidence rate of T2DM. RESULTS: The cumulative incidence rate of T2DM of the lowest baseline Ad group (≤5.2 µg/mL) was significantly higher than the other quartile groups. The cumulative incidence rates of T2DM were significantly lower in the largest (≥21.5%) and the second largest (9.3% to 21.4%) %ΔAd-increased subgroups compared with the %ΔAd-decreased subgroup (P < 0.001 and P = 0.005, respectively). The cumulative incidence rates of T2DM were significantly lower in the endpoint Ad >5.2 µg/mL subgroup than in the ≤5.2 µg/mL subgroup (P < 0.001). CONCLUSIONS: Increases in serum Ad levels of at least ~10% or >5.2 µg/mL can potentially reduce the risk of development of T2DM in Japanese men with low baseline Ad levels who are at a high risk of developing T2DM.
RESUMO
CONTEXT: Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects. PURPOSE: The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations. METHODS: We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m2) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ≥15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia. RESULTS: The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11). CONCLUSIONS: To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.
RESUMO
This study revealed that the absence of histamine in histidine decarboxylase gene-knockout (HDC(-/-)) mice resulted in delayed cutaneous wound healing and that exogenously administered histamine compensated this process. With the overproduction of histamine in HDC gene-transgenic mice, the healing was accelerated compared to the HDC(+/+) mice. These results indicate that histamine positively accelerated the cutaneous wound healing. Macrophage recruitment and angiogenesis at the wound edge were specifically impaired in HDC(-/-) mice, and histamine-treated wounds in HDC(-/-) mice demonstrated increased macrophage recruitment and angiogenesis. The amount of basic fibroblast growth factor (bFGF) in protein level at the wound edge was higher in HDC(+/+) mice, especially on the 3rd and 5th day of wound healing compared to those in HDC(-/-) mice. Topically administered SU5402, a specific antagonist to fibroblast growth factor receptor-1 tyrosine kinase, to the wound surface suppressed the wound healing in HDC(+/+) mice but not in HDC(-/-) mice. Moreover, SU5402 reduced macrophage recruitment and angiogenesis in HDC(+/+) mice. From these observations, it was concluded that the accelerated wound-healing activity of histamine was mediated by the activity of bFGF, which leads to angiogenesis, and macrophage recruitment in the wound-healing process.
Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Histamina/farmacologia , Histamina/fisiologia , Pele/metabolismo , Cicatrização/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Animais , Fator 2 de Crescimento de Fibroblastos/análise , Histidina Descarboxilase/genética , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Fisiológica/efeitos dos fármacos , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Pele/citologia , Pele/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/genética , Cicatrização/fisiologiaRESUMO
The hypothesis that histaminergic neurons are involved in brain arousal is supported by many studies. However, the effects of the selective long-term abolition of histaminergic neurons on the sleep-wake cycle, indispensable in determining their functions, remain unknown. We have compared brain histamine(HA)-immunoreactivity and the cortical-EEG and sleep-wake cycle under baseline conditions or after behavioral or pharmacological stimuli in wild-type (WT) and knock-out mice lacking the histidine decarboxylase gene (HDC-/-). HDC-/-mice showed an increase in paradoxical sleep, a decrease in cortical EEG power in theta-rhythm during waking (W), and a decreased EEG slow wave sleep/W power ratio. Although no major difference was noted in the daily amount of spontaneous W, HDC-/-mice showed a deficit of W at lights-off and signs of somnolence, as demonstrated by a decreased sleep latencies after various behavioral stimuli, e.g., WT-mice placed in a new environment remained highly awake for 2-3 hr, whereas HDC-/-mice fell asleep after a few minutes. These effects are likely to be attributable to lack of HDC and thus of HA. In WT mice, indeed, intraperitoneal injection of alpha-fluoromethylhistidine (HDC-inhibitor) caused a decrease in W, whereas injection of ciproxifan (HA-H3 receptor antagonist) elicited W. Both injections had no effect in HDC-/-mice. Moreover, PCR and immunohistochemistry confirmed the absence of the HDC gene and brain HA-immunoreactive neurons in the HDC-/-mice. These data indicate that disruption of HA-synthesis causes permanent changes in the cortical-EEG and sleep-wake cycle and that, at moments when high vigilance is required (lights off, environmental change em leader ), mice lacking brain HA are unable to remain awake, a prerequisite condition for responding to behavioral and cognitive challenges. We suggest that histaminergic neurons also play a key role in maintaining the brain in an awake state faced with behavioral challenges.
Assuntos
Encéfalo/metabolismo , Ritmo Circadiano/fisiologia , Histamina/metabolismo , Histidina Descarboxilase/deficiência , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Eletrodos Implantados , Eletroencefalografia/efeitos dos fármacos , Eletromiografia , Inibidores Enzimáticos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histidina Descarboxilase/antagonistas & inibidores , Histidina Descarboxilase/genética , Imidazóis/farmacologia , Masculino , Metilistidinas/farmacologia , Camundongos , Camundongos Knockout , Fenótipo , Reação em Cadeia da Polimerase , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Sono REM/efeitos dos fármacos , Sono REM/fisiologia , Ritmo Teta/efeitos dos fármacos , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
Both phencyclidine (PCP) and methamphetamine (MAP) can cause schizophrenia-like symptoms. To identify the molecules relating to the drug-induced psychotic state, we used serial analysis of gene expression in rodent cerebral cortices isolated 1 h after intraperitoneal injection of saline, PCP (10 mg/kg), or MAP (4 mg/kg). We analyzed a total of 150,000 tags and found significantly up- or down-regulated genes. The number of MAP-, PCP-, and MAP and PCP-reactive tags were 229, 215, and 41, respectively.
Assuntos
Córtex Cerebral/fisiologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Metanfetamina/farmacologia , Fenciclidina/farmacologia , Animais , Sequência de Bases , Córtex Cerebral/efeitos dos fármacos , Dano ao DNA , Primers do DNA , Injeções Intraperitoneais , Metanfetamina/administração & dosagem , Proteínas do Tecido Nervoso/genética , Fenciclidina/administração & dosagem , RatosRESUMO
The precise biochemical mechanisms underlying the reduction of HDL levels in hypertriglyceridemic states are currently not known. In humans, we showed that triglyceride (TG) enrichment of HDL, as occurs in hypertriglyceridemic states, enhances the clearance of HDL-associated apolipoprotein A-I (apoA-I) from the circulation. In the New Zealand White rabbit (an animal model naturally deficient in hepatic lipase [HL]), however, TG enrichment of HDL is not sufficient to alter the clearance of either the protein or lipid moieties of HDL. In the present study, therefore, we determined in the New Zealand White rabbit the combined effects of ex vivo TG enrichment and lipolytic transformation of HDL by HL on the subsequent metabolic clearance of HDL apoA-I. Results of the in vivo kinetic studies (n=18 animals) showed that apoA-I associated with TG-enriched rabbit HDL modified ex vivo by catalytically active HL was cleared 22% more rapidly versus TG-enriched HDL incubated with heat-inactivated HL, and 26% more rapidly than fasting (TG-poor) HDL incubated with active HL (P<0.05 for both). Furthermore, a strong correlation was observed between the HDL TG content and apoA-I fractional catabolic rate (0.59, P<0.05) in the combined active HL groups. These data establish that TG enrichment of HDL with subsequent lipolysis by HL enhances HDL apoA-I clearance, but neither TG enrichment of HDL without HL lipolysis nor HL lipolysis in the absence of previous TG enrichment of HDL is sufficient to enhance HDL clearance. These data further support the important interaction between HDL TG enrichment and HL action in the pathogenesis of HDL lowering in hypertriglyceridemic states.
Assuntos
Hipertrigliceridemia/sangue , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Triglicerídeos/metabolismo , Animais , Apolipoproteína A-I/sangue , Hipertrigliceridemia/metabolismo , Cinética , Lipase/metabolismo , Lipólise , Lipoproteínas HDL/química , Fígado/enzimologia , Masculino , Coelhos , Triglicerídeos/análiseRESUMO
We previously reported that histamine H(1) receptor gene knockout mice (H1KO) showed lower spontaneous nociceptive threshold to pain stimuli when compared to wild-type mice. The objective of the present study was to examine the antinociceptive effect of intrathecally-administered morphine in H1KO mice. The antinociceptive effects of morphine were examined using assays for thermal (tail-flick, hot-plate, paw-withdrawal), mechanical (tail-pressure) and chemical nociception (formalin and capsaicin tests) using H1KO and wild-type mice. In these nociceptive assays, intrathecally-administered morphine produced significant antinociceptive effects in wild-type mice. The antinociceptive effect produced by intrathecally administered morphine was enhanced in the knockout mice. We also examined the effect of an histamine H(1) receptor antagonist, an active (d-) isomer of chlorpheniramine, on morphine-induced antinociception in ICR mice. The intrathecal co-administration of d-chlorpheniramine enhanced the effect of morphine in all nociceptive assays examined. The pharmacological experiments using d-chlorpheniramine further substantiate the evidence for the histamine H(1) receptor-mediated suppression of morphine-induced antinociception. These results suggest that existing H(1) receptors play an inhibitory role in morphine-induced antinociception at the spinal cord level.
Assuntos
Analgésicos/farmacologia , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Receptores Histamínicos H1/deficiência , Receptores Histamínicos H1/genética , Animais , Clorfeniramina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Temperatura Alta , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Medição da Dor/métodos , Estimulação Física , Estimulação QuímicaRESUMO
1 Carcinine (beta-alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. 2 Carcinine was highly selective for the histamine H3 receptor over H1 or H2 receptor (Ki (microM)=0.2939+/-0.2188 vs 3621.2+/-583.9 or 365.3+/-232.8 microM, respectively). 3 Carcinine at a dose of 20 mg kg(-1) slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186+/-0.069 to 0.227+/-0.009 pmol mg protein(-1) min(-1)). In addition, carcinine (10, 20, and 50 mg kg(-1)) significantly decreased histamine levels in mice brain. 4 Like thioperamide, a histamine H3 receptor antagonist, carcinine (20, 50 microM) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. 5 Carcinine (20 mg kg(-1)) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completely reversed by (R)-alpha-methylhistamine, a representative H3 receptor agonist, and alpha-fluromethylhistidine, a selective HDC inhibitor. 6 Carcinine (20 mg kg(-1)) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)-alpha-methylhistamine as evaluated by the passive avoidance test in mice. 7 Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. 8 The results of this study provide first and direct evidence that carcinine, as a novel histamine H3 receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit.
Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Carnosina/análogos & derivados , Carnosina/farmacologia , Histamina/fisiologia , Neurônios/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Convulsivantes/farmacologia , Dopamina/metabolismo , Histamina/metabolismo , Histidina Descarboxilase/metabolismo , Técnicas In Vitro , Excitação Neurológica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Pentilenotetrazol/farmacologia , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Receptores Histamínicos H3/efeitos dos fármacos , Escopolamina/antagonistas & inibidores , Escopolamina/farmacologia , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Serotonina/metabolismoRESUMO
The central histamine (HA) neurons that originate from the posterior hypothalamus modulate a variety of physiological functions. In order to investigate the roles of brain histaminergic neuron system in the behavioral effects of methamphetamine (METH), we administrated METH repeatedly to L-histidine decarboxylase (HDC)-, histamine H1 receptor-, H2 receptor-gene knockout (KO) mice, H1/H2 receptor-gene double KO mice, and wild type (WT) mice corresponding to each of them, and we measured locomotor activities. We also measured the contents of monoamines and amino acids in the brain of HDC-gene KO and WT mice after a single administration of METH. METH-induced locomotor hyperactivity and the development of behavioral sensitization were facilitated more in the HDC-gene KO mice and H1/H2 gene double KO mice than the WT mice, suggesting that brain histamine has an inhibitory effect on the METH action through both H1 and H2 receptors. In addition, neurochemical study suggested the involvement of the GABAergic neuron system in the inhibitory effect of brain histamine.
Assuntos
Encéfalo/efeitos dos fármacos , Histamina/deficiência , Metanfetamina/farmacologia , Animais , Encéfalo/metabolismo , Histamina/genética , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Receptores Histamínicos H1/deficiência , Receptores Histamínicos H1/genética , Receptores Histamínicos H2/deficiência , Receptores Histamínicos H2/genéticaRESUMO
The role of brain histamine on seizure development of pentylenetetrazol (PTZ)-induced kindling was examined in H(1)-receptor gene knockout (H(1)KO), histidine decarboxylase-deficient (HDC(-/-)) and mast cell-deficient (W/W(v)) mice. All H(1)KO, HDC(-/-) and W/W(v) mice had accelerated seizure development of PTZ-induced kindling when compared to their respective wild-type mice. The daily PTZ-kindling increased histamine content in the cortex and diencephalon of H(1)KO mice, whereas the histamine content in the diencephalon of W/W(v) mice was decreased. The present study indicates that histamine plays a suppressive role in seizure development through H(1)-receptors.
Assuntos
Convulsivantes/efeitos adversos , Histidina Descarboxilase/metabolismo , Mastócitos/fisiologia , Pentilenotetrazol/efeitos adversos , Receptores Histamínicos H1/metabolismo , Convulsões/induzido quimicamente , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica , Convulsivantes/administração & dosagem , Histamina/análise , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Pentilenotetrazol/administração & dosagem , Receptores Histamínicos H1/deficiência , Receptores Histamínicos H1/genética , Convulsões/genética , Convulsões/metabolismo , Estatísticas não ParamétricasRESUMO
Intrathecal (i.t.) injection of histamine elicited a significant hyperalgesic response as assayed by the tail-flick test. This hyperalgesic effect peaked at 15 min following i.t. administration of histamine (800 pmol) and returned to control level with 30 min. Hyperalgesia produced by histamine was inhibited dose-dependently by i.t. co-administration of the histamine H(1) receptor antagonist, d-chlorpheniramine, but not the histamine H(2) receptor antagonist, ranitidine. The tachykinin NK(1) receptor antagonists, (+)-[(2S,3S)-3-(2-methoxy-benzyl-amino)-2-phenylpiperidine] (CP-99,994), and [Tyr(6), D-Phe(7), D-His(9)]substance P-(6-11) (sendide), inhibited histamine-induced hyperalgesic response in a dose-dependent manner. A significant antagonistic effect of [D-Phe(7), D-His(9)]substance P-(6-11), a selective antagonist for substance P receptors, was observed against histamine-induced hyperalgesic response. The tachykinin NK(2) receptor antagonist, Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH(2) (MEN-10,376), had no effect on hyperalgesia elicited by histamine. The competitive N-methyl-D-aspartate (NMDA) receptor antagonists, and D-(-)-2-amino-5-phosphonovaleric acid (D-APV), (+/-)-3-(2-carboxypiperazin-yl)propyl-1-phosphoric acid (CPP), the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), and L-N(G)-nitro arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, markedly inhibited histamine-induced hyperalgesic response. The present results suggest that hyperalgesic response induced by i.t. injection of histamine may be mediated by tachykinin NK(1) receptors, but not NK(2) receptors in the spinal cord. In addition, spinal NMDA receptor-NO system may also contribute to elicitation of hyperalgesia following i.t. injection of histamine.
Assuntos
Histamina/farmacologia , Hiperalgesia/induzido quimicamente , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores da Neurocinina-1/fisiologia , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Masculino , Camundongos , Piperidinas/farmacologiaRESUMO
Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.
Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Metanfetamina/farmacologia , Animais , Área Sob a Curva , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/farmacocinética , Estimulantes do Sistema Nervoso Central/farmacologia , Clorfeniramina/farmacologia , Interações Medicamentosas , Masculino , Metanfetamina/sangue , Metanfetamina/farmacocinética , Atividade Motora/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Distribuição TecidualRESUMO
Hypertriglyceridemia, low plasma concentrations of high density lipoproteins (HDL) and qualitative changes in low density lipoproteins (LDL) comprise the typical dyslipidemia of insulin resistant states and type 2 diabetes. Although isolated low plasma HDL-cholesterol (HDL-c) and apolipoprotein A-I (apo A-I, the major apolipoprotein component of HDL) can occur in the absence of hypertriglyceridemia or any other features of insulin resistance, the majority of cases in which HDL-c is low are closely linked with other clinical features of insulin resistance and hypertriglyceridemia. We and others have postulated that triglyceride enrichment of HDL particles secondary to enhanced CETP-mediated exchange of triglycerides and cholesteryl ester between HDL and triglyceride-rich lipoproteins, combined with the lipolytic action of hepatic lipase (HL), are driving forces in the reduction of plasma HDL-c and apoA-I plasma concentrations. The present review focuses on these metabolic alterations in insulin resistant states and their important contributions to the reduction of HDL-c and HDL-apoA-I plasma concentrations.