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1.
Anat Histol Embryol ; 49(4): 440-450, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32128873

RESUMO

The present study was conducted to evaluate the effect of histamine and to characterise its receptor subtypes in reticular groove (RG) smooth muscle of adult goats. The studies were done using floor and lip regions of RG. We used tension experiments on smooth muscle of RG isolated from adult goat for functional characterisation of H1 and H2 receptors. Western blotting and immunohistochemistry experiments were conducted for molecular characterisation of these receptors. Histamine evoked concentration-dependent contraction of isolated RG circular and longitudinal smooth muscle preparation. Pyrilamine antagonised the action of histamine. Histamine did not induce any relaxant effect on RG preparations. Additionally, cimetidine did not produce any significant effect on histamine-induced response. Non-selective histaminic receptor antagonist cyproheptadine attenuated the contraction response to histamine in the smooth muscle. Molecular characterisation and localisation of H1 and H2 receptor proteins confirmed the presence of these receptors in RG. It is most likely that histamine-induced contractile effect in RG smooth muscle of goats is mediated by H1 histaminic receptors.


Assuntos
Cabras/metabolismo , Histamina/metabolismo , Músculo Liso/fisiologia , Receptores Histamínicos/fisiologia , Estômago de Ruminante/fisiologia , Animais , Western Blotting , Cimetidina/farmacologia , Ciproeptadina/farmacologia , Relação Dose-Resposta a Droga , Cabras/anatomia & histologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Imuno-Histoquímica , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Pirilamina/farmacologia , Receptores Histamínicos/classificação , Estômago de Ruminante/anatomia & histologia
2.
PLoS One ; 14(8): e0220776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437163

RESUMO

Cell-to-cell communication is a key element of microvascular blood flow control, including rapidly carrying signals through the vascular endothelium in response to local stimuli. This cell-to-cell communication is negatively impacted during inflammation through the disruption of junctional integrity. Such disruption is associated with promoting the onset of cardiovascular diseases as a result of altered microvascular blood flow regulation. Therefore, understanding the mechanisms how inflammation drives microvascular dysfunction and compounds that mitigate such inflammation and dysfunction are of great interest for development. As such we aimed to investigate extracts of mushrooms as potential novel compounds. Using intravital microscopy, the medicinal mushroom, Inonotus obliquus was observed, to attenuate histamine-induced inflammation conducted vasodilation in second-order arterioles in the gluteus maximus muscle of C57BL/6 mice. Mast cell activation by C48/80 similarly disrupted endothelial junctions and conducted vasodilation but only histamine was blocked by the histamine antagonist, pyrilamine not C48/80 suggesting the importance of mast cell activation. Data presented here supports that histamine induced inflammation is a major disruptor of junctional integrity, and highlights the important anti-inflammatory properties of Inonotus obliquus focusing future assessment of mast cells as putative target for Inonotus obliquus.


Assuntos
Basidiomycota/isolamento & purificação , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Agaricales/isolamento & purificação , Agaricales/metabolismo , Animais , Arteríolas/efeitos dos fármacos , Basidiomycota/metabolismo , Endotélio Vascular/efeitos dos fármacos , Histamina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Pirilamina/farmacologia , Vasodilatação/efeitos dos fármacos
3.
Sci Rep ; 9(1): 7906, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133718

RESUMO

Drug-target binding kinetics are suggested to be important parameters for the prediction of in vivo drug-efficacy. For G protein-coupled receptors (GPCRs), the binding kinetics of ligands are typically determined using association binding experiments in competition with radiolabelled probes, followed by analysis with the widely used competitive binding kinetics theory developed by Motulsky and Mahan. Despite this, the influence of the radioligand binding kinetics on the kinetic parameters derived for the ligands tested is often overlooked. To address this, binding rate constants for a series of histamine H1 receptor (H1R) antagonists were determined using radioligands with either slow (low koff) or fast (high koff) dissociation characteristics. A correlation was observed between the probe-specific datasets for the kinetic binding affinities, association rate constants and dissociation rate constants. However, the magnitude and accuracy of the binding rate constant-values was highly dependent on the used radioligand probe. Further analysis using recently developed fluorescent binding methods corroborates the finding that the Motulsky-Mahan methodology is limited by the employed assay conditions. The presented data suggest that kinetic parameters of GPCR ligands depend largely on the characteristics of the probe used and results should therefore be viewed within the experimental context and limitations of the applied methodology.


Assuntos
Ligação Competitiva , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Sondas Moleculares/química , Ensaio Radioligante/métodos , Receptores Histamínicos H1/metabolismo , Cetirizina/química , Cetirizina/farmacocinética , Conjuntos de Dados como Assunto , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Células HEK293 , Antagonistas dos Receptores Histamínicos H1/química , Humanos , Ligantes , Sondas Moleculares/farmacocinética , Cloridrato de Olopatadina/química , Cloridrato de Olopatadina/farmacocinética , Ligação Proteica , Pirilamina/química , Pirilamina/farmacocinética , Trítio
4.
Neuropharmacology ; 151: 64-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30943384

RESUMO

Behavioral studies using pharmacological tools have implicated histamine H1 receptors in cognitive function via their interactions with N-methyl-D-aspartate receptors (NMDARs) in the hippocampus. However, little is known about the neurophysiological mechanism that underlies the interaction between H1 receptors and NMDARs. To explore how H1 receptor activation affects hippocampal excitatory neurotransmission and synaptic plasticity, this study aimed to examine the effect of H1 receptor ligands on both NMDAR-mediated synaptic currents and long-term potentiation (LTP) at synapses between Schaffer collaterals and CA1 pyramidal neurons using acute mouse hippocampal slices. We found that the H1 receptor antagonist/inverse agonists, pyrilamine (0.1 µM) and cetirizine (10 µM), decreased the NMDAR-mediated component of stimulation-induced excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons without affecting the AMPA receptor-mediated component of EPSCs and its paired pulse ratio. Pretreatment of slices with either the glial metabolism inhibitor, fluoroacetate (5 mM), or D-serine (100 µM) diminished the pyrilamine- or cetirizine-induced attenuation of the NMDAR-mediated EPSCs. Furthermore, the LTP of field excitatory postsynaptic potentials induced following high frequency stimulation of Schaffer collaterals was attenuated with application of pyrilamine or cetirizine. Pretreatment with D-serine again attenuated the pyrilamine-induced suppression of LTP. Our data suggest that H1 receptors in the CA1 can undergo persistent activation induced by their constitutive receptor activity and/or tonic release of endogenous histamine, resulting in facilitation of the NMDAR activity in a manner dependent of astrocytes and the release of D-serine. This led to the enhancement of NMDA-component EPSC and LTP at the Schaffer collateral-CA1 pyramidal neuron synapses.


Assuntos
Astrócitos/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Serina/farmacologia , Animais , Astrócitos/metabolismo , Região CA1 Hipocampal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Camundongos , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirilamina/farmacologia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Valina/análogos & derivados , Valina/farmacologia
5.
Sci Rep ; 9(1): 3899, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846750

RESUMO

The mechanisms underlying bladder contractile disorders such as overactive bladder are not fully understood, and there is limited understanding of the receptor systems modulating spontaneous bladder contractions. We investigated the potential for histamine to have a role in mediating contractility of the urothelium with lamina propria (U&LP) or detrusor via the H1-H4 histamine receptor subtypes. Isolated strips of porcine U&LP or detrusor smooth muscle were mounted in gassed Krebs-bicarbonate solution and responses to histamine obtained in the absence and presence of selective receptor antagonists. The presence of histamine increases the frequency of U&LP spontaneous phasic contractions and baseline tensions. In response to histamine, H1-antagonists pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting contractile responses. Cimetidine (H2-antagonist) enhanced increases in baseline tension in response histamine, whereas amthamine (H2-agonist) induced relaxation. Although thioperamide (H3/H4-antagonist) increased baseline tension responses to histamine, selective H1/H2-receptor antagonism revealed no influence of these receptors. In detrusor preparations, pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting baseline tension increases in response to histamine. Our findings provide evidence that histamine produces contractile responses both in the U&LP and detrusor via the H1-receptor, and this response is significantly inhibited by activation of the H2-receptor in the U&LP but not the detrusor.


Assuntos
Histamina/farmacologia , Membrana Mucosa/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H2/metabolismo , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Animais , Ciproeptadina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Membrana Mucosa/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Pirilamina/farmacologia , Suínos , Terfenadina/análogos & derivados , Terfenadina/farmacologia , Bexiga Urinária/metabolismo , Urotélio/metabolismo
6.
BMC Vet Res ; 15(1): 55, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744618

RESUMO

BACKGROUND: H1 receptor antagonists are commonly used for the treatment of allergic diseases. The aim of this study was to find out, if antihistaminic compounds like mepyramine have the ability to influence the activity of antibacterials. Therefore, the checkerboard method was chosen to detect these possible effects in vitro. Studies were performed with two different Escherichia coli (E. coli) strains as test microbes, treated with antibacterials in combination with mepyramine. RESULTS: The minimum inhibitory concentration (MIC) of E. coli ATCC® 25922™ and E. coli PIG 01 was reduced by combinations of the tested antibacterials with mepyramine. CONCLUSIONS: These results have to be confirmed in vivo, before the use of antihistamines should be considered as potential way to minimize the amount of used antibacterials for treatment of E. coli infections.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antibacterianos/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Pirilamina/administração & dosagem , Pirilamina/farmacologia
7.
Physiol Res ; 68(Suppl 3): S275-S285, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31928045

RESUMO

Pulmonary surfactant has a relaxing effect on the airway smooth muscle (ASM), which suggests its role in the pathogenesis of respiratory diseases associated with hyperreactivity of the ASM, such as asthma and chronic obstructive pulmonary disease (COPD). The ASM tone may be directly or indirectly modified by bacterial wall component lipopolysaccharide (LPS). This study elucidated the effect of LPS on the ASM reactivity and the role of surfactant in this interaction. The experiments were performed using ASM of adult guinea pigs by in vitro method of tissue organ bath (ASM unexposed-healthy or exposed to LPS under in vitro conditions) and ASM of animals intraperitoneally injected with LPS at a dose 1 mg/kg of b.w. once a day during 4-day period. Variable response of LPS was controlled by cyclooxygenase inhibitor indomethacin and relaxing effect of exogenous surfactant was studied using leukotriene and histamine receptor antagonists. The exogenous surfactant has relaxing effect on the ASM, but does not reverse LPS-induced smooth muscle contraction. The results further indicate participation of prostanoids and potential involvement of leukotriene and histamine H1 receptors in the airway smooth muscle contraction during LPS exposure.


Assuntos
Músculo Liso/efeitos dos fármacos , Surfactantes Pulmonares/farmacologia , Acetatos , Animais , Cobaias , Lipopolissacarídeos , Masculino , Relaxamento Muscular/efeitos dos fármacos , Pirilamina , Quinolinas
8.
J Chromatogr Sci ; 56(10): 903-911, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085004

RESUMO

The pharmaceutical combination of dexpanthenol (DPA), lidocaine hydrochloride (LIH) and mepyramine maleate (MAM) is used for their anti-allergic, anti-inflammatory, anti-pruritic, anesthetic and antiseptic properties. The present study was aimed to develop and validate a new, first and rapid high performance liquid chromatographic method for simultaneous determination of DPA, LIH and MAM in the presence of their stress-induced degradation products in pharmaceutical gel/fluigel formulations. The chromatographic separation was performed on an Inertsil ODS-3 V, 250 × 4.6 mm (5 µm) column using a gradient mobile phase of an aqueous solution of ammonium acetate (0.01 M) and methanol mixture at gradient flow rates of 1.3 mL/min and 1.5 mL/min with detection at 230 nm. The retention times for DPA, LIH and MAM were ~3.28 min, 11.67 min and 12.99 min, respectively. The method was validated in accordance with International Conference on Harmonisation guidelines. Calibration curves were linear in the ranges of 9-54 µg/mL for MAM and LIH and 30-180 µg/mL for DPA with satisfactory correlation coefficients (R2 > 0.999). The mean % recoveries obtained were found to be 99.9% for MAM, 100.3% for LIH and 99.3% for DPA. Precision % RSD was <2. Robustness results were uniform, there were no marked changes, so method is highly validated. All drugs were subjected to stress conditions and degradation products were separated with acceptable peak tailing (T ≤ 2) and good resolution (Rs > 2). The validated method therefore can be adapted for quality control procedures of the drugs in pharmaceutical dosage forms and their stability studies.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Lidocaína/análise , Ácido Pantotênico/análogos & derivados , Pirilamina/análise , Lidocaína/química , Limite de Detecção , Modelos Lineares , Pomadas , Ácido Pantotênico/análise , Ácido Pantotênico/química , Pirilamina/química , Reprodutibilidade dos Testes
9.
J Recept Signal Transduct Res ; 38(3): 204-212, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29863427

RESUMO

CONTEXT: Mast cell (MC) activation through H4R releases various inflammatory mediators which are associated with allergic asthma. OBJECTIVES: To investigate the siRNA-mediated gene silencing effect of H4R on human mast cells (HMCs) functions and the activation of stress-activated protein kinases (SAPK)/jun amino-terminal kinases (JNK) signaling pathways for the release of ineterleukin-1ß (IL-1ß) in HMCs. MATERIALS AND METHODS: H4R expression was analyzed by RT-PCR and western blotting in human mast cell line-1 (HMC-1) cells and H4RsiRNA transfected cells. The effect of H4RsiRNA and H4R-antagonist on H4R mediated MC functions such as intracellular Ca2+ release, degranulation, IL-6 and IL-1ß release, and the activation SAPK/JNK signaling pathways were studied. HMC-1 cells were stimulated with 10 µM of histamine (His) and 4-methylhistamine (4-MH) and pretreated individually with H4R-antagonist JNJ7777120 (JNJ), histamine H1 receptor (H1R)-antagonist mepyramine, and signaling molecule inhibitors SP600125 (SP) and Bay117082. RESULTS: We found that the HMC-1 cells expressed H4R and H4RsiRNA treatment down regulated the H4R expression in HMC-1 cells. Both His and 4-MH induced the intracellular Ca2+ release and degranulation whereas; H4R siRNA and JNJ inhibited the effect. Furthermore, the activation of H4R caused the phosphorylation of SAPK/JNK pathways. H4R gene silencing and pretreatment with SP and JNJ decreased His and 4-MH induced phosphorylation of SAPK/JNK. We found that the activation of H4R caused the release of IL-1ß (124.22 pg/ml) and IL-6 (122.50 pg/ml) on HMC-1 cells. Whereas, SAPK/JNK inhibitor (68.36 pg/ml) inhibited the H4R mediated IL-1ß release. CONCLUSIONS: Taken together, the silencing of H4R inhibited the H4R mediated MC functions and SAPK/JNK phosphorylation. Furthermore, the H4R activation utilized SAPK/JNK signaling pathway for IL-1ß release in HMC-1 cells.


Assuntos
Interleucina-1beta/genética , MAP Quinase Quinase 4/genética , Mastócitos/metabolismo , Receptores Histamínicos H4/genética , Cálcio/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Histamina/farmacologia , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Metilistaminas/farmacologia , Piperazinas/farmacologia , Pirilamina/farmacologia , RNA Interferente Pequeno/genética , Receptores Histamínicos H4/antagonistas & inibidores
10.
Pharmacol Biochem Behav ; 170: 14-24, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29729290

RESUMO

Novel non-imidazole histamine H3 receptor (H3R) antagonists (2-8) were developed and assessed for in-vitro antagonist binding affinities at the human histamine H1-H4R. These novel H3R antagonists (2-8) were examined in-vivo for anticonvulsant effects in three different convulsion models in male adult rats. Compound 6 significantly and dose-dependently exhibited decreased duration of tonic hind limb extension (THLE) in the maximal electroshock (MES)- and fully protected animals against pentylenetetrazole (PTZ)-induced convulsion, following acute systemic administration (5, 10, and 20 mg/kg, i.p.). Contrary, all compounds 2-8 showed moderate protection in the strychnine (STR)-induced convulsion model following acute pretreatment (10 mg/kg, i.p.). Moreover, the acute systemic administration of H3R antagonist 6 (10 mg/kg, i.p.) significantly prolonged latency time for MES convulsions. Furthermore, the anticonvulsant effect observed with compound 6 in MES-model was entirely abrogated when rats were co-injected with the brain penetrant H1R antagonist pyrilamine (PYR) but not the brain penetrant H2R antagonist zolantidine (ZOL). However, PYR and ZOL failed to abolish the full protection provided by the H3R antagonist 6 in PTZ- and STR-models. No mutagenic or antiproliferative effects or potential metabolic interactions were shown for compound 6 when assessing its antiproliferative activities and metabolic profiling applying in-vitro methods. These findings demonstrate the potential of non-imidazole H3R antagonists as novel antiepileptic drugs (AEDs) either for single use or in addition to currently available epilepsy medications.


Assuntos
Anticonvulsivantes/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Convulsões/tratamento farmacológico , Animais , Benzotiazóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Masculino , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Pirilamina/farmacologia , Ratos , Ratos Wistar , Tempo de Reação , Estricnina/farmacologia
11.
Am J Chin Med ; 46(1): 55-68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29298517

RESUMO

This study investigated the influence of the histamine H1 receptor antagonists, chlorpheniramine (CHL) and pyrilamine, on the analgesic effects of acupuncture in mice. Nociceptive response was evaluated by the acetic acid-induced abdominal writhe test. Electroacupuncture (EA) at bilateral ST36 reduced the manifestations of acetic acid-induced abdominal writhing, whereas needle insertion without electrostimulation had no such effect. Notably, EA treatment was not associated with any analgesic effects in mice pretreated with naloxone. Low doses of CHL (0.6[Formula: see text]mg/kg; p.o.) or pyrilamine (2.5[Formula: see text]mg/kg; i.p.) as monotherapy did not affect acetic acid-induced abdominal writhing. However, when each agent was combined with EA, acetic acid-induced abdominal writhing was reduced by a greater extent when compared with EA alone. Interestingly, the effects of CHL on acupuncture analgesia were not completely reversed by naloxone treatment. Acetic acid induced increases of phospho-p38 expression in spinal cord, as determined by immunofluorescence staining and Western blot analysis. These effects were attenuated by EA at ST36 and by low doses of histamine H1 receptor antagonists, alone or in combination. Our findings show that relatively low doses of histamine H1 receptor antagonists facilitate EA analgesia via non-opioid receptors. These results suggest a useful strategy for increasing the efficacy of EA analgesia in a clinical situation.


Assuntos
Dor Abdominal/fisiopatologia , Dor Abdominal/terapia , Clorfeniramina/administração & dosagem , Clorfeniramina/farmacologia , Eletroacupuntura , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Pirilamina/administração & dosagem , Pirilamina/farmacologia , Estimulação Elétrica Nervosa Transcutânea/métodos , Dor Abdominal/induzido quimicamente , Ácido Acético/efeitos adversos , Animais , Combinação de Medicamentos , Masculino , Camundongos Endogâmicos ICR , Medição da Dor
12.
J Neurochem ; 144(1): 68-80, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29063596

RESUMO

Gq/11 protein-coupled human histamine H1 receptors in Chinese hamster ovary cells stimulated with histamine undergo clathrin-dependent endocytosis followed by proteasome/lysosome-mediated down-regulation. In this study, we evaluated the effects of a sustained increase in intracellular Ca2+ concentrations induced by a receptor-bypassed stimulation with ionomycin, a Ca2+ ionophore, on the endocytosis and down-regulation of H1 receptors in Chinese hamster ovary cells. All cellular and cell-surface H1 receptors were detected by the binding of [3 H]mepyramine to intact cells sensitive to the hydrophobic and hydrophilic H1 receptor ligands, mepyramine and pirdonium, respectively. The pretreatment of cells with ionomycin markedly reduced the mepyramine- and pirdonium-sensitive binding sites of [3 H]mepyramine, which were completely abrogated by the deprivation of extracellular Ca2+ and partially by a ubiquitin-activating enzyme inhibitor (UBEI-41), but were not affected by inhibitors of calmodulin (W-7 or calmidazolium) and protein kinase C (chelerythrine or GF109203X). These ionomycin-induced changes were also not affected by inhibitors of receptor endocytosis via clathrin (hypertonic sucrose) and caveolae/lipid rafts (filipin or nystatin) or by inhibitors of lysosomes (E-64, leupeptin, chloroquine, or NH4 Cl), proteasomes (lactacystin or MG-132), and a Ca2+ -dependent non-lysosomal cysteine protease (calpain) (MDL28170). Since H1 receptors were normally detected by confocal immunofluorescence microscopy with an antibody against H1 receptors, even after the ionomycin treatment, H1 receptors appeared to exist in a form to which [3 H]mepyramine was unable to bind. These results suggest that H1 receptors are apparently down-regulated by a sustained increase in intracellular Ca2+ concentrations with no process of endocytosis and lysosomal/proteasomal degradation of receptors.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/farmacologia , Receptores Histamínicos H1/biossíntese , Animais , Astrocitoma , Células CHO , Ionóforos de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Calmodulina/antagonistas & inibidores , Calpaína/antagonistas & inibidores , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Regulação para Baixo/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Histamina/farmacologia , Humanos , Fosfatos de Inositol/metabolismo , Ionomicina/farmacologia , Lisossomos/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirilamina/metabolismo , Receptores Histamínicos H1/genética , Proteínas Recombinantes/biossíntese
13.
Int Rev Neurobiol ; 137: 65-98, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29132544

RESUMO

The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist α-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.


Assuntos
Nanofios/administração & dosagem , Óxido Nítrico Sintase Tipo I/metabolismo , Receptores Histamínicos/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/prevenção & controle , Regulação para Cima/fisiologia , Animais , Cimetidina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Pirilamina/administração & dosagem , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
14.
Life Sci ; 188: 76-82, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28866099

RESUMO

AIMS: Nicotine is rapidly absorbed from the lung alveoli into systemic circulation during cigarette smoking. However, mechanism underlying nicotine transport in alveolar epithelial cells is not well understood to date. In the present study, we characterized nicotine uptake in lung epithelial cell lines A549 and NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. MATERIALS AND METHODS: Characteristics of [3H]nicotine uptake was studied using these cell lines. KEY FINDINGS: Nicotine uptake in A549 cells occurred in a time- and temperature-dependent manner and showed saturation kinetics, with a Km value of 0.31mM. Treatment with some organic cations such as diphenhydramine and pyrilamine inhibited nicotine uptake, whereas treatment with organic cations such as carnitine and tetraethylammonium did not affect nicotine uptake. Extracellular pH markedly affected nicotine uptake, with high nicotine uptake being observed at high pH up to 11.0. Modulation of intracellular pH with ammonium chloride also affected nicotine uptake. Treatment with valinomycin, a potassium ionophore, did not significantly affect nicotine uptake, indicating that nicotine uptake is an electroneutral process. For comparison, we assessed the characteristics of nicotine uptake in another lung epithelial cell line NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. Interestingly, these cell lines showed similar characteristics of nicotine uptake with respect to pH dependency and inhibition by various organic cations. SIGNIFICANCE: The present findings suggest that a similar or the same pH-dependent transport system is involved in nicotine uptake in these cell lines. A novel molecular mechanism of nicotine transport is proposed.


Assuntos
Transporte Biológico/efeitos dos fármacos , Células Epiteliais/metabolismo , Pulmão/metabolismo , Nicotina/farmacocinética , Carnitina/farmacologia , Células Cultivadas , Difenidramina/farmacologia , Interações Medicamentosas , Humanos , Concentração de Íons de Hidrogênio , Pirilamina/farmacologia , Temperatura , Tetraetilamônio/farmacologia , Fatores de Tempo , Trítio/metabolismo , Valinomicina/farmacologia
15.
J Dermatol Sci ; 87(2): 130-137, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28495120

RESUMO

BACKGROUND: Histamine 4 receptor (H4R) antagonists are considered as new therapeutics for the treatment of atopic dermatitis (AD) and first clinical trials have already shown promising results. Histamine 1 receptor (H1R) antagonists are traditionally used to treat AD although the evidence for the efficacy is weak. The combined blockade of both, H1R and H4R, might provide synergistic anti-inflammatory. OBJECTIVE: The study was performed to test the anti-inflammatory potential of a combined treatment with an H1R and an H4R antagonist in a mouse AD model. METHODS: The development of ovalbumin-induced AD-like skin lesions was analysed mice treated with the H1R inverse agonist mepyramine, the H4R antagonist JNJ-39758979 or a combination of both. RESULTS: Mice treated with mepyramine plus JNJ-39758979 showed less severe skin lesions, with a diminished influx of inflammatory cells, a reduced epidermal thickening and a lower level of IL-33 in lesional skin. Scratching behaviour was ameliorated in mice treated with the combination. Moreover, total numbers of skin-draining lymph node cells and splenocytes were significantly reduced. Both substances given alone did not elicit this strong anti-inflammatory effect. CONCLUSION: H1R and H4R antagonists provide synergistic anti-inflammatory effects in a mouse model of AD. The combined therapy with H1R and H4R antagonists might represent a new strategy for the treatment of AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Pirilamina/uso terapêutico , Pirimidinas/uso terapêutico , Pirrolidinas/uso terapêutico , Receptores Histamínicos H4/antagonistas & inibidores , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Epiderme/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade
16.
Physiol Rep ; 5(8)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28438982

RESUMO

The histaminergic system modulates numerous physiological functions such as wakefulness, circadian rhythm, feeding, and thermoregulation. However, it is not yet known if this system is also involved in psychological stress-induced hyperthermia (PSH) and, if so, which histamine (H) receptor subtype mediates the effect. Therefore, we investigated the effects of pretreatments with intraperitoneal injections of mepyramine (an H1 receptor inverse agonist), cimetidine (an H2 receptor antagonist), and ciproxifan (an H3 receptor inverse agonist) on cage-exchange stress-induced hyperthermia (a model of PSH) by monitoring core body temperature (Tc) during both light (10:00 am-12:00 pm) and dark (10:00 pm-12:00 am) phases in conscious, freely moving rats. We also investigated the effects of these drugs on stress-induced changes in locomotor activity (La) to rule out the possibility that effects on Tc are achieved secondary to altered La Cage-exchange stress increased Tc within 20 min followed by a gradual decrease back to baseline Tc during both phases. In the light phase, mepyramine and cimetidine markedly attenuated PSH, whereas ciproxifan did not affect it. In contrast, in the dark phase, mepyramine dropped Tc by 1°C without affecting cage-exchange stress-induced hyperthermia, whereas cimetidine and ciproxifan did not affect both postinjection Tc and PSH Cage-exchange stress induced an increase in La, especially in the light phase, but none of these drugs altered cage-exchange stress-induced La in either circadian rhythm phase. These results suggest that the histaminergic system is involved in the physiological mechanisms underlying PSH, particularly through H1 and H2 receptors, without influencing locomotor activity.


Assuntos
Febre/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Histamina/metabolismo , Estresse Fisiológico , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Cimetidina/farmacologia , Febre/etiologia , Imidazóis/farmacologia , Masculino , Pirilamina/farmacologia , Ratos , Ratos Wistar
17.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 46(1): 1-6, 2017 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-28436624

RESUMO

Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed. Results: Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all P<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all P<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all P<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine. Conclusion: Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.


Assuntos
Transtornos da Memória/tratamento farmacológico , Receptores Histamínicos H2/efeitos dos fármacos , Receptores Histamínicos H2/fisiologia , Memória Espacial/efeitos dos fármacos , Animais , Benzotiazóis/farmacologia , Química Encefálica/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/complicações , Hipocampo/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Histidina/farmacologia , Hipotálamo/química , Excitação Neurológica/fisiologia , Transtornos da Memória/etiologia , Pentilenotetrazol , Fenoxipropanolaminas/farmacologia , Piperidinas/farmacologia , Pirilamina/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Fluorescência , Tálamo/química
18.
J Control Release ; 254: 34-43, 2017 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-28351667

RESUMO

Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H+/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H+/OC antiporter in a pH-dependent, Na+-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC0-t and Cmax in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H+/OC antiporter.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiporters/metabolismo , Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Fármacos Neuroprotetores/farmacologia , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Pirilamina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/química , Transporte Biológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Potenciais da Membrana , Camundongos , Fármacos Neuroprotetores/química , Prótons , Ratos Wistar , Sódio/metabolismo , Distribuição Tecidual
19.
Can J Physiol Pharmacol ; 95(1): 51-58, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27831743

RESUMO

Experiments using nonsteroidal anti-inflammatory drugs (NSAIDs) alone have produced limited antinociceptive effects in animal models. For this reason, the number of studies involving the administration of NSAIDs along with an adjuvant drug harboring different mechanisms of action has increased enormously. Here, combinations of diclofenac and pyrilamine were used to determine their influence on nociception (formalin test), inflammation (paw inflammation produced by carrageenan), and gastric damage in rodents. Diclofenac, pyrilamine, or combinations of diclofenac and pyrilamine produced antinociceptive and anti-inflammatory effects in the rat. The systemic administration of diclofenac alone and in combination with pyrilamine produced significant gastric damage. Effective dose (ED) values were determined for each individual drug, and isobolograms were prepared. The theoretical ED values for the antinociceptive (systemic, 35.4 mg/kg; local, 343.4 µg/paw) and the anti-inflammatory (37.9 mg/kg) effects differed significantly from the experimental ED values (systemic antinociception, 18.1 mg/kg; local antinociception, 183.3 µg/paw; anti-inflammation, 10.6 mg/kg). Therefore, it was concluded that the interactions between diclofenac and pyrilamine are synergistic. The data suggest that the diclofenac-pyrilamine combinations can interact at the systemic and local peripheral levels, thereby offering a therapeutic alternative for the clinical management of inflammatory pain.


Assuntos
Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Inflamação/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Pirilamina/farmacologia , Pirilamina/uso terapêutico , Estômago/efeitos dos fármacos , Estômago/patologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Carragenina , Diclofenaco/efeitos adversos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada/efeitos adversos , Feminino , Inflamação/induzido quimicamente , Destreza Motora/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Pirilamina/efeitos adversos , Ratos
20.
Inflamm Res ; 66(4): 311-322, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27904941

RESUMO

BACKGROUND: Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo. METHODS AND RESULTS: The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat's hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT1A or 3 receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT1A or 3 receptors. CONCLUSION: Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.


Assuntos
Histamina/metabolismo , Dor/metabolismo , Serotonina/metabolismo , Substância P/metabolismo , Canais de Cátion TRPC/metabolismo , Acetanilidas/farmacologia , Animais , Antagonistas dos Receptores Histamínicos H1/farmacologia , Isotiocianatos , Masculino , Oligonucleotídeos Antissenso/farmacologia , Dor/induzido quimicamente , Piperazinas/farmacologia , Purinas/farmacologia , Pirilamina/farmacologia , Quinuclidinas/farmacologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores da Neurocinina-1/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Canal de Cátion TRPA1 , Canais de Cátion TRPC/agonistas , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , p-Metoxi-N-metilfenetilamina/farmacologia
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