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1.
Pharmacol Res Perspect ; 12(2): e1188, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38483045

RESUMO

Considering the importance of pain and stress, we decided to investigate the intra-anterior cingulate cortex (ACC) microinjection of histamine and mepyramine alone and concurrently on acute pain induced by hot plate following restraint stress in male rats. 24-gauge, 10 mm stainless steel guide cannula was implanted over the ACC in the incised scalp of 4 groups. Restraint stress in healthy rats produced a significant increase (p < .05) in the pain threshold. The simultaneous microinjection of 4 µg/side histamine and 8 µg/side mepyramine as a histaminergic system inverse agonist in healthy nonrestraint animals did not affect the pain threshold. Although Histamine decreased the threshold of pain meaningfully, mepyramine elevated it in a significant manner (p < .05). In the restrained animals, intra-ACC microinjection of histamine produced no significant impact on the pain threshold. However, intra-ACC microinjection of mepyramine before histamine, significantly (p < .01) altered the result and enhanced the threshold of pain. The results of our study demonstrated that histaminergic neurons have an important role in the processing of pain in the ACC following restraint stress.


Assuntos
Histamina , Receptores Histamínicos H1 , Ratos , Masculino , Animais , Receptores Histamínicos H1/metabolismo , Giro do Cíngulo/metabolismo , Pirilamina , Nociceptividade , Agonismo Inverso de Drogas , Dor
2.
Mol Pharmacol ; 105(2): 84-96, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-37977823

RESUMO

The zebrafish (Danio rerio) histamine H1 receptor gene (zfH1R) was cloned in 2007 and reported to be involved in fish locomotion. Yet, no detailed characterization of its pharmacology and signaling properties have so far been reported. In this study, we pharmacologically characterized the zfH1R expressed in HEK-293T cells by means of [3H]-mepyramine binding and G protein-signaling assays. The zfH1R [dissociation constant (KD), 0.7 nM] displayed similar affinity for the antagonist [3H]-mepyramine as the human histamine H1 receptor (hH1R) (KD, 1.5 nM), whereas the affinity for histamine is 100-fold higher than for the human H1R. The zfH1R couples to Gαq/11 proteins and activates several reporter genes, i.e., NFAT, NFÏ°B, CRE, VEGF, COX-2, SRE, and AP-1, and zfH1R-mediated signaling is prevented by the Gαq/11 inhibitor YM-254890 and the antagonist mepyramine. Molecular modeling of the zfH1R and human H1R shows that the binding pockets are identical, implying that variations along the ligand binding pathway could underly the differences in histamine affinity instead. Targeting differentially charged residues in extracellular loop 2 (ECL2) using site-directed mutagenesis revealed that Arg21045x55 is most likely involved in the binding process of histamine in zfH1R. This study aids the understanding of the pharmacological differences between H1R orthologs and the role of ECL2 in histamine binding and provides fundamental information for the understanding of the histaminergic system in the zebrafish. SIGNIFICANCE STATEMENT: The use of the zebrafish as in vivo models in neuroscience is growing exponentially, which asks for detailed characterization of the aminergic neurotransmitter systems in this model. This study is the first to pharmacologically characterize the zebrafish histamine H1 receptor after expression in HEK-293T cells. The results show a high pharmacological and functional resemblance with the human ortholog but also reveal interesting structural differences and unveils an important role of the second extracellular loop in histamine binding.


Assuntos
Histamina , Receptores Histamínicos H1 , Animais , Humanos , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Pirilamina/farmacologia , Pirilamina/metabolismo , Peixe-Zebra , Transdução de Sinais
3.
Ars pharm ; 64(2): 139-147, abr.-jun. 2023. tab, graf
Artigo em Inglês | IBECS | ID: ibc-217818

RESUMO

Introducción: La histamina es un ligando endógeno que ejerce sus acciones biológicas uniéndose a 4 subtipos de receptores de histamina (HR), sus efectos en el tracto gastrointestinal son complejos siendo el efecto dominante la contracción de las células musculares. Método: El objetivo de este estudio fue verificar el efecto antagónico de la mepiramina (10-10M – 10-7M) y la tubocurarina (10-7M – 10-4M) en la acción contráctil de la histamina (10-11M – 10-4M) en el íleon de cobaya, para ello se utilizó el programa Virtual Organ Bath 16 V 2.8 que permitió cuantificar el cambio de fuerza (g) producido por la contracción del músculo liso en presencia de estas sustancias. Las curvas de concentración-respuesta se obtuvieron mediante el uso del programa gráfico GraphPad Prism®. La determinación del carácter competitivo del antagonista y el cálculo de la constante de afinidad se realizaron mediante el método de Schild. Resultados: La mepiramina es un antagonista competitivo de la histamina (10-10M a 10-7M), convirtiéndola en un agente terapéutico potencial para el tratamiento del síndrome de intestino irritable. Por otro lado, no se encuentra que la tubocurarina sea un antagonista de los receptores de histamina. Conclusiones: Los resultados obtenidos proporcionan evidencia acerca de que el efecto contráctil de la histamina, sobre el músculo liso de células intestinales aisladas en cobaya, es antagonizado competitivamente por la mepiramina. Además, mediante el cálculo del parámetro pKB se encontró que este compuesto presenta mayor potencia que otros antihistamínicos. (AU)


Introduction: Histamine is an endogenous ligand which exerts its biological actions by binding to 4 subtypes of histamine receptors (HR). Its effects on the gastrointestinal tract are complex being the dominant effect contraction of muscle cells. Method: The aim of this study was to verify the antagonistic effect of mepyramine (10-10M - 10-7M) and tubocurarine (10-7M - 10-4M) in the contractile action of histamine (10-11M - 10-4M) in guinea pig ileum, for this purpose it was used the program Virtual Organ Bath 16 V 2.8, which allow quantify the change in strength(g) produced by smooth muscle contraction in the presence of these substances. Concentration-response curves were obtained through GraphPad Prism® graphic program. The determination of the competitive nature of the antagonist and the calculation of the affinity constant was performed through Schild method. Results: Mepyramine is a competitive antagonist of histamine (10-10M to 10-7M), making it a potential therapeutic agent for the treatment of irritable bowel syndrome. On the other hand, it is not understood that tubocurarine is an antagonist of histamine receptors. Conclusions: The results obtained provide evidence that the contractile effect of histamine on the smooth muscle of intestinal cells isolated from guinea pig is competitively antagonized by mepyramine. In addition, by calculating the pKB parameter, it was found that this compound has greater potency than other antihistamines. (AU)


Assuntos
Humanos , Pirilamina , Tubocurarina , Histamina , Síndrome do Intestino Irritável , Músculo Liso
4.
Sleep ; 45(5)2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35554581

RESUMO

STUDY OBJECTIVES: Sleep is a prominent behavioral and biochemical state observed in all animals studied, including platyhelminth flatworms. Investigations into the biochemical mechanisms associated with sleep-and wakefulness-are important for understanding how these states are regulated and how that regulation changed with the evolution of new types of animals. Unfortunately, beyond a handful of vertebrates, such studies on invertebrates are rare. METHODS: We investigated the effect of seven neurotransmitters, and one pharmacological compound, that modulate either sleep or wakefulness in mammals, on flatworms (Girardia tigrina). Flatworms were exposed via ingestion and diffusion to four neurotransmitters that promote wakefulness in vertebrates (acetylcholine, dopamine, glutamate, histamine), and three that induce sleep (adenosine, GABA, serotonin) along with the H1 histamine receptor antagonist pyrilamine. Compounds were administered over concentrations spanning three to five orders of magnitude. Flatworms were then transferred to fresh water and video recorded for analysis. RESULTS: Dopamine and histamine decreased the time spent inactive and increased distance traveled, consistent with their wake-promoting effect in vertebrates and fruit flies; pyrilamine increased restfulness and GABA showed a nonsignificant trend towards promoting restfulness in a dose-dependent manner, in agreement with their sleep-inducing effect in vertebrates, fruit flies, and Hydra. Similar to Hydra, acetylcholine, glutamate, and serotonin, but also adenosine, had no apparent effect on flatworm behavior. CONCLUSIONS: These data demonstrate the potential of neurotransmitters to regulate sleep and wakefulness in flatworms and highlight the conserved action of some neurotransmitters across species.


Assuntos
Platelmintos , Vigília , Acetilcolina , Adenosina , Animais , Dopamina , Ácido Glutâmico , Histamina , Mamíferos , Neurotransmissores/fisiologia , Pirilamina/farmacologia , Serotonina , Sono/fisiologia , Vigília/fisiologia , Ácido gama-Aminobutírico
5.
FASEB J ; 35(12): e22025, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34758144

RESUMO

Mepyramine, a first-generation antihistamine targeting the histamine H(1) receptor, was extensively prescribed to patients suffering from allergic reactions and urticaria. Serious adverse effects, especially in case of overdose, were frequently reported, including drowsiness, impaired thinking, convulsion, and coma. Many of these side effects were associated with the blockade of histaminergic or cholinergic receptors. Here we show that mepyramine directly inhibits a variety of voltage-gated sodium channels, including the Tetrodotoxin-sensitive isoforms and the main isoforms (Nav1.7, Nav1.8, and Nav1.9) of nociceptors. Estimated IC50 were within the range of drug concentrations detected in poisoned patients. Mepyramine inhibited sodium channels through fast- or slow-inactivated state preference depending on the isoform. Moreover, mepyramine inhibited the firing responses of C- and Aß-type nerve fibers in ex vivo skin-nerve preparations. Locally applied mepyramine had analgesic effects on the scorpion toxin-induced excruciating pain and produced pain relief in acute, inflammatory, and chronic pain models. Collectively, these data provide evidence that mepyramine has the potential to be developed as a topical analgesic agent.


Assuntos
Artrite Experimental/complicações , Gânglios Espinais/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.8/fisiologia , Nociceptores/efeitos dos fármacos , Dor/tratamento farmacológico , Pirilamina/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canal de Sódio Disparado por Voltagem NAV1.8/química , Nociceptores/metabolismo , Nociceptores/patologia , Dor/etiologia , Dor/metabolismo , Dor/patologia
6.
Pharmacol Res Perspect ; 9(5): e00879, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34628723

RESUMO

The unbound concentrations of 14 commercial drugs, including five non-efflux/uptake transporter substrates-Class I, five efflux transporter substrates-class II and four influx transporter substrates-Class III, were simultaneously measured in rat liver, muscle, and blood via microanalysis. Kpuu,liver and Kpuu,muscle were calculated to evaluate the membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver. For Class I compounds, represented by antipyrine, unbound concentrations among liver, muscle and blood are symmetrically distributed when compound hepatic clearance is low. And when compound hepatic clearance is high, unbound concentrations among liver, muscle and blood are asymmetrically distributed, such as Propranolol. For Class II and III compounds, overall, the unbound concentrations among liver, muscle, and blood are asymmetrically distributed due to a combination of hepatic metabolism and efflux and/or influx transporter activity.


Assuntos
Membrana Celular/metabolismo , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Músculo Esquelético/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Antipirina/sangue , Antipirina/metabolismo , Atenolol/sangue , Atenolol/metabolismo , Carbamazepina/sangue , Carbamazepina/metabolismo , Digoxina/sangue , Digoxina/metabolismo , Diltiazem/sangue , Diltiazem/metabolismo , Difenidramina/sangue , Difenidramina/metabolismo , Vias de Eliminação de Fármacos , Gabapentina/sangue , Gabapentina/metabolismo , Lamotrigina/sangue , Lamotrigina/metabolismo , Memantina/sangue , Memantina/metabolismo , Microdiálise , Ofloxacino/sangue , Ofloxacino/metabolismo , Preparações Farmacêuticas/sangue , Propranolol/sangue , Propranolol/metabolismo , Pirilamina/sangue , Pirilamina/metabolismo , Quinidina/sangue , Quinidina/metabolismo , Ratos , Terfenadina/análogos & derivados , Terfenadina/sangue , Terfenadina/metabolismo
7.
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
8.
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
9.
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
10.
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
11.
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 , 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 , Mucosa/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Pirilamina/farmacologia , Suínos , Terfenadina/análogos & derivados , Terfenadina/farmacologia , Bexiga Urinária/metabolismo , Urotélio/metabolismo
12.
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
13.
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 , Ciclopropanos , Cobaias , Lipopolissacarídeos , Masculino , Relaxamento Muscular/efeitos dos fármacos , Pirilamina , Quinolinas , Sulfetos
14.
Artigo em Inglês | WPRIM (Pacífico Ocidental) | ID: wpr-763015

RESUMO

Paeonol has neuroprotective function, which could be useful for improving central nervous system disorder. The purpose of this study was to characterize the functional mechanism involved in brain transport of paeonol through blood-brain barrier (BBB). Brain transport of paeonol was characterized by internal carotid artery perfusion (ICAP), carotid artery single injection technique (brain uptake index, BUI) and intravenous (IV) injection technique in vivo. The transport mechanism of paeonol was examined using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) as an in vitro model of BBB. Brain volume of distribution (V(D)) of [³H]paeonol in rat brain was about 6-fold higher than that of [¹⁴C]sucrose, the vascular space marker of BBB. The uptake of [³H]paeonol was concentration-dependent. Brain volume of distribution of paeonol and BUI as in vivo and inhibition of analog as in vitro studies presented significant reduction effect in the presence of unlabeled lipophilic compounds such as paeonol, imperatorin, diphenhydramine, pyrilamine, tramadol and ALC during the uptake of [³H]paeonol. In addition, the uptake significantly decreased and increased at the acidic and alkaline pH in both extracellular and intracellular study, respectively. In the presence of metabolic inhibitor, the uptake reduced significantly but not affected by sodium free or membrane potential disruption. Similarly, paeonol uptake was not affected on OCTN2 or rPMAT siRNA transfection BBB cells. Interestingly. Paeonol is actively transported from the blood to brain across the BBB by a carrier mediated transporter system.


Assuntos
Animais , Ratos , Barreira Hematoencefálica , Encéfalo , Artérias Carótidas , Artéria Carótida Interna , Sistema Nervoso Central , Difenidramina , Células Endoteliais , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Potenciais da Membrana , Perfusão , Pirilamina , RNA Interferente Pequeno , Sódio , Tramadol , Transfecção
15.
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
16.
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
17.
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
18.
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
19.
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
20.
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
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