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1.
Rev Cardiovasc Med ; 20(3): 139-151, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601088

RESUMO

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca²âº channels to Ca²âº influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca²âº channel inhibitors and Ca²âº antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca²âº channel - the voltage independent store-operated Ca²âº channel - has been implicated in the regulation and fine tuning of Ca²âº entry in both cardiac and smooth muscle cells. Store-operated Ca²âº channels are activated by the depletion of Ca²âº stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca²âº, thereby facilitating agonist-induced Ca²âº influx. Store-operated Ca²âº entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca²âº entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca²âº channels acting at the level of both STIM and Orai channels have been shown to depress Ca²âº influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca²âº channels that act in vascular smooth muscles for the improved treatment of hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , Moléculas de Interação Estromal/antagonistas & inibidores , Vasodilatadores/uso terapêutico , Animais , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Moléculas de Interação Estromal/metabolismo , Resultado do Tratamento , Vasodilatadores/efeitos adversos
2.
Life Sci ; 227: 74-81, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002920

RESUMO

AIMS: Benidipine is a dihydropyridine (DHP) derived Ca2+ antagonist, can block triple Ca2+ channels (L, N, and T). It has been used as a safety anti-hypertensive drug because of its long-acting relaxant effect on vascular smooth muscle (VSM). However, whether benidipine has similar pharmacological actions in airway smooth muscle (ASM) is unknown. This research aims to reveal the relaxant property and Ca2+ antagonistic effect of benidipine on ASM. MAIN METHODS: The relaxant property of mouse ASM was investigated by tissue tension tests, and Ca2+ antagonistic effect was evaluated through patch-clamp techniques. KEY FINDINGS: Benidipine caused dose-dependent relaxations on high K+ (80 mM) induced precontraction in mouse ASM, which relied on inhibition of extracellular Ca2+ influx, and 1 µM benidipine totally blocked L-type voltage-dependent Ca2+ channels (LVDCCs) currents in airway smooth muscle cells (ASMCs). Benidipine also showed dose-dependent inhibition of ACh-induced precontraction with or without the LVDCCs blocker nifedipine, and 100 µM benidipine blocked ACh-stimulated Ca2+ influx through not only LVDCCs but also non-selective cation channels (NSCCs). SIGNIFICANCE: Benidipine blocked LVDCCs and NSCCs to abolish these channels-mediated Ca2+ influx, which relaxed precontracted ASM. This study represented benidipine with a new potential medicinal value for ASM hypercontractility.


Assuntos
Di-Hidropiridinas/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Di-Hidropiridinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Técnicas de Patch-Clamp , Sistema Respiratório/efeitos dos fármacos
3.
J Pharmacol Sci ; 139(3): 240-248, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30826245

RESUMO

Here we aimed to observe the effects of total ginsenosides (TG) against isoproterenol (ISO) induced myocardial ischemia (MI) and to explore its underlying mechanisms based on L-type Ca2+ current (ICa-L), intracellular Ca2+ ([Ca2+]i) and contraction in isolated rat myocytes. Rat model of MI was induced by subcutaneously injection of ISO (85 mg/kg) for 2 consecutive days. J-point elevation, heart rate, serum levels of creatine kinase (CK) and lactated dehydrogenase (LDH), and heart morphology changes were observed. Influences of TG on ICa-L, [Ca2+]i and contraction in isolated rat myocytes were observed by the patch-clamp technique and IonOptix detection system. TG significantly reduced J-point elevation, heart rate, serum levels of CK and LDH, and improved heart pathologic morphology. TG decreased ICa-L in concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 31.65 µg/mL. TG (300 µg/mL) decreased ICa-L of normal and ischemic ventricular myocytes by 64.33 ± 1.28% and 61.29 ± 1.38% respectively. At 30 µg/mL, TG reduced Ca2+ transient by 21.67 ± 0.94% and cell shortening by 38.43 ± 6.49%. This study showed that TG displayed cardioprotective effects on ISO-induced MI rats and the underlying mechanisms may be related to inhibition of ICa-L, damping of [Ca2+]i and decrease of contractility.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Cardiotônicos/farmacologia , Ginsenosídeos/farmacologia , Isquemia Miocárdica/prevenção & controle , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Modelos Animais de Doenças , Ginsenosídeos/administração & dosagem , Homeostase/efeitos dos fármacos , Concentração Inibidora 50 , Isoproterenol/toxicidade , Masculino , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
4.
Cardiovasc Toxicol ; 19(1): 48-55, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29992493

RESUMO

The following study examined the impact of IL-2 on Ca2+ channel activity in the event of several hours' incubation in IL-2. The right ventricle free wall for action potential measurements was isolated and perfused with Tyrode solution. The whole-cell voltage clamp experiments were performed on enzymatically isolated single cardiomyocytes. The whole-cell voltage clamp recording of Ca2+ currents was performed using the Cs+-based pipette and bath solutions. The protocol with depolarizing prepulse (- 40 mV) was used to inactivate both Na+ current and Ca2+T-type current. The L-type Ca2+ current was elicited by a series of 250 ms depolarizing square pulses with 10 mV increments. At the 15th minute of continuous recording, the peak density at 0 mV was - 3.036 ± 0.3015 pA/pF under IL-2 and - 3.008 ± 0.3452 pA/pF in control conditions. The IL-2 in moderate concentration (1 ng/mL) has no acute effects on ICa.L in rat ventricular cells. In contrast, to the lack of acute effects, the long-term incubation with IL-2 (2 h or more) produced a prominent enhancement of Ca2+L-type current. In rat, ventricular myocardium IL-2 (1 ng/mL) produced a very gradual prolongation of subendocardial APs which reached a maximal extent after 3-4 h of treatment. The patch clamp study shows an IL-2-induced ICa.L current activation, while the action potential studies on multicellular ventricular preparations suggest an IL-2-induced L-type Ca2+ channel participation in the development of AP.


Assuntos
Agonistas dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Interleucina-2/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Ventrículos do Coração/citologia , Ventrículos do Coração/metabolismo , Cinética , Masculino , Miócitos Cardíacos/metabolismo , Ratos
5.
Am J Physiol Gastrointest Liver Physiol ; 316(2): G291-G303, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30540489

RESUMO

The P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellular calcium concentration ([Ca2+]i) via histamine 1 receptors involving T-type voltage-gated calcium channels (VGCCs). Sensitivity to histamine was enhanced by pretreatment with the inflammatory cytokine tumor necrosis factor-α (TNF-α). In accordance with the relief it offers some inflammatory bowel disease patients, otilonium bromide, a gut-impermeable inhibitor of T-type (and L-type) VGCCs and muscarinic ACh receptors, efficiently inhibited the [Ca2+]i responses induced by histamine plus ACh or by histamine alone in P-STS cells. It will take clinical studies to show whether otilonium bromide has promise for the treatment of adverse food reactions. The cells did not react to the nutrient constituents glutamate, capsaicin, cinnamaldehyde, or amylase-trypsin inhibitors and the transient receptor potential channel vanilloid 4 agonist GSK-1016790A. The bacterial product butyrate evoked a rise in [Ca2+]i only when added together with ACh. Lipopolysaccharide had no effect on [Ca2+]i despite the presence of Toll-like receptor 4 protein. Our results indicate that inflammatory conditions with elevated levels of TNF-α might enhance histamine-induced serotonin release from intestinal neuroendocrine cells. NEW & NOTEWORTHY We show that histamine synergistically enhances the intracellular calcium response to the physiological agonist acetylcholine in human ileal enterochromaffin tumor cells. This synergistic activation and cell activation by histamine alone largely depend on T-type voltage-gated calcium channels and are inhibited by the antispasmodic otilonium bromide. The cells showed no response to wheat amylase-trypsin inhibitors, suggesting that enterochromaffin cells are not directly involved in nongluten wheat sensitivity.


Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo T/efeitos dos fármacos , Células Enterocromafins/efeitos dos fármacos , Histamina/farmacologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Células Enterocromafins/metabolismo , Histamina/metabolismo , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia
6.
Behav Brain Res ; 361: 86-94, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30550947

RESUMO

Here, we aimed to investigate the effects of fluoxetine on morphine-induced analgesia, as well as preventive effects of it on morphine induced tolerance and dependence in mice. We also elucidate the involvement of L-type Ca2+ channels in these phenomena. To induce morphine tolerance, mice were treated with morphine (50 mg/kg) for 3 consecutive days. To evaluate the involvement of the calcium channel in the effects of fluoxetine (5, 20 mg/kg), combination ineffective doses of the two L-type calcium channel blockers, nimodipine (5 mg/kg) or diltiazem (20 mg/kg) with flouxetine were used with each morphine dose. Nociceptive behavior was evaluated using hot-plate test, while physical dependence assessed by naloxone-precipitated withdrawal on the fourth day of experiment. The expression of Cav1.2 and Cav1.3 subunits of the L-type calcium channels in cortex and mesolimbic tissues were measured using western immunoassay. Results showed that co-administration of fluoxetine (20 mg/kg) with morphine increased its acute analgesia effect and prevented the induction of morphine antinociceptive tolerance and physical dependence in mice. Moreover, these effects was potentiated by pre-treatment with diltiazem or nimodipine. Results also showed up-regulation of the Cav1.3 and Cav1.2 expression in the cerebral cortex and mesolimbic regions through the development of morphine dependence. Moreover, chronic administration of fluoxetine with morphine reduced the observed up-regulation of Cav1.3 and Cav1.2 expression in cortex and mesolimbic tissues. Our data indicated that co-administering of fluoxetine with morphine could potentiate the antinociceptive effect of morphine, prevent morphine analgesia tolerance and attenuated the morphine withdrawal signs during induction phases. Moreover, we also pointed out for the first time the role of L-type Ca2+ channel channels in the modulatory effects of fluoxetine on the morphine-related effects.


Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Fluoxetina/farmacologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Analgésicos Opioides/farmacologia , Animais , Diltiazem/farmacologia , Tolerância a Medicamentos/fisiologia , Masculino , Camundongos , Morfina/farmacologia , Dependência de Morfina/metabolismo , Nimodipina/farmacologia , Dor/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
7.
Pharmacol Rep ; 71(1): 128-132, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30550993

RESUMO

BACKGROUND: Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α1-adrenoceptors (α1-ARs). Inhibition of such an activity at α1-AR subtypes by antagonists with negative efficacy is difficult to be adequately tested. METHODS: In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α1-AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α1A/α1B-α1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α1D-AR, that is the α1- AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist. RESULTS: We found that all the three benzodioxane-related α1-AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers. CONCLUSIONS: Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α1-AR antagonist is related neither to a particular profile of α1-AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α1-AR antagonists with L-type Ca2+ channels.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Dioxanos/farmacologia , Músculo Liso/efeitos dos fármacos , Miocárdio , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animais , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Dioxanos/química , Agonismo Inverso de Drogas , Feminino , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Estrutura Molecular , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Relação Estrutura-Atividade
8.
Chemosphere ; 220: 169-175, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30583209

RESUMO

The study aimed to investigate the effects of drinking water fluorosis on L-type calcium channels (LTCCs) in mouse hippocampal neurons. A total of 60 newly weaned ICR male mice were randomly divided into control, low fluoride and high fluoride groups. After 3 and 6 months of exposure to fluoride, the patch clamp technique was used to detect the peak and relative values (I/Imax), steady-state activation curve ratio (G/Gmax), decay time constant, and tail current time constant of LTCCs currents in hippocampal CA1 region of mouse brain slices. Fluoride greatly reduced the serum and urinary calcium concentrations in mice, and the chronic fluorosis has a greater impact than subchronic fluorosis. The peak value of LTCCs current in pyramidal neurons of hippocampal CA1 area was significant and increased with the prolonged exposure time. The relative values of current and steady-state coefficients were changed greatly. The decay and tail current time increased significantly. High fluorine concentration indicates great peak value and open time of LTCCs opening. LTCCs are sensitive to fluoride exposure. The activation voltage of calcium channels induced by fluoride exposure is decreased, the opening time of calcium channels is prolonged, and the calcium influx per unit time increased, thereby overloading calcium concentration in neurons and this may be an explanation for intracellular calcium overload caused by fluoride. The imbalance of calcium metabolism caused by fluorosis may be a pathogenesis of brain injury induced by fluoride. Furthermore, the risk of brain damage from low-fluorine exposure cannot be ignored.


Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Água Potável/química , Fluorose Dentária/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Fluoretos/farmacologia , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/química , Técnicas de Patch-Clamp
9.
J Toxicol Sci ; 43(10): 579-586, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30298846

RESUMO

Bisphenol A (BPA) is an endocrine disrupting chemical used on a wide range in industry. This compound has been used in the production of polycarbonate plastics and epoxy resins. For this reason and their global use, BPA is one of the most common environmental chemicals to which humans are exposed. This exposure can cause several adverse health outcomes, including at the cardiovascular level. The regulation of ion channels in vascular smooth muscle is pivotal and important for vasoreactivity, and changes in their flux can be involved in the pathophysiology of some cardiovascular diseases. This study aims to analyse in rat aorta whether the vasorelaxant effect of BPA is mediated by L-type Ca2+ channels inhibition. Using male Wistar rat aorta artery rings in the organ bath we analysed the contractility, and to study the activity of calcium current in A7r5 cells we used the whole cell configuration of Patch Clamp technique. Regarding the contractility experiences we observed that in both NA and KCl contraction, BPA caused a rapid and concentration-dependent relaxation. The electrophysiology experiments showed that BPA inhibited the basal and BAY K8644-stimulated whole-cell L-type Ca2+ channel (W-CLTCC) currents, indicating that this drug blocks the L-type Ca2+ channels. Our results suggest that BPA inhibits the W-CLTCC, leading to the relaxation of vascular smooth muscle.


Assuntos
Aorta/efeitos dos fármacos , Compostos Benzidrílicos/efeitos adversos , Bloqueadores dos Canais de Cálcio , Canais de Cálcio Tipo L/efeitos dos fármacos , Poluentes Ambientais/efeitos adversos , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Fenóis/efeitos adversos , Animais , Cálcio/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Masculino , Técnicas de Patch-Clamp , Ratos Wistar
10.
J Pharmacol Sci ; 137(3): 299-304, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30098911

RESUMO

Diallyl trisulfide (DATS) is an active organosulfide component of allicin and has several beneficial effects, including antimicrobial, antioxidant, cardioprotective and anticancer effects. Few studies have shown the modulatory effect of DATS on L-type calcium channels in rat colonic smooth muscle cells and colonic motility. To investigate the modulatory effect of DATS on L-type calcium channels in rat colonic smooth muscle and colonic contraction, L-type calcium channel currents were recorded, and colonic contractility in longitudinal and circular smooth muscle strips was measured. DATS attenuated L-type calcium channel currents without affecting steady-state activation or inactivation kinetics and inhibited the spontaneous contractions of both longitudinal and circular smooth muscle strips dose-dependently. In conclusion, DATS has an inhibitory effect on the contractions of colonic muscle strips that is related to its regulation of L-type calcium channels.


Assuntos
Compostos Alílicos/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Colo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Sulfetos/farmacologia , Animais , Depressão Química , Relação Dose-Resposta a Droga , Alho , Motilidade Gastrointestinal/efeitos dos fármacos , Técnicas In Vitro , Masculino , Ratos Wistar
11.
Toxicol Appl Pharmacol ; 356: 182-190, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30125596

RESUMO

Taurine-magnesium coordination compound (TMCC) exhibits antiarrhythmic effects in cesium-chloride-and ouabain-induced arrhythmias; however, the mechanism underlying these effects on arrhythmia remains poorly understood. Here, we investigated the effects of TMCC on aconitine-induced arrhythmia in vivo and the electrophysiological effects of this compound in rat ventricular myocytes in vitro. Aconitine was used to induce arrhythmias in rats, and the dosages required to produce ventricular premature contraction (VPC), ventricular tachycardia (VT), ventricular fibrillation (VF), and cardiac arrest (CA) were recorded. Additionally, the sodium current (INa) and L-type calcium current (ICa,L) were analyzed in normal and aconitine-treated ventricular myocytes using whole-cell patch-clamp recording. In vivo, intravenous administration of TMCC produced marked antiarrhythmic effects, as indicated by the increased dose of aconitine required to induce VPC, VT, VF, and CA. Moreover, this effect was abolished by administration of sodium channel opener veratridine and calcium channel agonist Bay K8644. In vitro, TMCC inhibited aconitine-induced increases in INa and ICa,L. These results revealed that TMCC inhibited aconitine-induced arrhythmias through effects on INa and ICa,L.


Assuntos
Aconitina , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Canais Iônicos/efeitos dos fármacos , Compostos de Magnésio/uso terapêutico , Taurina/uso terapêutico , Animais , Canais de Cálcio Tipo L/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/prevenção & controle , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Canais de Sódio/efeitos dos fármacos
12.
BMC Neurosci ; 19(1): 42, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012109

RESUMO

BACKGROUND: Striatal fast-spiking interneurons (FSI) are a subset of GABAergic cells that express calcium-binding protein parvalbumin (PV). They provide feed-forward inhibition to striatal projection neurons (SPNs), receive cortical, thalamic and dopaminergic inputs and are coupled together by electrical and chemical synapses, being important components of the striatal circuitry. It is known that dopamine (DA) depolarizes FSI via D1-class DA receptors, but no studies about the ionic mechanism of this action have been reported. Here we ask about the ion channels that are the effectors of DA actions. This work studies their Ca2+ currents. RESULTS: Whole-cell recordings in acutely dissociated and identified FSI from PV-Cre transgenic mice were used to show that FSI express an array of voltage gated Ca2+ channel classes: CaV1, CaV2.1, CaV2.2, CaV2.3 and CaV3. However, CaV1 Ca2+ channel carries most of the whole-cell Ca2+ current in FSI. Activation of D1-like class of DA receptors by the D1-receptor selective agonist SKF-81297 (SKF) enhances whole-cell Ca2+ currents through CaV1 channels modulation. A previous block of CaV1 channels with nicardipine occludes the action of the DA-agonist, suggesting that no other Ca2+ channel is modulated by D1-receptor activation. Bath application of SKF in brain slices increases the firing rate and activity of FSI as measured with both whole-cell and Ca2+ imaging recordings. These actions are reduced by nicardipine. CONCLUSIONS: The present work discloses one final effector of DA modulation in FSI. We conclude that the facilitatory action of DA in FSI is in part due to CaV1 Ca2+ channels positive modulation.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Cálcio/metabolismo , Agonistas de Dopamina/farmacologia , Animais , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Interneurônios/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Camundongos Transgênicos , Parvalbuminas/metabolismo
13.
Toxicol Lett ; 295: 162-172, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29935216

RESUMO

In pancreatic ß cells, which produce and secrete insulin, Ca2+ signals contribute to insulin production and secretion. Bisphenol A (BPA) and octylphenol (OP) are reported to increase plasma insulin levels and insulin transcription factors, but regulation of plasma glucose levels did not decrease proportionally to the insulin increase. We hypothesized that BPA and OP disrupt calcium homeostasis resulting in insulin resistance through induction of endoplasmic reticulum (ER) stress. BPA and OP treatment leads to survival of pancreatic ß cells against streptozotocin, but despite an increased insulin level, serum glucose regulation is not properly regulated. The expression of genes involved in transporting calcium ions to the cytosol and ER decreased while the expression of those affecting the removal of calcium from the cytosol and ER increased. Depletion of calcium from the ER leads to ER stress and can induce insulin resistance. Insulin resistance is also confirmed by insulin-responsive gene, such as glucose transporter 4 (GLUT4) and IRS2, expression. Taken together, these results imply that disruption of calcium homeostasis by BPA and OP induces ER stress and leads to insulin resistance, especially in a streptozotocin (STZ) -induced type 1 diabetes mellitus model.


Assuntos
Compostos Benzidrílicos/toxicidade , Cálcio/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Disruptores Endócrinos/toxicidade , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Fenóis/toxicidade , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Morte Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Homeostase , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos ICR , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/efeitos dos fármacos , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Estreptozocina , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo
14.
J Neurochem ; 147(1): 40-57, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29920676

RESUMO

Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, this study investigated the effects of neuritin on neurite and spine growth and intracellular Ca2+ concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) activity. Calcium imaging and western blot analysis revealed that neuritin enhanced the increase in intracellular Ca2+ level induced by high K+ , and stimulated the cell surface expression of CaV 1.2 and CaV 1.3 α subunits of the L-type calcium channel, which was suppressed by inhibition of IR or mitogen-activated protein kinase kinase/ERK. Treatment with inhibitors of L-type calcium channels, calmodulin, and calcineurin (CaN) abrogated the effects of neuritin on neurite length and spine density. A similar result was obtained by silencing nuclear factor of activated T cells c4, which is known to be activated by neuritin in CGNs. These results indicate that IR and ERK signaling as well as the Ca2+ /CaN/nuclear factor of activated T cells c4 axis mediate the effects of neuritin on neurite and spine growth in CGNs. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14195.


Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Cerebelo/citologia , Espinhas Dendríticas/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuropeptídeos/farmacologia , Animais , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/crescimento & desenvolvimento , Grânulos Citoplasmáticos/efeitos dos fármacos , Feminino , Proteínas Ligadas por GPI/farmacologia , Inativação Gênica , Humanos , Insulina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/genética , Ratos , Ratos Sprague-Dawley , Receptor de Insulina/antagonistas & inibidores
15.
Pharmacol Res ; 134: 109-117, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29890255

RESUMO

We previously reported a novel danshensu derivative (R)-(3,5,6-Trimethylpyrazinyl) methyl-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoate (ADTM) that exhibited promising cardiovascular protective activities, such as antioxidant and antiplatelet activities, as well as arterial relaxation. Particularly, ADTM treatment for 24 h exhibited anti-oxidative activity and effectively protected against acute myocardial infarction (MI) in a rat model. Here, we further investigated the pharmacological actions of 14 days of treatment with ADTM in alleviating and restoring the MI size by stimulating revascularization. The pro-angiogenesis activity of ADTM has been validated in multiple experimental models including MI mouse, zebrafish, human umbilical vein endothelial cells (HUVECs) and A7r5 vascular smooth muscle cells (VSMCs). In addition, the effect of ADTM on L-type Ca2+ current (ICaL) was determined. We demonstrated that ADTM (12-24 mg/kg) treatment for 14 days significantly decreased myocardial infarct size, increased the blood vessel density compared to vehicle in the myocardial peri-infarct area, and ADTM (24 mg/kg) enhanced the serum VEGF level in MI mice (P < 0.05). We also demonstrated that treatment with ADTM at 50-200 µM rescued chemical-induced blood vessel loss in zebrafish. Although ADTM did not directly promote the features of angiogenesis in HUVECs, ADTM significantly increased VEGF production in a dose-dependent manner in A7r5 cells (P < 0.05). A patch clamp experiment demonstrated that ADTM (200 µM) inhibited ICaL at all depolarizing voltages, with > 50% inhibition at + 10 mV. Taken together, our results indicated that ADTM served as a Ca2+ current blocker, promoted angiogenesis and reduced experimental myocardial infarct size in mice, probably through stimulation of VEGF production in VSMCs.


Assuntos
Indutores da Angiogênese/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fenilpropionatos/farmacologia , Pirazinas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Fator A de Crescimento do Endotélio Vascular/sangue , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
16.
J Cell Physiol ; 233(11): 8701-8710, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29797580

RESUMO

The zafirlukast has been reported to be anti-inflammatory and widely used to alleviate the symptoms of asthma. However, its influence on insulin secretion in pancreatic ß-cells has not been investigated. Herein, we examined the effects of zafirlukast on insulin secretion and the potential underlying mechanisms. Among the cysteinyl leukotriene receptor 1 antagonists, zafirlukast, pranlukast, and montelukast, only zafirlukast enhanced insulin secretion in a concentration-dependent manner in both low and high glucose conditions and elevated the level of [Ca2+ ]i , further activating Ca2+ /calmodulin-dependent protein kinase II (CaMKII), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) signaling. These effects were nearly abolished by the L-type Ca2+ channel antagonist nifedipine, while treatment with thapsigargin, a sarco/endoplasmic reticulum Ca2+ ATPase inhibitor, did not have the same effect, suggesting that zafirlukast primarily induces the entry of extracellular Ca2+ rather than intracellular Ca2+ from the endoplasmic reticulum. Zafirlukast treatment resulting in a significant drop in glucose levels and increased insulin secretion in C57BL/6J mice. These findings will contribute to an improved understanding of the side effects of zafirlukast and potential candidate for a therapeutic intervention in diabetes.


Assuntos
Canais de Cálcio Tipo L/genética , Hipoglicemia/tratamento farmacológico , Secreção de Insulina/genética , Compostos de Tosil/administração & dosagem , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/administração & dosagem , Canais de Cálcio Tipo L/efeitos dos fármacos , Sinalização do Cálcio/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Glucose/genética , Glucose/metabolismo , Humanos , Hipoglicemia/genética , Hipoglicemia/patologia , Hipoglicemia/fisiopatologia , Insulina/genética , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos
17.
Neuropeptides ; 70: 47-54, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29803395

RESUMO

OBJECTIVE: This study sought to investigate the effect and underlying mechanism of thyrotrophin releasing hormone (TRH) on colonic contractile disorders induced by chronic water avoidance stress (WAS). METHODS: Male SD rats were exposed to daily 1-h WAS or sham WAS for 10 consecutive days. The presence of TRH in the serum and colonic mucosa were determined using enzyme immunoassay kits. Immunohistochemistry and western blotting were performed to detect the expression of TRH receptor 1 (TRH-R1). The contractions of proximal colonic smooth muscle were studied in an organ bath system. The whole-cell patch-clamp technique was used to record the currents of both L-type calcium currents (ICa,L) and large conductance Ca2+-activated K+ (BKCa) channels in colonic smooth muscle cells (SMCs) isolated from adult rats. RESULTS: Enzyme immunoassay revealed that TRH was present in both serum and colonic mucosa and that this expression increased in the WAS group. Immunohistochemistry revealed that the TRH-R1 level increased in colons devoid of mucosa and submucosa from the stressed rats as compared with the control group. TRH increased the spontaneous contractions of the longitudinal muscle and circular muscle strips in a dose-dependent manner in vitro. The effect was also confirmed in an vivo experiment, where an intraperitoneal injection of TRH in rats significantly increased fecal pellet output during a 24-h period as compared with the control group. Furthermore, intraperitoneal injection of a non-specific TRH receptor antagonist, chlordiazepoxide and a TRH-R1 antibody, partially decreased the fecal pellets of WAS rats during the 10-day stress period. Furthermore, TRH increased the peak current of L-type channels in colonic smooth muscle cells (SMCs) at a membrane potential of 0 mV, while the current of large conductance Ca2+-activated K+ (BKCa) channels was not changed following the addition of TRH. CONCLUSION: TRH may be involved in the dysmotility induced by chronic stress and may have some potential clinical therapeutic use in regulating gut motility.


Assuntos
Colo/efeitos dos fármacos , Desidratação/tratamento farmacológico , Músculo Liso/metabolismo , Hormônio Liberador de Tireotropina/farmacologia , Animais , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Miócitos de Músculo Liso/efeitos dos fármacos , Ratos Sprague-Dawley , Hormônio Liberador de Tireotropina/metabolismo
18.
Cardiovasc Toxicol ; 18(5): 407-419, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29603116

RESUMO

We have previously demonstrated that methylene blue (MB) counteracts the effects of hydrogen sulfide (H2S) cardiotoxicity by improving cardiomyocyte contractility and intracellular Ca2+ homeostasis disrupted by H2S poisoning. In vivo, MB restores cardiac contractility severely depressed by sulfide and protects against arrhythmias, ranging from bundle branch block to ventricular tachycardia or fibrillation. To dissect the cellular mechanisms by which MB reduces arrhythmogenesis and improves bioenergetics in myocytes intoxicated with H2S, we evaluated the effects of H2S on resting membrane potential (Em), action potential (AP), Na+/Ca2+ exchange current (INaCa), depolarization-activated K+ currents and ATP levels in adult mouse cardiac myocytes and determined whether MB could counteract the toxic effects of H2S on myocyte electrophysiology and ATP. Exposure to toxic concentrations of H2S (100 µM) significantly depolarized Em, reduced AP amplitude, prolonged AP duration at 90% repolarization (APD90), suppressed INaCa and depolarization-activated K+ currents, and reduced ATP levels in adult mouse cardiac myocytes. Treating cardiomyocytes with MB (20 µg/ml) 3 min after H2S exposure restored Em, APD90, INaCa, depolarization-activated K+ currents, and ATP levels toward normal. MB improved mitochondrial membrane potential (∆ψm) and oxygen consumption rate in myocytes in which Complex I was blocked by rotenone. We conclude that MB ameliorated H2S-induced cardiomyocyte toxicity at multiple levels: (1) reversing excitation-contraction coupling defects (Ca2+ homeostasis and L-type Ca2+ channels); (2) reducing risks of arrhythmias (Em, APD, INaCa and depolarization-activated K+ currents); and (3) improving cellular bioenergetics (ATP, ∆ψm).


Assuntos
Trifosfato de Adenosina/metabolismo , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/prevenção & controle , Metabolismo Energético/efeitos dos fármacos , Sulfeto de Hidrogênio/toxicidade , Canais Iônicos/efeitos dos fármacos , Azul de Metileno/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Canais Iônicos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Trocador de Sódio e Cálcio/efeitos dos fármacos , Trocador de Sódio e Cálcio/metabolismo
19.
Hum Exp Toxicol ; 37(11): 1169-1179, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29441826

RESUMO

Paracetamol (P), one of the most popular and commonly used analgesic and antipyretic agents, causes hepatotoxicity in overdoses. Amlodipine (AML), an L-type calcium channel blocker, has been shown to have anti-inflammatory activity by reversing the effect of calcium in the inflammation pathogenesis. In this study, the hepatoprotective activity of AML on P-induced hepatotoxicity was evaluated. Thirty male albino Wistar rats were divided into five groups: (1) control, (2) 2 g/kg of P, (3) 2 g/kg of P + 5 mg/kg of AML, (4) 2 g/kg of P + 10 mg/kg of AML, and (5) 10 mg/kg of AML. Some liver enzymes, oxidative parameters, cytokine mRNA expressions, histopathology, and immunohistochemical studies were performed in liver and blood samples. The serum levels of alanine aminotransferase and aspartate aminotransferase and the mRNA expression of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta in the liver tissues were significantly increased in the group treated with P. The superoxide dismutase and glutathione parameters decreased and malondialdehyde levels increased in the livers of the rats treated with P. All these parameters were increased with both doses of the AML similar to the control group. A histopathological examination of the liver showed that AML administration ameliorated the P-induced inflammatory liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the P group but not in other treatment groups when compared to the control. In conclusion, AML treatment showed significant protective effects against P-induced hepatotoxicity by increasing the activity of antioxidants and reducing inflammatory cytokines.


Assuntos
Acetaminofen , Anlodipino/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Canais de Cálcio Tipo L/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/metabolismo , Citoproteção , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
20.
Hypertens Res ; 41(4): 290-298, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29449705

RESUMO

Recent studies suggest that L-type calcium channel blockers (CCBs) contribute to reducing blood pressure (BP) variability. We investigated whether inhibition of the N-type calcium channel has an additional effect on BP variability by comparing the effect of L-type and L/N-type CCBs on home BP variability in elderly hypertensive patients. Twenty-six hypertensive patients (≥65 years) were subjected to repeated changes with the administration of amlodipine (L-type CCB) and cilnidipine (L/N-type CCB) every 2 months. They measured the home BP in the morning and evening, and the coefficient of variation (CV) was calculated. We measured the brachial-ankle pulse wave velocity (baPWV) and urinary catecholamine excretion as an index of the arterial stiffness and sympathetic nerve activity, respectively. There was no difference in the effect of both drugs on the CV in the morning and evening, while amlodipine was associated with a modestly higher pulse rate and lower BP than cilnidipine. By comparing individual patient data for the CV with each drug, we found that higher urinary catecholamine excretion was associated with the effectiveness of cilnidipine over amlodipine in the BP variability in the morning, which was not the case in the evening. In contrast, lower baPWV was associated with the effectiveness of amlodipine over cilnidipine on BP variability in the evening. Lower baPWV was also associated with lower BP variability in the evening. Cilnidipine has a similar capacity as amlodipine in reducing home BP variability, but the underlying mechanisms in reducing BP variability may differ.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo N/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Idoso , Anlodipino/uso terapêutico , Índice Tornozelo-Braço , Catecolaminas/urina , Di-Hidropiridinas/uso terapêutico , Feminino , Humanos , Masculino , Estudos Prospectivos , Sistema Nervoso Simpático/fisiopatologia , Rigidez Vascular
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