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1.
Life Sci ; 245: 117357, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31991180

RESUMO

AIMS: Schisandra is a good choice in Traditional Chinese Medicine for the therapy of cardiovascular diseases, but whether it contains a or some specific component (s) responsible these effects are still unclear. In the present study, we explored whether Schisantherin A (SCA) causes vasorelaxation in isolated rat thoracic aorta. MAIN METHODS: We selected SCA, one of the main monomers of lignans from Schisandra, to examine its vasorelaxant effect on the isolated rat thoracic aorta and also exploited several tool inhibitors to probe its underlying mechanisms. KEY FINDINGS: SCA produced relaxation concentration-dependently on the endothelium-intact (43.56 ± 2.17%) and endothelium-denuded thoracic aorta strips (18.76 ± 3.95%) pre-contracted by phenylephrine (PE). However, after treated with indomethacin or L-NAME, SCA showed only partial vasorelaxant effects. Whereas, this vasorelaxation by SCA was not changed with specific K+-channel inhibitors, i.e. barium chloride (BaCl2), 4-aminopyridine (4-AP), tetraethylamine (TEA), and glibenclamide. SCA had no effect on the aorta strips pre-contracted by PE in neither Ca2+-free nor CaCl2 conditions. But, in the Ca2+ free and high K+ environment, SCA partly abolished the vasocontraction induced by CaCl2. SIGNIFICANCE: It was the first report to demonstrate that SCA had endothelium-dependent and -independent vasorelaxant effects on the isolated rat thoracic aorta, and the underlying mechanisms might be involved into its promoting the production of nitric oxide (NO) and prostacyclin (PGI2), and inhibiting the voltage-dependent calcium channels (VDCCs) opening. This study may partially explain the use of Schisandra in cardiovascular diseases and facilitate further drug development as well.


Assuntos
Aorta Torácica/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Endotélio Vascular/efeitos dos fármacos , Lignanas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Western Blotting , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Artigo em Inglês | MEDLINE | ID: mdl-31683013

RESUMO

Thymol, a phenolic monoterpene, is well known for its antimicrobial, antifungal and antioxidant properties. In spite of wide use in oral care products, pharmaceutical and cosmetic preparation and in food industry, the effects of thymol on the neuronal activity and intrinsic properties have not been well studied. We studied the effects of thymol on the spontaneous activity and action potential properties of central neurons of snail Caucasotachea atrolabiata. Thymol (1 mM) altered action potentials characteristics and provoked epileptiform burst firing in snail neurons, which were partially reversible after washout. Before burst firing, action potentials had lower amplitude and maximum rising slope, while the threshold voltage was raised. These results suggest the inhibition of ion channels underlying action potential initiation and upstroke. The maximum falling slope and afterhyperpolarization were also considerably reduced, suggesting the inhibition of potassium channels. Thymol (0.5 mM) that was not able to induce burst firing in snail neurons, synergistically acted with potassium channel blocker, tetraethyl ammonium, to induce burst firing, which also supports the importance of potassium channel inhibition, especially delayed rectifier potassium channels, to the thymol-induced alteration of firing pattern. The thymol-induced burst firing seems to be dependent on both sodium and calcium currents. Our findings provide evidences for the ability of thymol in altering the firing mode of central neurons of snail, which apparently involves the inhibition of calcium and potassium currents. These results further support the interaction of thymol with ion channels and emphasize on the vulnerability of nervous system to this compound.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Gastrópodes/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Timol/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Gastrópodes/fisiologia
3.
Am J Pathol ; 190(1): 48-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31839145

RESUMO

Kv11.1 potassium channels are essential for heart repolarization. Prescription medication that blocks Kv11.1 channels lengthens the ventricular action potential and causes cardiac arrhythmias. Surprisingly little is known about the Kv11.1 channel expression and function in the lung tissue. Here we report that Kv11.1 channels were abundantly expressed in the large pulmonary arteries (PAs) of healthy lung tissues from humans and rats. Kv11.1 channel expression was increased in the lungs of humans affected by chronic obstructive pulmonary disease-associated pulmonary hypertension and in the lungs of rats with pulmonary arterial hypertension (PAH). In healthy lung tissues from humans and rats, Kv11.1 channels were confined to the large PAs. In humans with chronic obstructive pulmonary disease-associated pulmonary hypertension and in rats with PAH, Kv11.1 channels were expressed in both the large and small PAs. The increase in Kv11.1 channel expression closely followed the time-course of the development of pulmonary vascular remodeling in PAH rats. Treatment of PAH rats with dofetilide, an Kv11.1 channel blocker approved by the US Food and Drug Administration for use in the treatment of arrythmia, inhibited PAH-associated pulmonary vascular remodeling. Taken together, the findings from this study uncovered a novel role of Kv11.1 channels in lung function and their potential as new drug targets in the treatment of pulmonary hypertension. The protective effect of dofetilide raises the possibility of repurposing this antiarrhythmic drug for the treatment of patients with pulmonary hypertension.


Assuntos
Arritmias Cardíacas/prevenção & controle , Canal de Potássio ERG1/antagonistas & inibidores , Músculo Liso Vascular/efeitos dos fármacos , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Hipertensão Arterial Pulmonar/complicações , Sulfonamidas/farmacologia , Remodelação Vascular/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/patologia , Estudos de Casos e Controles , Canal de Potássio ERG1/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Prognóstico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Ratos Sprague-Dawley
4.
Life Sci ; 240: 117068, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751583

RESUMO

AIMS: Bradycardia contributes to tachy-brady arrhythmias or sinus arrest during heart failure (HF). Sinoatrial node (SAN) adenosine A1 receptors (ADO A1Rs) are upregulated in HF, and adenosine is known to exert negative chronotropic effects on the SAN. Here, we investigated the role of A1R signaling at physiologically relevant ADO concentrations on HF SAN pacemaker cells. MAIN METHODS: Dogs with tachypacing-induced chronic HF and normal controls (CTL) were studied. SAN tissue was collected for A1R and GIRK mRNA quantification. SAN cells were isolated for perforated patch clamp recordings and firing rate (bpm), slope of slow diastolic depolarization (SDD), and maximum diastolic potential (MDP) were measured. Action potentials (APs) and currents were recorded before and after addition of 1 and 10 µM ADO. To assess contributions of A1R and G protein-coupled Inward Rectifier Potassium Current (GIRK) to ADO effects, APs were measured after the addition of DPCPX (selective A1R antagonist) or TPQ (selective GIRK blocker). KEY FINDINGS: A1R and GIRK mRNA expression were significantly increased in HF. In addition, ADO induced greater rate slowing and membrane hyperpolarization in HF vs CTL (p < 0.05). DPCPX prevented ADO-induced rate slowing in CTL and HF cells. The ADO-induced inward rectifying current, IKado, was observed significantly more frequently in HF than in CTL. TPQ prevented ADO-induced rate slowing in HF. SIGNIFICANCE: An increase in A1R and GIRK expression enhances IKAdo, causing hyperpolarization, and subsequent negative chronotropic effects in canine chronic HF at relevant [ADO]. GIRK blockade may be a useful strategy to mitigate bradycardia in HF.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Adenosina/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Receptor A1 de Adenosina/metabolismo , Nó Sinoatrial/citologia , Nó Sinoatrial/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/farmacologia , Animais , Venenos de Abelha/farmacologia , Relógios Biológicos , Doença Crônica , Cães , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/antagonistas & inibidores , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/efeitos dos fármacos , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/farmacologia , Receptor A1 de Adenosina/efeitos dos fármacos , Xantinas/farmacologia
5.
Am J Physiol Heart Circ Physiol ; 318(2): H264-H282, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834834

RESUMO

The ß1-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the ß1-adrenergic signaling system can lead to cardiac hypertrophy and heart failure. To understand the mechanisms of action of ß1-adrenoceptors, a mathematical model of cardiac myocyte contraction that includes the ß1-adrenergic system was developed and studied. The model was able to simulate major experimental protocols for measurements of steady-state force-calcium relationships, cross-bridge release rate and force development rate, force-velocity relationship, and force redevelopment rate. It also reproduced quite well frequency and isoproterenol dependencies for intracellular Ca2+ concentration ([Ca2+]i) transients, total contraction force, and sarcomere shortening. The mathematical model suggested the mechanisms of increased contraction force and myocyte shortening on stimulation of ß1-adrenergic receptors is due to phosphorylation of troponin I and myosin-binding protein C and increased [Ca2+]i transient resulting from activation of the ß1-adrenergic signaling system. The model was used to simulate work-loop contractions and estimate the power during the cardiac cycle as well as the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The developed mathematical model can be used further for simulations of contraction of ventricular myocytes from genetically modified mice and myocytes from mice with chronic cardiac diseases.NEW & NOTEWORTHY A new mathematical model of mouse ventricular myocyte contraction that includes the ß1-adrenergic system was developed. The model simulated major experimental protocols for myocyte contraction and predicted the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The model also allowed for simulations of work-loop contractions and estimation of the power during the cardiac cycle.


Assuntos
Ventrículos do Coração , Contração Miocárdica/fisiologia , Miócitos Cardíacos/fisiologia , Receptores Adrenérgicos beta 1/fisiologia , Algoritmos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Cardiotônicos/farmacologia , Proteínas de Transporte/metabolismo , Simulação por Computador , Frequência Cardíaca/fisiologia , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Camundongos , Modelos Teóricos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Bloqueadores dos Canais de Potássio/farmacologia , Receptores Adrenérgicos beta 1/efeitos dos fármacos , Sarcômeros/fisiologia , Troponina I/metabolismo , Troponina I/fisiologia
6.
Dig Dis ; 38(2): 104-111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31846972

RESUMO

Less than 2 centuries have elapsed since the identification of hydrochloric acid in the stomach. The clarification of the molecular mechanisms allowed the effective therapeutic suppression of gastric acid secretion. The spectacular advances in the treatment of acid-related disorders represent a synthesis of the contributions of several brilliant pharmacologists, basic scientists, and clinical physicians. Effective gastric acid suppressive therapy has dramatically improved the therapy and outcome of acid-related disorders. The introduction of proton pump inhibitors (PPIs) in clinical practice has significantly changed the medical management of upper gastrointestinal disorders. PPIs represent the "gold-standard" therapy in acid-related disorders. However, some challenges persist in the therapy of acid related diseases, including management of patients who respond inadequately to PPI therapy, more effective gastroprotection, or more powerful antisecretory treatment for the eradication of Helicobacter pylori infection. New antisecretory drugs are currently being developed and investigated to further provide a more effective and profound gastric acid secretion inhibition. The major advance has been the development of acid pump -antagonists, the potassium channel acid blocking drugs (-P-CABs). Long-term studies comparing P-CABs with PPIs will help to define the exact place and safety profile of this class of drug in the management of acid-related disorders.


Assuntos
Ácido Gástrico/metabolismo , Fármacos Gastrointestinais/farmacologia , Desenvolvimento de Medicamentos , Fármacos Gastrointestinais/uso terapêutico , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Bloqueadores dos Canais de Potássio/farmacologia , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico
7.
Radiat Res ; 193(2): 171-185, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31877256

RESUMO

Radiation-induced lung injury (RILI) is a common and severe side effect of thoracic radiotherapy, which compromises patients' quality of life. Recent studies revealed that early vascular injury, especially microvascular damage, played a central role in the development of RILI. For this reason, early vascular protection is essential for RILI therapy. The ATP-sensitive K+ (KATP) channel is an ATP-dependent K+ channel with multiple subunits. The protective role of the KATP channel in vascular injury has been demonstrated in some published studies. In this work, we investigated the effect of KATP channel on RILI. Our findings confirmed that the KATP channel blocker glibenclamide, rather than the KATP channel opener pinacidil, remitted RILI, and in particular, provided protection against radiation-induced vascular injury. Cytology experiments verified that glibenclamide enhanced cell viability, increased the potential of proliferation after irradiation and attenuated radiation-induced apoptosis. Involved mechanisms included increased Ca2+ influx and PKC activation, which were induced by glibenclamide pretreatment. In conclusion, the KATP channel blocker glibenclamide remitted RILI and inhibited the radiation-induced apoptosis of vascular endothelial cells by increased Ca2+ influx and subsequent PKC activation.


Assuntos
Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Glibureto/farmacologia , Canais KATP/antagonistas & inibidores , Lesão Pulmonar/prevenção & controle , Proteína Quinase C/metabolismo , Lesões Experimentais por Radiação/prevenção & controle , Animais , Apoptose/efeitos da radiação , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Bloqueadores dos Canais de Potássio/farmacologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Pneumonite por Radiação/prevenção & controle
8.
Eur J Pharmacol ; 866: 172815, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31747546

RESUMO

Juglone (5-hydroxy-1, 4-naphthoquinone), is a natural phenolic compound that has been shown to relax smooth muscle. Therefore the aim of this study was to determine the effect of juglone on vascular tone using porcine coronary artery (PCA). Segments of PCA, with or without endothelium, were mounted for isometric tension recording in isolated tissue baths and precontracted with the thromboxane A2 analog U46619 or KCl. After pre-contraction, cumulative concentrations of juglone were added to the tissues, in the presence or absence of a variety of inhibitors on intracellular signaling pathways. Juglone (10-9 to 10-5 M) produced a concentration-dependent relaxation of the PCA which was reduced in endothelium-denuded vessels, as well as in vessels pre-treated with the nitric oxide synthase inhibitor L-NAME, indicating that at least part of the effect of juglone is mediated through an endothelium, NO-dependent mechanism. Juglone also inhibited contractions in response to influx of extracellular calcium and release of intracellular calcium, indicating that juglone may inhibit a common signaling pathway downstream of calcium. Contractions to the protein kinase C activator Phorbol 12-myristate 13-acetate were also reduced by juglone, suggesting that juglone might be acting through inhibition of protein kinase C. In summary, juglone produces a relaxation of the porcine coronary artery through activation of the nitric oxide pathway and inhibition of calcium-induced contractions.


Assuntos
Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiologia , Naftoquinonas/farmacologia , Suínos , Vasodilatadores/farmacologia , Animais , Cafeína/farmacologia , Cálcio/farmacologia , GMP Cíclico/metabolismo , Indóis/farmacologia , Ionomicina/farmacologia , Óxido Nítrico/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
9.
Eur J Pharmacol ; 866: 172820, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31760069

RESUMO

Recently, we found cardioprotective effects of ischemic preconditioning (IPC), and from a blocker of KCNQ voltage-gated K+ channels (KV7), XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), in isolated rat hearts. The purpose of the present study was to investigate the cardiovascular effects of IPC and XE991 and whether they are cardioprotective in intact rats. In conscious rats, we measured the effect of the KV7 channel blocker XE991 on heart rate and blood pressure by use of telemetry. In anesthetized rats, cardiac ischemia was induced by occluding the left coronary artery, and the animals received IPC (2 × 5 min of occlusion), XE991, or a combination. After a 2 h reperfusion period, the hearts were excised, and the area at risk and infarct size were determined. In both anesthetized and conscious rats, XE991 increased blood pressure, and the highest dose (7.5 mg/kg) of XE991 also increased heart rate, and 44% of conscious rats died. XE991 induced marked changes in the electrocardiogram (e.g., increased PR interval and prolonged QTC interval) without changing cardiac action potentials. The infarct size to area at risk ratio was reduced from 53 ± 2% (n = 8) in the vehicle compared to 36 ± 3% in the IPC group (P < 0.05, n = 9). XE991 (0.75 mg/kg) treatment alone or on top of IPC failed to reduce myocardial infarct size. Similar to the effect in isolated hearts, locally applied IPC was cardioprotective in intact animals exposed to ischemia-reperfusion. Systemic administration of XE991 failed to protect the heart against ischemia-reperfusion injury suggesting effects on the autonomic nervous system counteracting the cardioprotection in intact animals.


Assuntos
Precondicionamento Isquêmico Miocárdico , Canais de Potássio KCNQ/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Bloqueadores dos Canais de Potássio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antracenos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Ratos , Ratos Wistar
10.
Science ; 366(6472): 1486-1492, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31857479

RESUMO

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.


Assuntos
Síndrome de Angelman/metabolismo , Canais de Cálcio Tipo N/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Síndrome de Angelman/fisiopatologia , Animais , Epilepsia/metabolismo , Humanos , Camundongos , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Organoides , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Convulsões/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
11.
Fitoterapia ; 139: 104394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669719

RESUMO

Naturally occurring monoterpenes are known for their various pharmacological activities including anti-inflammation. KV1.3 ion channel is a voltage-gated potassium channel and has been validated as a drug target for autoimmune and chronic inflammatory diseases like psoriasis. Here we experimentally test the direct interaction between monoterpenes and KV1.3 ion channel. Our electrophysiological analysis determined that monoterpenes (geraniol, nerol, ß-citronellol, citral and linalool) have inhibitory effects on KV1.3 ion channel. Representatively, geraniol reversibly blocked KV1.3 currents in a voltage-dependent manner with an IC50 of 490.50 ±â€¯1.04 µM at +40 mV in HEK293T cells. At the effective concentrations, geraniol also inhibited cytokine secretion of activated human T cells, including IL-2, TNF-α and IFN-γ. In an imiquimod-induced psoriasis-like animal model, geraniol administration significantly reduced psoriasis area and severity index scores, ameliorated the deteriorating histopathology and decreased the degree of splenomegaly. Together, our findings not only suggest that monoterpenes may serve as lead molecules for the development of KV1.3 inhibitors, but also indicate that geraniol could be considered as a promising therapeutic candidate to treat autoimmune diseases.


Assuntos
Monoterpenos Acíclicos/farmacologia , Anti-Inflamatórios/farmacologia , Canal de Potássio Kv1.3/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Psoríase/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
12.
Bull Exp Biol Med ; 168(2): 187-192, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776956

RESUMO

The whole-cell patch-clamp technique was used to examine the effect of gadolinium Gd3+ (a non-specific blocker of mechanically gated current IMGCh, a component of late current IL) on ionic currents in insolated rat ventricular cardiomyocytes alone and in combination with the blockers of L-type calcium currents (ICaL) nifedipine (10 µM) or verapamil (1 µM). In K+in/K+out or Cs+in/Cs+out media, blockade of ICaL produced no effect on IL at negative potentials, but inhibited IL at positive ones. In K+in/K+out medium, Gd3+ (5 µM) decreased the net persistent current (Inp) at -45 mV from 198.6±6.4 to 96.7±9.5 pA over 15 min. Gd3+ alone or in combination with ICaL blockers shifted the reversal potential of IL to more negative values. At negative potentials, Gd3+ decreased IK1 and inward current including IMGCh. At positive potentials, Gd3+ alone or in combination with ICaL blockers decreased IL. When applied for 15 min in Cs+in/Cs+out medium at -45 mV, Gd3+ produced no effect on net current and inward and outward components of IL. Thus, Gd3+ can be viewed as a specific blocker of IMGCh only in Cs+ medium.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Gadolínio/farmacologia , Transporte de Íons/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Canais de Cálcio/metabolismo , Césio/metabolismo , Ventrículos do Coração/citologia , Masculino , Nifedipino/farmacologia , Técnicas de Patch-Clamp , Canais de Potássio/metabolismo , Ratos , Verapamil/farmacologia
13.
Prog Chem Org Nat Prod ; 110: 177-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621014

RESUMO

Interference with the hERG potassium ion channel may cause cardiac arrhythmia and can even lead to death. Over the last few decades, several drugs, already on the market, and many more investigational drugs in various development stages, have had to be discontinued because of their hERG-associated toxicity. To recognize potential hERG activity in the early stages of drug development, a wide array of computational tools, based on different principles, such as 3D QSAR, 2D and 3D similarity, and machine learning, have been developed and are reviewed in this chapter. The various available prediction tools Similarity Ensemble Approach, SuperPred, SwissTargetPrediction, HitPick, admetSAR, PASSonline, Pred-hERG, and VirtualToxLab™ were used to screen a dataset of known hERG synthetic and natural product actives and inactives to quantify and compare their predictive power. This contribution will allow the reader to evaluate the suitability of these computational methods for their own related projects. There is an unmet need for natural product-specific prediction tools in this field.


Assuntos
Produtos Biológicos/farmacologia , Biologia Computacional , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Química Farmacêutica , Humanos , Aprendizado de Máquina , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade
14.
J Physiol Pharmacol ; 70(3)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31566191

RESUMO

We hypothesized that the repolarization phase of action potentials (APs) in mammals with large body mass and high cardiac output could not be reliably controlled by only one of the delayed rectifier potassium IK current components. To test this hypothesis experimentally, we performed a comparative study of the response of AP phases to the rapid IKr channels blocker E-4031 and slow IKs blocker chromanol 293B in APs spontaneously generated in strips of sinoauricular (SA) tissue from mouse, guinea pig, and pig hearts. Application of a slow channels blocker chromanol 293B caused a decrease of Aps generation frequency in SA area strips from mouse, guinea-pig and pig by 5.3, 16, and 18% compared to the control. Treatment with the IKr blocker E-4031 caused a significant reduction of APs generation frequency in the mouse, guinea pig, and pig SA strips by 24, 26, and 36%, respectively, compared to the control values. These results suggest that the rapid IKr current is the key component responsible for AP generation in sinoauricular node cells of the pig heart.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais de Potássio/metabolismo , Potássio/metabolismo , Nó Sinoatrial/fisiologia , Animais , Cromanos/farmacologia , Cobaias , Masculino , Camundongos , Bloqueadores dos Canais de Potássio/farmacologia , Nó Sinoatrial/metabolismo , Sulfonamidas/farmacologia , Suínos
15.
Expert Rev Clin Pharmacol ; 12(11): 1013-1018, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31639317

RESUMO

Introduction: Lambert-Eaton myasthenic syndrome is an autoimmune disease of the neuromuscular junction characterized by a presynaptic defect of neuromuscular transmission resulting in muscle weakness and fatigability. Diagnostic features are specific neurophysiological alterations and autoantibody detection. The present review is focused on the use of Amifampridine Phosphate to treat LEMS patients.Areas covered: Medline search from 1990 to 2019 was examined using the free subject terms: Lambert-Eaton myasthenic syndrome, LEMS, Amifampridine, 3,4-diaminopyridine, which were then combined with Treatment, Therapy, Clinical Trial, Controlled Clinical Trial, Randomized Clinical Trial and Cochrane Review. The author has done a supervised analysis of the retrieved articles and focused on those subjectively evaluated as most relevant.Expert commentary: Data from randomized clinical trials and case series have demonstrated that Lambert-Eaton myasthenic syndrome symptoms were successfully treated by Amifampridine Phosphate. Hence, the drug represents a substantial step forward in the symptomatic treatment of the disease due to its efficacy, safety and reliable GMP formulation. As Amifampridine Phosphate works by enhancing the release of acetylcholine at the neuromuscular junction by blocking K+ efflux at the pre-synaptic membrane, it is also conceivable to use it for other diseases of the neuromuscular junction in which such an effect is searched for.


Assuntos
Amifampridina/administração & dosagem , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Fármacos Neuromusculares/administração & dosagem , Amifampridina/efeitos adversos , Amifampridina/farmacologia , Humanos , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Fármacos Neuromusculares/efeitos adversos , Fármacos Neuromusculares/farmacologia , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/efeitos adversos , Bloqueadores dos Canais de Potássio/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Comprimidos
16.
Am J Physiol Regul Integr Comp Physiol ; 317(6): R921-R931, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31664867

RESUMO

There is significant interest in the potential utility of small-molecule activator compounds to mitigate cardiac arrhythmia caused by loss of function of hERG1a voltage-gated potassium channels. Zebrafish (Danio rerio) have been proposed as a cost-effective, high-throughput drug-screening model to identify compounds that cause hERG1a dysfunction. However, there are no reports on the effects of hERG1a activator compounds in zebrafish and consequently on the utility of the model to screen for potential gain-of-function therapeutics. Here, we examined the effects of hERG1a blocker and types 1 and 2 activator compounds on isolated zkcnh6a (zERG3) channels in the Xenopus oocyte expression system as well as action potentials recorded from ex vivo adult zebrafish whole hearts using optical mapping. Our functional data from isolated zkcnh6a channels show that under the conditions tested, these channels are blocked by hERG1a channel blockers (dofetilide and terfenadine), and activated by type 1 (RPR260243) and type 2 (NS1643, PD-118057) hERG1a activators with higher affinity than hKCNH2a channels (except NS1643), with differences accounted for by different biophysical properties in the two channels. In ex vivo zebrafish whole hearts, two of the three hERG1a activators examined caused abbreviation of the action potential duration (APD), whereas hERG1a blockers caused APD prolongation. These data represent, to our knowledge, the first pharmacological characterization of isolated zkcnh6a channels and the first assessment of hERG enhancing therapeutics in zebrafish. Our findings lead us to suggest that the zebrafish ex vivo whole heart model serves as a valuable tool in the screening of hKCNH2a blocker and activator compounds.


Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Coração/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Proteínas de Peixe-Zebra/metabolismo , Animais , Clorobenzenos/farmacologia , Cresóis/farmacologia , Canais de Potássio Éter-A-Go-Go/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1 não Sedativos/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Fenetilaminas/farmacologia , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Terfenadina/farmacologia , Xenopus laevis , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , ortoaminobenzoatos/farmacologia
17.
Neuron ; 104(2): 370-384.e5, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31537465

RESUMO

Sleep pressure increases during wake and dissipates during sleep, but the molecules and neurons that measure homeostatic sleep pressure remain poorly understood. We present a pharmacological assay in larval zebrafish that generates short-term increases in wakefulness followed by sustained rebound sleep after washout. The intensity of global neuronal activity during drug-induced wakefulness predicted the amount of subsequent rebound sleep. Whole-brain mapping with the neuronal activity marker phosphorylated extracellular signal-regulated kinase (pERK) identified preoptic Galanin (Galn)-expressing neurons as selectively active during rebound sleep, and the relative induction of galn transcripts was predictive of total rebound sleep time. Galn is required for sleep homeostasis, as galn mutants almost completely lacked rebound sleep following both pharmacologically induced neuronal activity and physical sleep deprivation. These results suggest that Galn plays a key role in responding to sleep pressure signals derived from neuronal activity and functions as an output arm of the vertebrate sleep homeostat.


Assuntos
Antagonistas GABAérgicos/farmacologia , Galanina/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Privação do Sono/metabolismo , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , 4-Aminopiridina/farmacologia , Aconitina/farmacologia , Animais , Cafeína/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Galanina/genética , Galanina/metabolismo , Homeostase , Mutação , Neurônios/metabolismo , Fosforilação , Bloqueadores dos Canais de Potássio/farmacologia , Área Pré-Óptica , Antagonistas de Receptores Purinérgicos P1/farmacologia , Sono/genética , Agonistas do Canal de Sódio Disparado por Voltagem/farmacologia , Vigília/genética , Peixe-Zebra
18.
PLoS Pathog ; 15(9): e1008041, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31553770

RESUMO

Filariae are parasitic nematodes that are transmitted to their definitive host as third-stage larvae by arthropod vectors like mosquitoes. Filariae cause diseases including: lymphatic filariasis with distressing and disturbing symptoms like elephantiasis; and river blindness. Filarial diseases affect millions of people in 73 countries throughout the topics and sub-tropics. The drugs available for mass drug administration, (ivermectin, albendazole and diethylcarbamazine), are ineffective against adult filariae (macrofilariae) at the registered dosing regimen; this generates a real and urgent need to identify effective macrofilaricides. Emodepside, a veterinary anthelmintic registered for treatment of nematode infections in cats and dogs, is reported to have macrofilaricidal effects. Here, we explore the mode of action of emodepside using adult Brugia malayi, one of the species that causes lymphatic filariasis. Whole-parasite motility measurement with Worminator and patch-clamp of single muscle cells show that emodepside potently inhibits motility by activating voltage-gated potassium channels and that the male is more sensitive than the female. RNAi knock down suggests that emodepside targets SLO-1 K channels. We expressed slo-1 isoforms, with alternatively spliced exons at the RCK1 (Regulator of Conductance of Potassium) domain, heterologously in Xenopus laevis oocytes. We discovered that the slo-1f isoform, found in muscles of males, is more sensitive to emodepside than the slo-1a isoform found in muscles of females; and selective RNAi of the slo-1a isoform in female worms increased emodepside potency. In Onchocerca volvulus, that causes river blindness, we found two isoforms in adult females with homology to Bma-SLO-1A and Bma-SLO-1F at the RCK1 domain. In silico modeling identified an emodepside binding pocket in the same RCK1 region of different species of filaria that is affected by these splice variations. Our observations show that emodepside has potent macrofilaricidal effects and alternative splicing in the RCK1 binding pocket affects potency. Therefore, the evaluation of potential sex-dependent effects of an anthelmintic compound is of importance to prevent any under-dosing of one or the other gender of nematodes once given to patients.


Assuntos
Brugia Malayi/efeitos dos fármacos , Brugia Malayi/fisiologia , Depsipeptídeos/farmacologia , Filaricidas/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Brugia Malayi/genética , Feminino , Filariose/tratamento farmacológico , Filariose/parasitologia , Técnicas de Silenciamento de Genes , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Alta/química , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Masculino , Modelos Moleculares , Movimento/efeitos dos fármacos , Movimento/fisiologia , Músculos/efeitos dos fármacos , Músculos/fisiologia , Peptídeos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Homologia de Sequência de Aminoácidos , Fatores Sexuais
19.
PLoS One ; 14(9): e0217733, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31479461

RESUMO

Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (IKr) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K+channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine is a cyclin-dependent kinase (CDK) inhibitor that induces apoptosis in colorectal, breast, prostate, multiple myeloma, other cancer cell lines, and tumor xenografts, in micromolar concentrations. It is well tolerated in phase II clinical trials. R-roscovitine inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or hERG pore mutant channels (T623A, S624A, Y652A, F656A) demonstrated that compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 µM R-roscovitine was ~ 48%, 29%, and 73% weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with a ~ 34% stronger inhibition. These findings were further supported by the IC50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be. Docking studies further support our findings. Thus, R-roscovitine's relatively unique features, coupled with its tolerance in clinical trials, could guide future drug screens.


Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/química , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Relação Dose-Resposta a Droga , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/genética , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Conformação Proteica , Relação Estrutura-Atividade
20.
J Ethnopharmacol ; 245: 112156, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31415847

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Uapaca togoensis is a medicinal plant used traditionally in Africa for the treatment of rheumatism, epilepsy, cough, pneumonia, vomitting and fever. Previously, the analgesic activity of its methanol stem bark extract has been scientifically demonstrated. However, the mechanism responsible for this activity remains to be investigated. AIM OF THE STUDY: To elucidate the possible mechanism(s) through which the methanol stem bark extract of Uapaca togoensis (MEUT) exhibits analgesic activity in mice. MATERIALS AND METHODS: Analgesic activity of MEUT was evaluated using acetic acid-induced abdominal writhing test in mice at doses of 250, 500 and 1000 mg/kg orally. For the mechanistic studies, mice were pre-treated with Naloxone (2 mg/kg), Atropine (1 mg/kg), Yohimbine (1 mg/kg), Glibenclamide (10 mg/kg), Prazosin (1 mg/kg) and Yohimbine (1 mg/kg) 15 min prior to MEUT (1000 mg/kg) administration, then assessed using AAWT 1 h later. Data was analysed using One way Anova followed by Bonferroni post hoc test. RESULTS: The extract (at the doses of 250, 500 and 1000 mg/kg) and morphine (10 mg/kg) significantly (p < 0.05) decreased the number of abdominal writhes. Naloxone (opioid receptor antagonist), Atropine (muscarinic receptor antagonist) and Glibenclamide (ATP-sensitive K+ channel blocker) significantly (p < 0.05) reversed the analgesic effect of MEUT. On the other hand, Prazosin and Yohimbine (α1 and α2 receptor antagonists respectively) had no effect on the analgesic action of MEUT. CONCLUSION: The results obtained from this study suggests the possible involvement of opioidergic, cholinergic and sensitive potassium ATP channel pathways in the analgesic activity of the methanol stem bark extract of Uapaca togoensis.


Assuntos
Analgésicos/uso terapêutico , Coffea , Dor/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ácido Acético , Analgésicos/toxicidade , Animais , Atropina/farmacologia , Feminino , Glibureto/farmacologia , Dose Letal Mediana , Masculino , Metanol/química , Camundongos , Antagonistas Muscarínicos/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Casca de Planta/química , Extratos Vegetais/toxicidade , Bloqueadores dos Canais de Potássio/farmacologia , Solventes/química
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