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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2303-2306, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018468

RESUMO

There is increasing evidence on the role of the autonomic nervous system in the pathogenesis of atrial fibrillation. Interventions targeting autonomic modulation of atrial electrical activity have been shown to reduce the incidence of atrial arrhythmias. Additionally, recent investigations have proved that pharmacological therapies inhibiting small-conductance calcium-activated potassium (SK) channels are able to lessen cholinergic effects in the atria.In this study we use computational modeling and simulation to test individual and combined effects of SK channel block and adrenergic stimulation in counteracting detrimental effects induced by the parasympathetic neurotransmitter acetylcholine (ACh) on human atrial electrophysiology. Cell and tissue models are built that incorporate descriptions of SK channels as well as of isoproterenol (Iso)- and ACh-mediated regulation of the atrial action potential (AP). Three different cellular AP models, representing a range of physiological AP shapes, are considered and both homogeneous and heterogeneous ACh distributions in atrial tissue are simulated.At the cellular level, SK channel block is demonstrated to partially revert shortening of AP duration (APD) mediated by ACh at various doses, whereas 1 µM Iso has a variable response depending on the AP shape. The combination of SK block and Iso is in all cases able to take APD back to baseline levels, recovering between 82% and 120% of the APD shortening induced by 0.1 µM ACh. At the tissue level, SK block and Iso alone or in combination do not exert remarkable effects on conduction velocity, but the combination of the two is able to notably prolong the ACh-mediated APD shortening, thus increasing the wavelength for reentry.In conclusion, the results from this study support the combination of SK channel block and adrenergic stimulation as a potential option to counteract parasympathetically-mediated proarrhythmic effects in the human atria.


Assuntos
Acetilcolina , Fibrilação Atrial , Acetilcolina/farmacologia , Adrenérgicos , Átrios do Coração , Humanos , Isoproterenol/farmacologia
2.
PLoS One ; 15(5): e0232530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32384091

RESUMO

BACKGROUND: Clinical and animal studies have found that anxiety and depression are significantly more common after acute myocardial infarction (AMI). The medial prefrontal cortex (PFC) has a dual role: in higher brain functions and in cardiovascular control, making it a logical candidate for explaining the perceived bidirectional heart-brain connection. We used parallel Electrocardiography (ECG) and Electrocorticography (ECoG) registration to investigate AMI-induced changes in medial PFC bioelectrical activity in a rat model of AMI. MATERIALS AND METHODS: Adult male Wistar albino rats were used in the study. Gold-plated recording electrodes were implanted over the frontal cortex for ECoG recording. ECG was recorded via two holter electrodes attached on the skin of the back fixed in place by a jacket. Induction of AMI was performed by isoprenaline (150 mg/kg, i.p.). ECoG and ECG signals were registered at baseline, during 3 hours after isoprenaline administration and at 24 hours after isoprenaline administration. RESULTS: Significant increases of theta, alpha, and beta electroencephalographic (EEG) band power were observed in different time intervals after isoprenaline administration. Significant increase of theta band peak frequency was also observed during the first hour after isoprenaline administration. No statistically significant differences in band-power activity were found between the pre-isoprenaline measurements and 24 hours after administration. CONCLUSION: Our results demonstrate significant increases in EEG band power of alpha beta and theta bands during isoprenaline-induced AMI model. These are the first findings to connect heart damage during isoprenaline- induced AMI to disturbances in the cortical bioelectrical activity.


Assuntos
Isoproterenol/farmacologia , Infarto do Miocárdio/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Ondas Encefálicas/fisiologia , Modelos Animais de Doenças , Eletrocardiografia , Eletrocorticografia , Eletroencefalografia , Masculino , Infarto do Miocárdio/induzido quimicamente , Ratos , Ratos Wistar
3.
J Pharmacol Sci ; 143(3): 133-140, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253104

RESUMO

Endogenous noradrenaline (NA) has multiple bioactive functions and, in the central nervous system (CNS), has been implicated in modulating neuroinflammation via ß-adrenergic receptors (ß-ARs). Microglia, resident macrophages in the CNS, have a central role in the brain immune system and have been reported to be activated by NA. However, intracellular signaling mechanisms of the AR-mediated proinflammatory responses of microglia are not fully understood. Using a rapid and stable in vitro reporter assay system to evaluate IL-1ß production in microglial BV2 cells, we found that NA and the ß-AR agonist isoproterenol upregulated the IL-1ß reporter activity. This effect was suppressed by ß-AR antagonists. We further examined the involvement of EPAC (exchange protein directly activated by cAMP) and TPL2 (tumor progression locus 2, MAP3K8) and found that inhibitors for EPAC and TPL2 reduced AR agonist-induced IL-1ß reporter activity. These inhibitors also suppressed NA-induced endogenous Il1b mRNA expression and IL-1ß protein production. Our results suggest that EPAC and TPL2 are involved in ß-AR-mediated IL-1ß production in microglial cells, and extend our understanding of its intracellular signaling mechanism.


Assuntos
Acetilcisteína/análogos & derivados , Eritromicina/análogos & derivados , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinases/farmacologia , Microglia/metabolismo , Proteínas Proto-Oncogênicas/farmacologia , Acetilcisteína/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Eritromicina/farmacologia , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Isoproterenol/farmacologia , MAP Quinase Quinase Quinases/fisiologia , Camundongos , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Adrenérgicos beta , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
4.
Biol Pharm Bull ; 43(3): 493-502, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115508

RESUMO

The ß-adrenoceptor (ß-AR)-mediated pharmacological effects of catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (ß2-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (ß1-AR dominant), normetadrenaline (NMA) and MA (10-4 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10-4 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10-4 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10-4 M) significantly suppressed ISO-induced relaxation. DHPG (10-4 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10-4 M) significantly suppressed relaxation induced by CGP-12177 A (a ß3-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess ß2-AR agonistic action; 2) NMA and MA augment ß2-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing ß1-, ß2-AR antagonistic action (ß2 > ß1); 3) DHPG exhibits ß1-, ß2-, ß3-AR antagonistic action, and this is particularly marked for ß3-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Aorta/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Animais , Carbacol/farmacologia , Cobaias , Isoproterenol/farmacologia , Masculino , Camundongos , Propranolol/farmacologia , Ratos , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 2/metabolismo
5.
Life Sci ; 249: 117476, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32119962

RESUMO

Mangiferin is a well-known xanthone extracted from mango leaves (Mangifera indica Linn). Mangiferin is widely distributed in the bark, peel, leaf, seed, stalk, and kernel of mango and higher plants. The pharmacological properties of mangiferin, including its antioxidant, anticancer, antiaging, antiviral, hepatoprotective, analgesic, and immunomodulatory activities, have been described in several studies. We investigated the effect of mangiferin on isoproterenol-induced apoptosis. Experimental heart failure was induced in rats by intraperitoneal administration of isoproterenol (5 mg/kg) for 7 consecutive days. Rats were divided into five groups: group I (sham rats), group II (isoproterenol alone control), group III (isoproterenol + 25 mg/kg mangiferin), group IV (isoproterenol + 50 mg/kg mangiferin), and group V (isoproterenol + 0.0225 mg/kg digitalis as a positive control). Hemodynamic parameters and body weight, heart weight and liver weight, apoptosis induction, and caspase-3, Bax, and Bcl-2 protein levels were measured, and a histopathological analysis of cardiomyocytes was performed. In addition, apoptosis and protein expression of caspase-3, cleaved caspase-3, Bax, and Bcl-2 were measured in cardiac H9c2 cells. Mangiferin supplementation significantly increased heart rate and improved the maximum rate of decrease in left ventricular (LV) pressure, the maximum rate of increase in LV pressure, and LV systolic pressure. Mangiferin reduced inflammatory cell infiltration and the number of broken myocardial fibers, and decreased apoptosis in cardiomyocytes by reducing proteins levels of caspase-3 and Bax and increasing those of Bcl-2. Our findings suggest that mangiferin has a cardioprotective effect against isoproterenol-induced apoptosis in cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Xantonas/farmacologia , Animais , Cardiotônicos/administração & dosagem , Injeções Intraperitoneais , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Ratos
6.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1248-L1260, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32209026

RESUMO

Emerging evidence suggests that gut microbiota-derived short-chain fatty acids (SCFAs; acetate, propionate, and butyrate) are important modulators of the inflammatory state in diseases such as asthma. However, the functional expression of the Gi protein-coupled free fatty acid receptors (FFAR2/GPR43 and FFAR3/GPR41) has not been identified on airway smooth muscle (ASM). Classically, acute activation of Gi-coupled receptors inhibits cyclic AMP (cAMP) synthesis, which impairs ASM relaxation and can also induce crosstalk between Gi- and Gq-signaling pathways, potentiating increases in intracellular Ca2+ concentration ([Ca2+]i), favoring ASM contraction. In contrast, chronic activation of Gi-coupled receptors can sensitize adenylyl cyclase resulting in increased cAMP synthesis favoring relaxation. We questioned whether the Gi-coupled FFAR2 or FFAR3 is expressed in human ASM, whether they modulate cAMP and [Ca2+]i, and whether SCFAs modulate human ASM tone. We detected the protein expression of FFAR3 but not FFAR2 in native human ASM and primary cultured human airway smooth muscle (HASM) cells. In HASM cells, acute activation of FFAR3 with SCFAs inhibited forskolin-stimulated cAMP accumulation, but chronic activation did not sensitize cAMP synthesis. SCFAs induced [Ca2+]i increases that were attenuated by pertussis toxin, gallein, U73122, or xestospongin C. Acute treatment with SCFAs potentiated acetylcholine-stimulated [Ca2+]i increases and stress fiber formation in cells and contraction of ex vivo human airway tissues. In contrast, chronic pretreatment of human ASM with propionate did not potentiate airway relaxation. Together, these findings demonstrate that FFAR3 is expressed in human ASM and contributes to ASM contraction via reduced cAMP and increased [Ca2+]i.


Assuntos
Pulmão/fisiologia , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Receptores Acoplados a Proteínas-G/metabolismo , Acetilcolina/farmacologia , Adulto , Cálcio/metabolismo , Células Cultivadas , Colforsina/farmacologia , AMP Cíclico/metabolismo , Ácidos Graxos Voláteis/farmacologia , Humanos , Isoproterenol/farmacologia , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-32101015

RESUMO

The hyperconstriction of airway smooth muscle (ASM) is the main driving mechanism during an asthmatic attack. The airway lumen is reduced, resistance to airflow increases, and normal breathing becomes more difficult. The tissue contraction can be temporarily relieved by using bronchodilator drugs, which induce relaxation of the constricted airways. In vitro studies indicate that relaxation of isolated, precontracted ASM is induced by mechanical oscillations in healthy subjects but not in asthmatic subjects. Further, short-term acute asthmatic subjects respond to superimposed pressure oscillations (SIPO) generated in the range of 5-15 Hz with ~50% relaxation of preconstricted sensitized airways. Mechanical oscillations, and specifically SIPO, are not widely characterized in asthmatic models. The objective of this in vivo study is to determine the effects of a range of oscillation patterns similar to our previous acute study differing from normal breathing. Both healthy and sensitized mice were observed, with their responses to SIPO treatments measured during induced bronchoconstriction resulting from acetylcholine (Ach) challenge. SIPO-generated results were compared with data from treatments using the bronchorelaxant isoproterenol (ISO). The study shows that SIPO in the range of 5-20 Hz induces relaxation in chronic sensitized airways, with significant improvements in respiratory parameters at SIPO values near 1.7 cmH2O irrespective of the frequency of generation.


Assuntos
Asma/terapia , Pulmão/imunologia , Músculo Liso/imunologia , Acetilcolina/farmacologia , Alérgenos/administração & dosagem , Animais , Antígenos de Plantas/administração & dosagem , Aspergillus/química , Aspergillus/imunologia , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Fenômenos Biomecânicos/imunologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Modelos Animais de Doenças , Feminino , Fungos/química , Fungos/imunologia , Isoproterenol/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Extratos Vegetais/administração & dosagem , Pressão , Pyroglyphidae/química , Pyroglyphidae/imunologia , Testes de Função Respiratória
8.
Sci Rep ; 10(1): 3426, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32099011

RESUMO

The study was conducted to evaluate the cardio-protective activity of combination (COMB) of syringic acid (SA) and resveratrol (RV) against isoproterenol (ISO) induced cardio-toxicity in rats. Rats were pre-treated orally with SA (50 mg/kg), RV (50 mg/kg) and combination of SA (25 mg/kg) and RV (25 mg/kg) along with positive control gallic acid (50 mg/kg) for 30 days. The effects of ISO on cardiac markers, lipid profile and lipid peroxidation marker, anti-oxidant enzymes and m-RNA expression of nuclear factor-kappa B (NF-kB) and tumor necrosis factor-α (TNF-α) were observed along with histopathological observations of simple and transmission electron microscopes (TEM). Serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and alkaline phosphatase were significantly increased while cardiac tissue CK-MB, LDH, superoxide dismutase and catalase were significantly decreased in ISO administered rats, which also exhibited a significant increase in total cholesterol, triglycerides, low density lipoprotein cholesterol, very low density lipoprotein cholesterol and thiobarbutyric acid reactive substances and significant decrease in high density lipoprotein cholesterol in serum and heart. The m-RNA levels of inflammatory markers NF-kB and TNF-α were significantly increased in ISO treated rats. COMB Pre-treatment significantly reversed the ISO actions. Histopathological studies of simple and TEM were also co-related with the above biochemical parameters. Docking studies with NF-kB were also performed. Evidence has shown for the first time in this approach that COMB pre-treatment ameliorated ISO induced cardio-toxicity in rats and revealed cardio-protection.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxicidade , Ácido Gálico/análogos & derivados , Isoproterenol/efeitos adversos , NF-kappa B/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Cardiotoxicidade/metabolismo , Cardiotoxicidade/prevenção & controle , Ácido Gálico/farmacologia , Isoproterenol/farmacologia , Masculino , Ratos , Ratos Wistar
9.
Cardiovasc Eng Technol ; 11(2): 205-218, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31916039

RESUMO

PURPOSE: The objective of this study was to bioengineer 3D patches from cardiac myocytes that have been reprogrammed from human adipogenic mesenchymal stem cells (hADMSCs). METHODS: Human adipogenic mesenchymal stem cells (hADMSCs) were reprogrammed to form cardiac myocytes using transcription factors ETS2 and MESP1. Reprogrammed cardiac myocytes were cultured in a fibrin gel to bioengineer 3D patch patches. The effect of initial plating density (1-25 million cells per patch), time (28-day culture period) and treatment with 1 µM isoproterenol and 1 µM epinephrine were evaluated. RESULTS: 3D patches were fabricated using cardiac myocytes that have been reprogrammed from hADMSCs. Based on optimization studies, it was determined that 10 million cells were needed to bioengineer a single patch, that measured 2 × 2 cm2. Furthermore, 3D patches fabricated 10 million cells were stable in culture for up to 28 days. Treatment of 3D patches with 1 µM isoproterenol and 1 µM epinephrine resulted in an increase in the electrical properties, as measured by electrical impulse amplitude and frequency. An increase in the expression of mTOR, KCNV1, GJA5, KCNJ16, CTNNT2, KCNV2, MYO3, FOXO1 and KCND2 was noted in response to treatment of 3D patches with isoproterenol and epinephrine. CONCLUSION: Based on the results of this study, there is evidence to support the successful fabrication of a highly functional 3D patches with measurable electrical activity using cardiac myocytes reprogrammed from hADMSCs. 3D patches fabricated using optimal conductions described in this study can be used to improve the functional properties of failing hearts. Predominantly, in case of the infarcted hearts with partial loss of electrical activity, the electrical properties of the 3D patches may restore the electrical activity of the heart.


Assuntos
Adipogenia , Técnicas de Reprogramação Celular , Reprogramação Celular , Insuficiência Cardíaca/cirurgia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Miócitos Cardíacos/transplante , Engenharia Tecidual , Agonistas Adrenérgicos/farmacologia , Células Cultivadas , Condutividade Elétrica , Epinefrina/farmacologia , Fibrina/metabolismo , Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Isoproterenol/farmacologia , Potenciais da Membrana , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Fatores de Tempo
10.
Braz J Med Biol Res ; 53(2): e8793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994601

RESUMO

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.


Assuntos
Amidas/administração & dosagem , Apoptose/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Fumaratos/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Angiotensina II/farmacologia , Animais , Western Blotting , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Fibrose/induzido quimicamente , Fibrose/prevenção & controle , Citometria de Fluxo , Isoproterenol/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos
11.
Sci Rep ; 10(1): 305, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941982

RESUMO

Sinus node dysfunction (SND) is often associated with atrial fibrillation (AF). Amiodarone is the most frequently used agent for maintaining sinus rhythm in patients with AF, but it impairs the sinoatrial node (SAN) function in one-third of AF patients. This study aims to gain mechanistic insights into the effects of the antiarrhythmic agents in the setting of AF-induced SND. We have adapted a human SAN model to characterize the SND conditions by incorporating experimental data on AF-induced electrical remodelling, and then integrated actions of drugs into the modified model to assess their efficacy. Reductions in pacing rate upon the implementation of AF-induced electrical remodelling associated with SND agreed with the clinical observations. And the simulated results showed the reduced funny current (If) in these remodelled targets mainly contributed to the heart rate reduction. Computational drug treatment simulations predicted a further reduction in heart rate during amiodarone administration, indicating that the reduction was the result of actions of amiodarone on INa, IKur, ICaL, ICaT, If and beta-adrenergic receptors. However, the heart rate was increased in the presence of disopyramide. We concluded that disopyramide may be a desirable choice in reversing the AF-induced SND phenotype.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Modelos Biológicos , Nó Sinoatrial/fisiologia , Acetilcolina/farmacologia , Amiodarona/farmacologia , Amiodarona/uso terapêutico , Antiarrítmicos/farmacologia , Fibrilação Atrial/patologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Isoproterenol/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Nó Sinoatrial/efeitos dos fármacos
12.
Am J Physiol Endocrinol Metab ; 318(2): E164-E172, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31821041

RESUMO

Epicardial adipose tissue (EAT) deposition has a strong clinical association with atrial arrhythmias; however, whether a direct functional interaction exists between EAT and the myocardium to induce atrial arrhythmias is unknown. Therefore, we aimed to determine whether human EAT can be an acute trigger for arrhythmias in human atrial myocardium. Human trabeculae were obtained from right atrial appendages of patients who have had cardiac surgery (n = 89). The propensity of spontaneous contractions (SCs) in the trabeculae (proxy for arrhythmias) was determined under physiological conditions and during known triggers of SCs (high Ca2+, ß-adrenergic stimulation). To determine whether EAT could trigger SCs, trabeculae were exposed to superfusate of fresh human EAT, and medium of 24 h-cultured human EAT treated with ß1/2 (isoproterenol) or ß3 (BRL37344) adrenergic agonists. Without exposure to EAT, high Ca2+ and ß1/2-adrenergic stimulation acutely triggered SCs in, respectively, 47% and 55% of the trabeculae that previously were not spontaneously active. Acute ß3-adrenergic stimulation did not trigger SCs. Exposure of trabeculae to either superfusate of fresh human EAT or untreated medium of 24 h-cultured human EAT did not induce SCs; however, specific ß3-adrenergic stimulation of EAT did trigger SCs in the trabeculae, either when applied to fresh (31%) or cultured (50%) EAT. Additionally, fresh EAT increased trabecular contraction and relaxation, whereas media of cultured EAT only increased function when treated with the ß3-adrenergic agonist. An acute functional interaction between human EAT and human atrial myocardium exists that increases the propensity for atrial arrhythmias, which depends on ß3-adrenergic rather than ß1/2-adrenergic stimulation of EAT.


Assuntos
Tecido Adiposo/fisiopatologia , Arritmias Cardíacas/fisiopatologia , Átrios do Coração/fisiopatologia , Coração/fisiopatologia , Pericárdio/fisiopatologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Idoso , Etanolaminas/farmacologia , Feminino , Humanos , Isoproterenol/farmacologia , Masculino , Contração Miocárdica , Miocárdio/metabolismo
13.
Life Sci ; 241: 117155, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837330

RESUMO

AIMS: ß-Adrenoceptors (ß-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on ß-ADR-mediated relaxation were examined. MAIN METHODS: The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA ß-ADR was detected using RT-PCR. KEY FINDINGS: In endothelium-denuded SMAs contracted with ≥10-7 M phenylephrine (an α1-ADR agonist), isoprenaline (a ß-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10-9-10-8 M propranolol (a ß1,2-ADR antagonist), but not further affected by ≥10-8 M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10-9-10-8 M; a ß2-ADR antagonist), it was competitively inhibited by atenolol (10-7-3 × 10-7 M; a ß1-ADR antagonist) in the presence of ICI-118,551. In the presence of 10-7 M propranolol, isoprenaline- and CGP-12177A (a ß3-ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a ß1,2,3-ADR antagonist), with pA2 values of 6.49 and 5.76, respectively. We detected the mRNA of ß1- and ß3-ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10-7 M propranolol, but not CGP-12177A-induced relaxation. SIGNIFICANCE: Isoprenaline-induced relaxation of rat SMAs is mediated by ß1- and ß3-ADRs. ß-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple ß3-ADRs with different pharmacological properties.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Artéria Mesentérica Superior/fisiologia , Relaxamento Muscular/fisiologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/metabolismo , Simpatectomia Química/métodos , Animais , Isoproterenol/farmacologia , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Propanolaminas/farmacologia , Ratos , Ratos Wistar
14.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 58-63, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31681945

RESUMO

Cardiac hypertrophy is considered to be a leading factor in heart function-related deaths. In this study, we explored the potential mechanism underlying cardiac hypertrophy induced by isoproterenol. Our results showed that isoproterenol induced cardiac hypertrophy in AC16 cells, as reflected by the increased cell surface area and increased hypertrophic markers, which was accompanied by increased ubiquitin-protein ligase E3a (UBE3A) expression. Moreover, UBE3A knockdown by siRNAs accelerated cardiac hypertrophy, suggesting that increased UBE3A expression induced by isoproterenol might be a protective response and UBE3A might be a protective factor against cardiac hypertrophy. Our study also revealed that UBE3A knockdown increased the protein expression of the TLR4/MMP-9 pathway that has been shown to be associated with cardiac hypertrophy, which suggested that UBE3A-mediated protection is likely to be associated with the blockade of the TLR4/MMP-9 signaling pathway. UBE3A might be thus a potential target gene for the treatment of cardiac hypertrophy.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Isoproterenol/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Receptor 4 Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Isoproterenol/efeitos adversos , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , Transfecção , Ubiquitina-Proteína Ligases/genética
15.
Biochem Pharmacol ; 172: 113774, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870769

RESUMO

Acetaminophen is both widely used to treat children with fever and is also responsible for thousands being hospitalised annually. Historically the antipyretic actions of acetaminophen were attributed to the inhibition of cyclooxygenase (COX-1/2) enzymes and more recently a novel COX-1 variant (COX-3) located in the brain. However, the evidence for acetaminophen-mediated COX inhibition remains contentious. This study assesses the impact of acetaminophen and other putative COX-3 inhibitors on the release of fatty acids during lipolysis as an alternative mechanism by which antipyretics can reduce body temperature during fever. 3T3-L1 adipocytes, primary brown adipocytes and isolated mitochondria were exposed to COX-3 inhibitors and lipolysis and mitochondrial electron transport chain function assessed. Acetaminophen, aminopyrine and antipyrine at 1-10 mM caused a significant decrease (up to 70%; P < 0.01, from control) in lipolysis within 1, 3 and 24 h without affecting cell viability. The inhibition was observed regardless of where along its signalling pathway lipolysis was stimulated. All three compounds were found to significantly attenuate mitochondrial function by up to 30% for complex I and 40% for complex II (P < 0.01, from control). These novel observations combined with the known limited inhibition of the COX enzymes by acetaminophen suggest both the antipyretic and hypothermia induced by acetaminophen and related compounds could be attributed to the direct inhibition of lipolysis and mitochondrial function, rather than cyclooxygenase inhibition centrally. Further these observations could provide new drug targets for reducing fever with the added bonus of fewer individuals being hospitalized by accidental acetaminophen overdose.


Assuntos
Acetaminofen/farmacologia , Adipócitos/efeitos dos fármacos , Antipiréticos/farmacologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Lipólise/efeitos dos fármacos , Células 3T3-L1 , 8-Bromo Monofosfato de Adenosina Cíclica/metabolismo , Adipócitos/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Aminopirina/farmacologia , Animais , Antipirina/farmacologia , Diferenciação Celular , Colforsina/metabolismo , Isoproterenol/farmacologia , Camundongos , Ratos , Ratos Wistar
16.
Artigo em Inglês | MEDLINE | ID: mdl-31886723

RESUMO

Rodent models are frequently employed in cardiovascular research, yet our understanding of pediatric cardiac physiology has largely been deduced from more simplified two-dimensional cell studies. Previous studies have shown that postnatal development includes an alteration in the expression of genes and proteins involved in cell coupling, ion channels, and intracellular calcium handling. Accordingly, we hypothesized that postnatal cell maturation is likely to lead to dynamic alterations in whole heart electrophysiology and calcium handling. To test this hypothesis, we employed multiparametric imaging and electrophysiological techniques to quantify developmental changes from neonate to adult. In vivo electrocardiograms were collected to assess changes in heart rate, variability, and atrioventricular conduction (Sprague-Dawley rats). Intact, whole hearts were transferred to a Langendorff-perfusion system for multiparametric imaging (voltage, calcium). Optical mapping was performed in conjunction with an electrophysiology study to assess cardiac dynamics throughout development. Postnatal age was associated with an increase in the heart rate (181 ± 34 vs. 429 ± 13 beats/min), faster atrioventricular conduction (94 ± 13 vs. 46 ± 3 ms), shortened action potentials (APD80: 113 ± 18 vs. 60 ± 17 ms), and decreased ventricular refractoriness (VERP: 157 ± 45 vs. 57 ± 14 ms; neonatal vs. adults, means ± SD, P < 0.05). Calcium handling matured with development, resulting in shortened calcium transient durations (168 ± 18 vs. 117 ± 14 ms) and decreased propensity for calcium transient alternans (160 ± 18- vs. 99 ± 11-ms cycle length threshold; neonatal vs. adults, mean ± SD, P < 0.05). Results of this study can serve as a comprehensive baseline for future studies focused on pediatric disease modeling and/or preclinical testing.NEW & NOTEWORTHY This is the first study to assess cardiac electrophysiology and calcium handling throughout postnatal development, using both in vivo and whole heart models.


Assuntos
Envelhecimento/fisiologia , Cálcio/metabolismo , Cálcio/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Coração/crescimento & desenvolvimento , Coração/fisiologia , Potenciais de Ação/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Animais Recém-Nascidos , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Circulação Coronária/fisiologia , Eletrocardiografia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Coração/efeitos dos fármacos , Sistema de Condução Cardíaco/crescimento & desenvolvimento , Sistema de Condução Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Técnicas In Vitro , Isoproterenol/farmacologia , Perfusão , Ratos , Ratos Sprague-Dawley
17.
Colloids Surf B Biointerfaces ; 186: 110682, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31846891

RESUMO

Over the past few years, cardiac tissue engineering has undergone tremendous progress. Various in vitro methods have been developed to improve the accuracy in the result of drug-induced cardiac toxicity screening. Herein, we propose a novel SU-8 cantilever integrated with an electromechanical-stimulator to enhance the maturation of cultured cardiac cells. The simultaneous electromechanical stimulation significantly enhances the contraction force of the cardiomyocytes, thereby increasing cantilever displacement. Fluorescence microscopy analysis was performed to confirm the improved maturation of the cardiomyocytes. After the initial experiments, the contractile behaviors of the cultured cardiomyocytes were investigated by measuring the mechanical deformation of the SU-8 cantilever. Finally, the proposed electromechanical-stimulator-integrated SU-8 cantilever was used to evaluate the adverse effects of different cardiac vascular drugs, i.e., verapamil, lidocaine, and isoproterenol, on the cultured cardiomyocytes. The physiology of the cardiac-drug-treated cardiomyocytes was examined with and without electrical stimulation of the cardiomyocytes. The experimental results indicate that the proposed cantilever platform can be used as a predictive assay system for preliminary cardiac drug toxicity screening applications.


Assuntos
Técnicas Biossensoriais , Compostos de Epóxi/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Polímeros/farmacologia , Animais , Técnicas Biossensoriais/instrumentação , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacologia , Compostos de Epóxi/química , Isoproterenol/química , Isoproterenol/farmacologia , Lidocaína/química , Lidocaína/farmacologia , Fenômenos Mecânicos , Tamanho da Partícula , Polímeros/química , Propriedades de Superfície , Verapamil/química , Verapamil/farmacologia
18.
Physiol Rep ; 7(24): e14308, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31872972

RESUMO

Obesity is characterized by a blunted lipolytic response in abdominal subcutaneous adipose tissue (SAT) and low circulating vitamin D levels. Here we investigated whether an impaired SAT lipolytic response coincides with an impaired SAT vitamin D release in eight lean and six obese men. 25-hydroxyvitamin D3 [25(OH)D3 ] and 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] fluxes across SAT were measured using arterio-venous blood sampling in combination with AT blood flow measurements after an overnight fast and during 1-hr intravenous infusion of the non-selective ß-adrenergic agonist isoprenaline (20 ng·kg FFM-1 ·min-1 ). 1,25(OH)2 D3 was released across abdominal SAT during isoprenaline infusion in lean [-0.01 (-0.04 to 0.00) pmol*100 g tissue-1 *min-1 , p = .017 vs. zero flux], but not in obese men [0.01 (0.00 to 0.02) pmol*100 g tissue-1 *min-1 , p = .116 vs. zero flux], and accompanied by an impaired isoprenaline-induced lipolytic response in abdominal SAT of obese versus lean men. Isoprenaline had no significant effects on net 25(OH)D3 release across abdominal SAT and plasma vitamin D metabolites in lean and obese men. To conclude, a blunted isoprenaline-mediated lipolysis is accompanied by reduced release of 1,25(OH)2 D3 vitamin D across abdominal SAT in obesity.


Assuntos
Gordura Abdominal/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Di-Hidroxicolecalciferóis/metabolismo , Isoproterenol/farmacologia , Obesidade/metabolismo , Gordura Abdominal/efeitos dos fármacos , Agonistas Adrenérgicos beta/administração & dosagem , Adulto , Di-Hidroxicolecalciferóis/sangue , Humanos , Infusões Intravenosas , Isoproterenol/administração & dosagem , Lipólise , Masculino , Pessoa de Meia-Idade
19.
Cell Mol Biol (Noisy-le-grand) ; 65(7): 132-137, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31880531

RESUMO

A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. ß-Arrestin2 has been shown to restore the inotropic reserve of ß-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of ß-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding ß-arrestin2, or ß-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD50 and APD90) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). ß-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of ß-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD50 and p < 0.001 for APD90), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of ß-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.


Assuntos
Potenciais de Ação/fisiologia , Arritmias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Potássio/metabolismo , beta-Arrestina 2/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Células Cultivadas , Cobaias , Isoproterenol/farmacologia , Masculino , Técnicas de Patch-Clamp , Fenilefrina/farmacologia , beta-Arrestina 2/genética
20.
BMC Cancer ; 19(1): 1142, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771535

RESUMO

BACKGROUND: Chronic stress is well known to promote tumor progression, however, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells. METHODS: The proliferation, migration and invasion of prostate cancer cells were assessed by CCK-8 and transwell assay. HIF-1α expression of osteoblasts and epithelial-mesenchymal transition (EMT) markers of prostate cancer cells were examined by Western blot. The mRNA level of cytokines associated with bone metastasis in osteoblasts and EMT markers in PC-3 and DU145 cells were performed by qRT-PCR. Functional rescue experiment of cells were performed by using siRNA, plasmid transfection and inhibitor treatment. RESULTS: Isoproterenol (ISO), a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT, migration and invasion of PC-3 and DU145 cells, which could be inhibited by ß2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the ß2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. CONCLUSIONS: These findings demonstrated that ß2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer.


Assuntos
Quimiocina CXCL12/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoproterenol/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Camundongos , Neoplasias da Próstata/metabolismo
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