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1.
Nat Commun ; 11(1): 3405, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636378

RESUMO

Omecamtiv mecarbil (OM) is a putative positive inotropic tool for treatment of systolic heart dysfunction, based on the finding that in vivo it increases the ejection fraction and in vitro it prolongs the actin-bond life time of the cardiac and slow-skeletal muscle isoforms of myosin. OM action in situ, however, is still poorly understood as the enhanced Ca2+-sensitivity of the myofilaments is at odds with the reduction of force and rate of force development observed at saturating Ca2+. Here we show, by combining fast sarcomere-level mechanics and ATPase measurements in single slow demembranated fibres from rabbit soleus, that the depressant effect of OM on the force per attached motor is reversed, without effect on the ATPase rate, by physiological concentrations of inorganic phosphate (Pi) (1-10 mM). This mechanism could underpin an energetically efficient reduction of systolic tension cost in OM-treated patients, whenever [Pi] increases with heart-beat frequency.


Assuntos
Miosinas Cardíacas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miosinas/metabolismo , Fosfatos/farmacologia , Ureia/análogos & derivados , Adenosina Trifosfatases/metabolismo , Animais , Cálcio/metabolismo , Sinergismo Farmacológico , Masculino , Músculo Esquelético/metabolismo , Coelhos , Sarcômeros/metabolismo , Estresse Mecânico , Ureia/farmacologia
2.
Int J Nanomedicine ; 15: 4393-4405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606684

RESUMO

Aim: The effects of polyamidoamine (PAMAM) dendrimers on the mammalian heart are not completely understood. In this study, we have investigated the effects of a sixth-generation cationic dendrimer (G6 PAMAM) on cardiac function in control and diabetic rat hearts following ischemia-reperfusion (I/R) injury. Methods: Isolated hearts from healthy non-diabetic (Ctr) male Wistar rats were subjected to ischemia and reperfusion (I/R). LV contractility and hemodynamics data were computed digitally whereas cardiac damage following I/R injury was assessed by measuring cardiac enzymes. For ex vivo acute exposure experiments, G6 PAMAM was administered during the first 10 mins of reperfusion in Ctr animals. In chronic in vivo studies, nondiabetic rats (Ctr) received either vehicle or daily i.p. injections of G6 PAMAM (40 mg/kg) for 4 weeks. Diabetic (D) animals received either vehicle or daily i.p. injections of G6 PAMAM (10, 20 or 40 mg/kg) for 4 weeks. The impact of G6 PAMAM on pacing-postconditioning (PPC) was also studied in Ctr and D rats. Results: In ex vivo studies, acute administration of G6 PAMAM to isolated Ctr hearts during reperfusion dose-dependently impaired recovery of cardiac hemodynamics and vascular dynamics parameters following I/R injury. Chronic daily i.p. injections of G6 PAMAM significantly (P<0.01) impaired recovery of cardiac function following I/R injury in nondiabetic animals but this was not generally observed in diabetic animals except for CF which was impaired by about 50%. G6 PAMAM treatment completely blocked the protective effects of PPC in the Ctr animals. Conclusion: Acute ex vivo or chronic in vivo treatment with naked G6 PAMAM dendrimer can significantly compromise recovery of non-diabetic hearts from I/R injury and can further negate the beneficial effects of PPC. Our findings are therefore extremely important in the nanotoxicological evaluation of G6 PAMAM dendrimers for potential clinical applications in physiological and pathological settings.


Assuntos
Dendrímeros/toxicidade , Coração/fisiopatologia , Mamíferos/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nanopartículas/toxicidade , Poliaminas/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Pós-Condicionamento Isquêmico , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Ratos Wistar
3.
Anesth Analg ; 131(2): 527-536, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32371741

RESUMO

BACKGROUND: Catecholamine inotropes are frequently used after cardiopulmonary bypass (CPB) but may have undesirable effects. The aim was to identify whether the routine use of inhaled pulmonary vasodilators might reduce the requirement for inotrope drugs after cardiac surgery. METHODS: Retrospective cohort study of sequential patients undergoing cardiac surgery at the Royal Melbourne Hospital performed by a single surgeon and anesthesia care team, within 14 months before and after routine implementation of inhaled pulmonary vasodilators, August 2017. Milrinone 4 mg and iloprost 20 µg were inhaled using a vibrating mesh nebulizer (Aerogen) before initiation of CPB and at chest closure. Other aspects of clinical management were unaltered over the time period. Two investigators blinded to each other extracted data from electronic and written medical records. The primary outcome was any use of inotropes in the perioperative period; a Fisher exact test was used to analyze any differences between the 2 groups. Demographic data, hemodynamic data, and use of inotropes and vasopressors were collected from induction of anesthesia to 36 hours postoperative in the intensive care unit (ICU). Hospital and ICU length of stay, cost, and complications were collected. RESULTS: Any use of inotropes was significantly lower with inhaled pulmonary dilators (62.5% vs 86.8%, odds ratio [95% confidence interval {CI}], 0.253 (0.083-0.764); P = .011), including intraoperative inotrope use (37.5% vs 86.8%, odds ratio [95% CI], 0.091 (0.03-0.275); P < .001). ICU length of stay was significantly lower with inhaled pulmonary dilators (45 hours, interquartile range [IQR], 27-65 vs 50 hours, IQR, 45-74; P = .026). There were no significant differences among major postoperative complications or costs between groups. CONCLUSIONS: Routine use of inhaled milrinone 4 mg and iloprost 20 µg before and after CPB is associated with reduced postoperative inotrope use.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Iloprosta/administração & dosagem , Complicações Intraoperatórias/prevenção & controle , Milrinona/administração & dosagem , Contração Miocárdica/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Administração por Inalação , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiotônicos/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Cuidados Intraoperatórios/métodos , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/etiologia , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Projetos Piloto , Estudos Retrospectivos
4.
Ecotoxicol Environ Saf ; 197: 110605, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32311614

RESUMO

Fluorosis is a worldwide public health problem, and its adverse effects on the heart have been confirmed by many studies. Abnormal myocardial contractions are often associated with impairment of cardiac function as a cause or consequence. We designed two-part experiments to search for biomarkers and clarify the underlying molecular mechanism of fluoride on myocardial contraction. First, we used Pressure-volume Loop analysis to evaluate changes in myocardial function indexes with multiple fluoride exposure levels in mice (0, 30, 70, and 150 mg/L) exposed for 4 weeks. The results showed that fluoride exposure affects the heart pump function and reduces cardiac contractility. Then, we established a rat model of fluoride exposure (0, 30, 60, and 90 mg/L) for 6 months to carry out proteomic analysis of fluoride-induced myocardial contractile injury. Hematoxylin-eosin (H&E) staining was used to determine the severity of myocardial injury, and myocardial tissue samples were submitted for isobaric tags for relative and absolute quantitation (ITRAQ) analysis. A total of 1607 proteins were successfully identified with 294 differentially expressed proteins (DEPs) in fluoride treated groups. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 12 DEPs were confirmed to be involved in pathways related to myocardial contraction. Furthermore, we constructed a protein-protein interaction (PPI) network for these 12 core DEPs to illustrate the role and location of each DEP in the myocardial contraction pathway. The results of this study are helpful for identify a potential mechanism and biomarkers of fluoride-induced myocardial contraction function damage, moreover, which can provide a new insight into the heart toxicity of fluoride in animals at the proteomics level.


Assuntos
Cardiomiopatias/induzido quimicamente , Fluoretos/toxicidade , Contração Miocárdica/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Ontologia Genética , Masculino , Camundongos , Mapeamento de Interação de Proteínas , Proteínas/metabolismo , Proteômica/métodos , Ratos
5.
J Pharmacol Sci ; 143(3): 156-164, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32278466

RESUMO

Safranal (SFR) is the major constituent of saffron. The purpose of this study was to observe the effect of SFR on myocardial ischemia induced by isoprenaline (ISO) and to explore its possible mechanism. The myocardial ischemia rat model was established by subcutaneous injection of ISO (85 mg/kg/d) on the 8th and 9th day of the experiment. Serum creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured, as were changes in calcium concentration, reactive oxygen species (ROS) and cardiac morphology of the myocardial tissue. The effects of SFR on cell contraction, Ca2+ transient and L-type Ca2+ current (ICa-L) in isolated rat myocardial cells were measured using the Ion Optix detection system and the whole-cell patch-clamp technique. SFR can decrease the activity of serum CK, LDH and MDA, and increase the activity of serum SOD, reduce intracellular calcium concentration and the manufacture of ROS. In addition, SFR can improve changes in heart morphology. SFR can significantly inhibit contraction, Ca2+ transients and ICa-L in isolated ventricular myocytes. SFR has a cardioprotective role in ISO-induced MI rats, and the underling mechanism is related to the inhibition of oxidative stress, myocardial contractility, ICa-L and the regulation of Ca2+ homeostasis.


Assuntos
Cálcio/metabolismo , Crocus/química , Cicloexenos/farmacologia , Cicloexenos/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Terpenos/farmacologia , Terpenos/uso terapêutico , Animais , Cardiotônicos , Células Cultivadas , Cicloexenos/isolamento & purificação , Modelos Animais de Doenças , Isoproterenol/efeitos adversos , Masculino , Malondialdeído/metabolismo , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/induzido quimicamente , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Terpenos/isolamento & purificação
6.
Braz J Med Biol Res ; 53(3): e8761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32159612

RESUMO

Nitric oxide (NO) inhibition by high-dose NG-nitro-L-arginine methyl ester (L-NAME) is associated with several detrimental effects on the cardiovascular system. However, low-dose L-NAME increases NO synthesis, which in turn induces physiological cardiovascular benefits, probably by activating a protective negative feedback mechanism. Aerobic exercise, likewise, improves several cardiovascular functions in healthy hearts, but its effects are not known when chronically associated with low-dose L-NAME. Thus, we tested whether the association between low-dose L-NAME administration and chronic aerobic exercise promotes beneficial effects to the cardiovascular system, evaluating the cardiac remodeling process. Male Wistar rats were randomly assigned to control (C), L-NAME (L), chronic aerobic exercise (Ex), and chronic aerobic exercise associated to L-NAME (ExL). Aerobic training was performed with progressive intensity for 12 weeks; L-NAME (1.5 mg·kg-1·day-1) was administered by orogastric gavage. Low-dose L-NAME alone did not change systolic blood pressure (SBP), but ExL significantly increased SBP at week 8 with normalization after 12 weeks. Furthermore, ExL promoted the elevation of left ventricle (LV) end-diastolic pressure without the presence of cardiac hypertrophy and fibrosis. Time to 50% shortening and relaxation were reduced in ExL, suggesting a cardiomyocyte contractile improvement. In addition, the time to 50% Ca2+ peak was increased without alterations in Ca2+ amplitude and time to 50% Ca2+ decay. In conclusion, the association of chronic aerobic exercise and low-dose L-NAME prevented cardiac pathological remodeling and induced cardiomyocyte contractile function improvement; however, it did not alter myocyte affinity and sensitivity to intracellular Ca2+ handling.


Assuntos
Cálcio/análise , Inibidores Enzimáticos/farmacologia , Contração Miocárdica/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Adiposidade , Animais , Peso Corporal/fisiologia , Inibidores Enzimáticos/administração & dosagem , Hemodinâmica , Masculino , Modelos Animais , Atividade Motora/fisiologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/metabolismo , Ratos Wistar , Pressão Ventricular/efeitos dos fármacos
8.
Artigo em Inglês | MEDLINE | ID: mdl-32159365

RESUMO

Cardiac inflammation has been proposed as one of the primary mechanisms of anthracycline-induced acute cardiotoxicity. A reduction in cardiac inflammation might also reduce cardiotoxicity. This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cell stabilizer treatment but not by regular exercise. As a heart disease indicator, increased ß-myosin heavy chain expression induced by doxorubicin could only be prevented by estrogen supplementation. Decrease in shortening and intracellular Ca2+ transients of cardiomyocytes were due to absence of female sex hormones without further effects of doxorubicin. Again, estrogen supplementation and mast cell stabilizer treatment prevented these changes but exercise training did not. Histological analysis indicated that the hyperactivation of cardiac mast cells in ovariectomized rats was augmented by doxorubicin. Estrogen supplementation and mast cell stabilizer treatment completely prevented both increases in mast cell density and degranulation, whereas exercise training partially attenuated the hyperactivation. Our results, therefore, suggest that estrogen supplementation acts similarly to mast cell stabilizers in attenuating the effects of doxorubicin. Ineffectiveness of regular exercise in preventing the acute cardiotoxicity of doxorubicin might be due to a lesser effect on preventing cardiac inflammation.


Assuntos
Degranulação Celular/efeitos dos fármacos , Doxorrubicina , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios , Terapia por Exercício , Mastócitos/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cardiotoxicidade , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/metabolismo , Mastócitos/metabolismo , Mastócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-32108522

RESUMO

This study tested the hypothesis that (pyr)apelin-13 dose-dependently augments myocardial contractility and coronary blood flow, irrespective of changes in systemic hemodynamics. Acute effects of intravenous (pyr)apelin-13 administration (10 to 1,000 nM) on blood pressure, heart rate, left ventricular pressure and volume, and coronary parameters were measured in dogs and pigs. Administration of (pyr)apelin-13 did not influence blood pressure (P = 0.59), dP/dtmax (P = 0.26), or dP/dtmin (P = 0.85) in dogs. However, heart rate dose-dependently increased > 70% (P < 0.01), which was accompanied by a significant increase in coronary blood flow (P < 0.05) and reductions in left ventricular end-diastolic volume and stroke volume (P < 0.001). In contrast, (pyr)apelin-13 did not significantly affect hemodynamics, coronary blood flow, or indexes of contractile function in pigs. Furthermore, swine studies found no effect of intracoronary (pyr)apelin-13 administration on coronary blood flow (P = 0.83) or vasorelaxation in isolated, endothelium-intact (P = 0.89) or denuded (P = 0.38) coronary artery rings. Examination of all data across (pyr)apelin-13 concentrations revealed an exponential increase in cardiac output as peripheral resistance decreased across pigs and dogs (P < 0.001; R2 = 0.78). Assessment of the Frank-Starling relationship demonstrated a significant linear relationship between left ventricular end-diastolic volume and stroke volume across species (P < 0.001; R2 = 0.70). Taken together, these findings demonstrate that (pyr)apelin-13 does not directly influence myocardial contractility or coronary blood flow in either dogs or pigs.NEW & NOTEWORTHY Our findings provide much needed insight regarding the pharmacological cardiac and coronary effects of (pyr)apelin-13 in larger animal preparations. In particular, data highlight distinct hemodynamic responses of apelin across species, which are independent of any direct effect on myocardial contractility or perfusion.


Assuntos
Circulação Coronária/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Contração Miocárdica/efeitos dos fármacos , Animais , Pressão Sanguínea , Vasos Coronários/efeitos dos fármacos , Cães , Frequência Cardíaca , Masculino , Volume Sistólico , Suínos , Vasodilatação
10.
Circ J ; 84(4): 551-558, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32092718

RESUMO

BACKGROUND: In non-diabetic patients with acute coronary syndrome, stress hyperglycemia occasionally occurs and is related to their mortality. Whether transient elevation of glucose affects arrhythmia susceptibility in non-diabetic hearts with non-uniform contraction was examined.Methods and Results:Force, intracellular Ca2+([Ca2+]i), and membrane potential were measured in trabeculae from rat hearts. Non-uniform contraction was produced by a jet of paralyzing solution. Ca2+waves and arrhythmias were induced by electrical stimulation (2.0 mmol/L [Ca2+]o). The activity of Ca2+/calmodulin-dependent protein kinaseII (CaMKII) was measured. An elevation of glucose from 150 to 400 mg/dL increased the velocity of Ca2+waves and the number of spontaneous action potentials triggered by electrical stimulation. Besides, the elevation of glucose increased the CaMKII activity. In the presence of 1 µmol/L KN-93, the elevation of glucose did not increase the velocity of Ca2+waves and the number of triggered action potentials. In addition, in the presence of 1 µmol/L autocamtide-2 related inhibitory peptide or 50 µmol/L diazo-5-oxonorleucine, the elevation of glucose did not increase the number of triggered action potentials. Furthermore, the elevation of glucose by adding L-glucose did not increase their number. CONCLUSIONS: In non-diabetic hearts with non-uniform contraction, transient elevation of glucose increases the velocity of Ca2+waves by activating CaMKII,probably through glycosylation with O-linked ß-N-acetylglucosamine, thereby increasing arrhythmia susceptibility.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Glucose/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ativação Enzimática , Glicosilação , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Miócitos Cardíacos/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
11.
J Cardiovasc Electrophysiol ; 31(2): 579-592, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31930579

RESUMO

Cardiac arrhythmias constitute a major public health problem. Pharmacological intervention remains mainstay to their clinical management. This, in turn, depends upon systematic drug classification schemes relating their molecular, cellular, and systems effects to clinical indications and therapeutic actions. This approach was first pioneered in the 1960s Vaughan-Williams classification. Subsequent progress in cardiac electrophysiological understanding led to a lag between the fundamental science and its clinical translation, partly addressed by The working group of the European Society of Cardiology (1991), which, however, did not emerge with formal classifications. We here utilize the recent Revised Oxford Classification Scheme to review antiarrhythmic drug pharmacology. We survey drugs and therapeutic targets offered by the more recently characterized ion channels, transporters, receptors, intracellular Ca2+ handling, and cell signaling molecules. These are organized into their strategic roles in cardiac electrophysiological function. Following analysis of the arrhythmic process itself, we consider (a) pharmacological agents directly targeting membrane function, particularly the Na+ and K+ ion channels underlying depolarizing and repolarizing events in the cardiac action potential. (b) We also consider agents that modify autonomic activity that, in turn, affects both the membrane and (c) the Ca2+ homeostatic and excitation-contraction coupling processes linking membrane excitation to contractile activation. Finally, we consider (d) drugs acting on more upstream energetic and structural remodeling processes currently the subject of clinical trials. Such systematic correlations of drug actions and arrhythmic mechanisms at different molecular to systems levels of cardiac function will facilitate current and future antiarrhythmic therapy.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos , Animais , Antiarrítmicos/efeitos adversos , Antiarrítmicos/classificação , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Terapia de Alvo Molecular , Contração Miocárdica/efeitos dos fármacos , Resultado do Tratamento , Remodelação Ventricular/efeitos dos fármacos
12.
Nat Commun ; 11(1): 535, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988308

RESUMO

To date, numerous biosensing platforms have been developed for assessing drug-induced cardiac toxicity by measuring the change in contractile force of cardiomyocytes. However, these low sensitivity, low-throughput, and time-consuming processes are severely limited in their real-time applications. Here, we propose a cantilever device integrated with a polydimethylsiloxane (PDMS)-encapsulated crack sensor to measure cardiac contractility. The crack sensor is chemically bonded to a PDMS thin layer that allows it to be operated very stably in culture media. The reliability of the proposed crack sensor has been improved dramatically compared to no encapsulation layer. The highly sensitive crack sensor continuously measures the cardiac contractility without changing its gauge factor for up to 26 days (>5 million heartbeats), while changes in contractile force induced by drugs are monitored using the crack sensor-integrated cantilever. Finally, experimental results are compared with those obtained via conventional optical methods to verify the feasibility of building a contraction-based drug-toxicity testing system.


Assuntos
Técnicas Biossensoriais , Dimetilpolisiloxanos/química , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Miócitos Cardíacos/fisiologia , Quinidina/toxicidade , Ratos Sprague-Dawley , Verapamil/toxicidade
13.
Int J Cardiovasc Imaging ; 36(4): 703-712, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31950298

RESUMO

Cardiovascular magnetic resonance feature tracking (CMR-FT) is a novel technique for non-invasive assessment of myocardial motion and deformation. Although CMR-FT is standardized in humans, literature on comparative analysis from animal models is scarce. In this study, we measured the reproducibility of global strain under various inotropic states and the sample size needed to test its relative changes in pigs. Ten anesthetized healthy Landrace pigs were investigated. After baseline (BL), two further steps were performed: (I) dobutamine-induced hyper-contractility (Dob) and (II) verapamil-induced hypocontractility (Ver). Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS) were assessed. This study shows a good to excellent inter- and intra-observer reproducibility of CMR-FT in pigs under various inotropic states. The highest inter-observer reproducibility was observed for GLS at both BL (ICC 0.88) and Ver (ICC 0.79). According to the sample size calculation for GLS, a small number of animals could be used for future trials.


Assuntos
Ventrículos do Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Contração Miocárdica , Função Ventricular Esquerda , Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Anestesia Geral , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Dobutamina/farmacologia , Feminino , Ventrículos do Coração/efeitos dos fármacos , Modelos Animais , Contração Miocárdica/efeitos dos fármacos , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Tamanho da Amostra , Sus scrofa , Função Ventricular Esquerda/efeitos dos fármacos , Verapamil/farmacologia
14.
J Cardiovasc Med (Hagerstown) ; 21(3): 223-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31990748

RESUMO

AIMS: Myocardial work is a new transthoracic echocardiogram (TTE) parameter that enhances the information provided through left ventricular (LV) global longitudinal strain (GLS). Nothing is known about the impact of sacubitril/valsartan (LCZ696) therapy on myocardial work parameters. The aim of this study was to evaluate the effects of LCZ696 on LV myocardial work in heart failure patients. METHODS: Prospective evaluation of chronic heart failure patients with LV ejection fraction of 40% or less despite optimized standard of care therapy, in which LCZ696 therapy was started and no other heart failure treatment was expected to change. TTE study was performed before and 6 months after LCZ696 therapy. A semiautomated analysis of LV GLS was made and myocardial work estimated using custom software of the GE Vivid E95 ultrasound system. RESULTS: Of the 42 patients, 35 (83.3%) completed the 6 months, follow-up, since 2 (4.8%) patients died and 5 (11.9%) discontinued treatment due to adverse events. Mean age was 58.6 ±â€Š11.1 years. TTE data showed a significant reduction in LV dimensions and atrial volumes, as well as an improvement in LV ejection fraction (29.3 vs. 35.2%, P = 0.001) and GLS (-7.0 vs. -8.9%, P = 0.001). Myocardial work had a significant increase in global constructive work (720.2 vs. 900.6 mmHg%, P = 0.016) and global work efficiency (78.6 vs. 86.6%, P = 0.027), with a nonsignificant decrease in global wasted work (150.2 vs. 136.8 mmHg%, P = 0.441) at 6 months. CONCLUSION: LCZ696 therapy was associated with signs of reverse remodelling by usual TTE parameters and LV myocardial work at 6 months, including an increase in global constructive work and work efficiency.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Ecocardiografia , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Inibidores de Proteases/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Tetrazóis/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Valor Preditivo dos Testes , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Recuperação de Função Fisiológica , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Remodelação Ventricular/efeitos dos fármacos
15.
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
16.
Anesth Analg ; 130(1): 90-98, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633505

RESUMO

BACKGROUND: Timing and onset of myocardial ischemia are mostly unpredictable. Therefore, postconditioning could be an effective cardioprotective intervention. Because ischemic postconditioning is an invasive and not practicable treatment, pharmacological postconditioning would be a more suitable alternative cardioprotective measure. For the α2-adrenoreceptor agonist, dexmedetomidine postconditioning has been shown. However, data on a concentration-dependent effect of dexmedetomidine are lacking. Furthermore, it is unclear whether the time point and/or duration of dexmedetomidine administration in the reperfusion period is of relevance. We set out to determine whether infarct size reduction by dexmedetomidine is concentration dependent and whether time point and/or duration of dexmedetomidine application has an impact on the effect size of cardio protection. METHODS: Hearts of male Wistar rats were randomized and placed on a Langendorff system perfused with Krebs-Henseleit buffer at a constant pressure of 80 mm Hg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. In part I of the study, a concentration-response effect was determined by perfusing hearts with various concentrations of dexmedetomidine (0.3-100 nM) at the onset of reperfusion. Based on these results, part II of the study was conducted with 3 nM dexmedetomidine. Application of dexmedetomidine started directly at the onset of reperfusion (Dex60) and 15 minutes (Dex15), 30 minutes (Dex30), or 45 minutes (Dex45) after the start of reperfusion and lasted always until the end of the reperfusion period. Infarct size was determined by triphenyltetrazolium chloride staining. RESULTS: In part I, infarct size in control (Con) hearts was 62% ± 4%. Three-nanometer dexmedetomidine was the lowest most effective cardioprotective concentration and reduced infarct size to 24% ± 7% (P < .0001 versus Con). Higher concentrations did not confer stronger protection. Infarct size in control hearts from part II was 66% ± 6%. Different starting times and/or durations of application resulted in similar infarct size reduction (all P < .0001 versus Con). CONCLUSIONS: Postconditioning by dexmedetomidine is concentration dependent in ranges between 0.3 and 3 nM. Increased concentrations above 3 nM do not further enhance this cardioprotective effect. This cardioprotective effect is independent of time point and length of application in the reperfusion period.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Dexmedetomidina/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Preparação de Coração Isolado , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Ratos Wistar , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos
17.
Antioxid Redox Signal ; 32(1): 60-77, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31680536

RESUMO

Aim: Impairment of tissue responsiveness to exogenous and endogenous nitric oxide (NO•), known as NO• resistance, occurs in many cardiovascular disease states, prominently in diabetes and especially in the presence of marked hyperglycemia. In this study, we sought to determine in moderate and severe diabetes (i) whether NO• resistance also occurs in the myocardium, and (ii) whether the NO• redox sibling nitroxyl (HNO) circumvents this. Results: The spectrum of acute NO• effects (induced by diethylamine-NONOate), including vasodilation, and enhanced myocardial contraction and relaxation were impaired by moderately diabetic rats ([blood glucose] ∼20 mM). In contrast, acute HNO effects (induced by isopropylamine-NONOate) were preserved even in more severe diabetes ([blood glucose] >28 mM). Intriguingly, the positive inotropic effects of HNO were significantly enhanced in diabetic rat hearts. Further, progressive attenuation of soluble guanylyl cyclase (sGC) contribution to myocardial NO• responses occurred with increasing severity of diabetes. Nevertheless, activation of sGC by HNO remained intact in the myocardium. Innovation: Diabetes is associated with marked attenuation of vascular and myocardial effects of NO and NO donors, and this NO• resistance is circumvented by HNO, suggesting potential therapeutic utility for HNO donors in cardiovascular emergencies in diabetics. Conclusion: These results provide the first evidence that NO• resistance occurs in diabetic hearts, and that HNO largely circumvents this problem. Further, the positive inotropic and lusitropic effects of HNO are enhanced in a severely diabetic myocardium, a finding that warrants further mechanistic interrogation. The results support a potential role for therapeutic HNO administration in acute treatment of ischemia and/or heart failure in diabetics.


Assuntos
Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/metabolismo , Óxido Nítrico/metabolismo , Óxidos de Nitrogênio/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/etiologia , Guanilato Ciclase/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Ratos , Estreptozocina , Vasodilatação/efeitos dos fármacos
18.
J Toxicol Sci ; 44(12): 859-870, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31813905

RESUMO

We validated a motion field imaging (MFI) assay with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) as a model to assess multiple cardiac liabilities by comparing the guinea-pig Langendorff heart with hiPS-CMs using 4 reference compounds and 9 internal compounds. We investigated repolarization duration, beating rate (BR), conduction speed, contractility, and inhibitory profile of three cardiac ion channels: hERG, Cav1.2, and Nav1.5. For repolarization, the contraction-relaxation duration (CRDc) of hiPS-CMs was generally consistent with the QTc interval of Langendorff heart. However, 2 internal compounds shortened CRDc despite QTc prolongation in Langendorff heart. Cardiac ion channel profiling revealed that hiPS-CMs could not be used to detect QTc prolongation when the value of Cav1.2 IC50 / hERG IC50 for a compound was between 1 and 10, whereas hiPS-CMs showed responses largely consistent with Langendorff heart when Cav1.2 IC50 / hERG IC50 was below 1 or above 10. The accuracy of hiPS-CMs for the BR was not high, mainly because the BR of hiPS-CMs was increased by an inhibition of Cav1.2. The hiPS-CMs were highly sensitive to conduction speed and contractility, able to detect QRS widening caused by Nav1.5-inhibition, as well as decreased LVdP/dtmax caused by the inhibition of Cav1.2 and/or Nav1.5. In conclusion, the MFI assay with hiPS-CMs would be useful for evaluating multiple cardiac liabilities. The ion channel profile helps to interpret the results of MFI assay and correctly evaluate cardiac risks. Therefore, an integrated cardiac safety assessment with MFI and ion channel profiling is recommended.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Canais Iônicos/metabolismo , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Cardiotoxicidade , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Cobaias , Testes de Função Cardíaca , Humanos , Masculino , Microeletrodos , Microscopia de Vídeo , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Preparações Farmacêuticas/administração & dosagem
19.
Int J Mol Sci ; 20(24)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847081

RESUMO

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17ß-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine.


Assuntos
Estradiol/farmacologia , Modelos Cardiovasculares , Contração Miocárdica/efeitos dos fármacos , Caracteres Sexuais , Peixe-Zebra/metabolismo , Animais , Feminino , Masculino
20.
Bull Exp Biol Med ; 167(6): 716-719, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31655986

RESUMO

The effects of neuropeptide Y (10-9-10-6 M) on electrical activity of right atrial cardiomyocytes of rats aging 7, 21, and 100 days were examined in vitro. Neuropeptide Y affected the amplitude-temporal parameters of the action potential in these cells. It decreased the duration of repolarization phase in 7-day-old rats in concentrations of 10-8 and 10-7 M, in 21-day-old rats at 10-8 and 10-6 M, and in 100-day-old at 10-6 M. The data indicate elevation of total membrane potassium current under the action of neuropeptide Y.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/crescimento & desenvolvimento , Miócitos Cardíacos/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Átrios do Coração/citologia , Potenciais da Membrana/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos
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