RESUMO
Systemic arterial hypertension is accompanied by autonomic impairments that, if not contained, promotes cardiac functional and morphological damages. Pyridostigmine bromide (PYR) treatment results in positive effects on autonomic control and beneficial cardiac remodeling. These findings were also observed after aerobic physical training (APT). However, little is known about PYR effects on left ventricular contractility, mainly when it is combined with APT. We aimed to investigate the effects of chronic acetylcholinesterase inhibition on cardiac autonomic tone balance, coronary bed reactivity, and left ventricular contractility in spontaneously hypertensive rats (SHR) submitted to APT. Male SHR (18 weeks) were divided into two groups (N = 16): untrained and submitted to APT for 14 weeks (18th to 32nd week). Half of each group was treated with PYR (15 mg/kg/day) for two weeks (31st to 32nd week). The experimental protocol consisted of recording hemodynamic parameters, double autonomic blockade with atropine and propranolol, and assessment of coronary bed reactivity and ventricular contractility in isolated hearts using the Langendorff technique. PYR and APT reduced blood pressure, heart rate, and sympathetic influence on the heart. The Langendorff technique showed that APT increased coronary perfusion pressure and left ventricle contractility in response to coronary flow and ß-agonist administration. However, treatment with PYR annulled the effects of APT. In conclusion, although chronic treatment with PYR reduces cardiac sympathetic tonic influence, it does not favor coronary bed reactivity and cardiac contractility gains. PYR treatment in the trained SHR group nullified the coronary vascular reactivity and cardiac contractility gains.
Assuntos
Inibidores da Colinesterase , Hipertensão , Contração Miocárdica , Condicionamento Físico Animal , Brometo de Piridostigmina , Ratos Endogâmicos SHR , Animais , Inibidores da Colinesterase/farmacologia , Masculino , Ratos , Contração Miocárdica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Brometo de Piridostigmina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Acetilcolinesterase/metabolismoRESUMO
BACKGROUND: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). METHODS: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. RESULTS: Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury. CONCLUSIONS: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.
RESUMO
Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to minimize the deleterious effects of MI. However, little is known about the effects of resistance training combined with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on the inflammatory profile after MI. Thus, in the present study, male Wistar rats were randomly assigned into: control (Cont); sedentary infarcted (Inf); PYR - treated sedentary infarcted rats (Inf+P); infarcted rats undergoing resistance exercise training (Inf+RT); and infarcted rats undergoing PYR treatment plus resistance training (Inf+RT+P). After 12 weeks of resistance training (15-20 climbs per session, with a 1-min rest between each climb, at a low to moderate intensity, 5 days a week) and/or PYR treatment (0.14 mg/mL of drink water), hemodynamic function, autonomic modulation, and cytokine expressions were evaluated. We observed that 3 months of PYR treatment, either alone or in combination with exercise, can improve the deleterious effects of MI on left ventricle dimensions and function, baroreflex sensitivity, and autonomic parameters, as well as systemic and tissue inflammatory profile. Furthermore, additional benefits in a maximal load test and anti-inflammatory state of skeletal muscle were found when resistance training was combined with PYR treatment. Thus, our findings suggest that the combination of resistance training and PYR may be a good therapeutic strategy since they promote additional benefits on skeletal muscle anti-inflammatory profile after MI.
RESUMO
Pyridostigmine bromide (PB) is a reversible acetylcholinesterase (AChE) inhibitor and the first-choice for the treatment of symptoms associated with myasthenia gravis and other neuromuscular junction disorders. However, evidence suggested that PB could be associated with the Gulf War Illness characterised by the presence of fatigue, headaches, cognitive dysfunction, and musculoskeletal respiratory and gastrointestinal disturbances. Given that a potential neurotoxic effect of PB has not yet been completely elucidated, the present investigation used neural SH-SY5Y cells to evaluate the effect of PB on the cellular viability, cell apoptosis, modulation of the cell cycle, oxidative stress, and genotoxicity variables, which indicate neurodegeneration. As expected, a PB concentration curve based on the therapeutic dose of the drug showed an inhibition of the AChE activity. However, this effect was transient and did not involve differential AChE gene regulation by PB. These results confirmed that undifferentiated SH-SY5Y cells can be used as a cholinergic in vitro model. In general, PB did not trigger oxidative stress, and at a slightly higher PB concentration (80ng/mL), higher levels of protein carbonylation and DNA damage were detected, as determined by the marker 8-deoxyguanosine. The PB genotoxic effects at 80ng/mL were confirmed by the upregulation of the p53 and DNA methyltransferase 1 (DNMT1) genes, which are associated with cellular DNA repair. PB at 40ng/mL, which is the minimal therapeutic dose, led to higher cell proliferation and mitochondrial activity compared with the control group. The effects of PB were corroborated by the upregulation of the telomerase gene. In summary, despite the methodological constrains related to the in vitro protocols, our results suggested that exposure of neural cells to PB, without other chemical and physical stressors did not cause extensive toxicity or indicate any neurodegeneration patterns.
Assuntos
Inibidores da Colinesterase/toxicidade , Neurônios/efeitos dos fármacos , Brometo de Piridostigmina/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miastenia Gravis/tratamento farmacológico , Neurônios/citologia , Estresse Oxidativo/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para CimaRESUMO
The current work was conducted to verify the contribution of neuromuscular transmission defects at the neuromuscular junction to Duchenne Muscular Dystrophy disease progression and respiratory dysfunction. We tested pyridostigmine and pyridostigmine encapsulated in liposomes (liposomal PYR), an acetylcholinesterase inhibitor to improve muscular contraction on respiratory muscle function in mdx mice at different ages. We evaluated in vivo with the whole-body plethysmography, the ventilatory response to hypercapnia, and measured in vitro diaphragm strength in each group. Compared to C57BL10 mice, only 17 and 22 month-old mdx presented blunted ventilatory response, under normocapnia and hypercapnia. Free pyridostigmine (1mg/kg) was toxic to mdx mice, unlike liposomal PYR, which did not show any side effect, confirming that the encapsulation in liposomes is effective in reducing the toxic effects of this drug. Treatment with liposomal PYR, either acute or chronic, did not show any beneficial effect on respiratory function of this DMD experimental model. The encapsulation in liposomes is effective to abolish toxic effects of drugs.
Assuntos
Inibidores da Colinesterase/farmacologia , Distrofia Muscular de Duchenne/complicações , Brometo de Piridostigmina/farmacologia , Transtornos Respiratórios , Músculos Respiratórios/efeitos dos fármacos , Fatores Etários , Animais , Inibidores da Colinesterase/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Técnicas In Vitro , Lipossomos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Contração Muscular/efeitos dos fármacos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Pletismografia , Brometo de Piridostigmina/uso terapêutico , Transtornos Respiratórios/tratamento farmacológico , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/patologia , Taxa Respiratória/efeitos dos fármacos , Espectrofotometria Ultravioleta , Volume de Ventilação Pulmonar/efeitos dos fármacosRESUMO
We determined the pyridostigmine prescription pattern in a population of patients with myasthenia gravis (MG). A descriptive cross-sectional study was conducted by using a prescription database of 3.5 million individuals from which patients who had been diagnosed with MG and for whom pyridostigmine had been prescribed were selected. A total of 306 outpatients with MG were found, and 258 were receiving pyridostigmine (mean age 53.0 ± 18.0 years). The calculated prevalence of MG was 86.7 cases per million persons. Monotherapy was used by 53.1% of the patients, prednisolone was used by 21.7%, and 30.2% used other immunomodulators. Medications for other comorbidities were taken by 74.8% of the patients, and 43.4% had prescriptions that could potentially trigger worsening symptoms. Pyridostigmine is being prescribed at doses close to the defined daily doses predominantly as monotherapy. A high proportion of patients were also prescribed a medication that could aggravate their condition, including some that can trigger a myasthenic crisis. Muscle Nerve 56: 1041-1046, 2017.
Assuntos
Prescrições de Medicamentos , Fatores Imunológicos/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/epidemiologia , Brometo de Piridostigmina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Inibidores da Colinesterase/administração & dosagem , Colômbia/epidemiologia , Estudos Transversais , Prescrições de Medicamentos/estatística & dados numéricos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Hypertension is often accompanied by autonomic dysfunction, which is detrimental to cardiac regulation. On the other hand, cholinergic stimulation through inhibition of acetylcholinesterase appears to have beneficial effects on cardiac autonomic control. Thus, our objective was to investigate the effects of chronic cholinergic stimulation on hemodynamic and cardiovascular autonomic control parameters in spontaneously hypertensive rats (SHR). For this, 26-week-old SHR (N = 32) and Wistar Kyoto rats (WK; N = 32) were divided into two groups: one treated with vehicle (H2O; N = 16) and the other treated with pyridostigmine bromide (PYR; N = 16) in drinking water (25 mg/kg/day) for 2 weeks. All groups were subjected to recording of arterial pressure (AP) and heart rate (HR), quantification of ejection fraction (EF), evaluation of cardiac tonic autonomic balance by means of double autonomic blockade with methylatropine and propranolol, analysis of systolic AP (SAP) and HR variability (HRV), and evaluation of baroreflex sensitivity (BRS). AP, HR, and EF were reduced in the SHR-PYR group compared with the SHR-H2O group. Evaluation of autonomic parameters revealed an increase in vagal tone participation in cardiac tonic autonomic balance and reduced SAP variability; however, no changes were observed in HRV or BRS. These results suggest that chronic cholinergic stimulation with pyridostigmine bromide promotes reduction in the hemodynamic parameters AP, HR, and EF. Additionally, tonic autonomic balance was improved and a reduction in LF oscillations of SAP variability was observed that could not be attributed to BRS, as the latter did not change. Further studies should be conducted to identify the mechanisms involved in the observed responses.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Volume Sistólico/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Masculino , Brometo de Piridostigmina/farmacologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Volume Sistólico/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiopatologiaRESUMO
In the present study we evaluated the effects of short-term pyridostigmine bromide (0.14 mg/mL) treatment started early after myocardial infarction (MI) on left ventricular (LV) and autonomic functions in rats. Male Wistar rats were divided into control, pyridostigmine, infarcted and infarcted + pyridostigmine-treated groups. Pyridostigmine was administered in the drinking water, starting immediately after MI or sham operation, for 11 days. Left ventricular function was evaluated indirectly by echocardiography and directly by LV catheterization. Cardiovascular autonomic control was evaluated by baroreflex sensitivity (BRS), heart rate variability (HRV) and pharmacological blockade. All evaluations started after 7 days pyridostigmine treatment and were finalized after 11 days treatment. Pyridostigmine prevented the impairment of +dP/dT and reduced the MI area in infarcted + pyridostigmine compared with infarcted rats (7 ± 3% vs 17 ± 4%, respectively). Mean blood pressure was restored in infarcted + pyridostigmine compared with infarcted rats (103 ± 3 vs 94 ± 3 mmHg, respectively). In addition, compared with the infarcted group, pyridostigmine improved BRS, as evaluated by tachycardic (1.6 ± 0.2 vs 2.5 ± 0.2 b.p.m./mmHg, respectively) and bradycardic (-0.42 ± 0.01 vs -1.9 ± 0.1 b.p.m./mmHg) responses, and reduced the low frequency/high frequency ratio of HRV (0.81 ± 0.11 vs 0.24 ± 0.14, respectively). These improvements are probably associated with increased vagal tone and reduced sympathetic tone in infarcted + pyridostigmine compared with infarcted rats. In conclusion, the data suggest that short-term pyridostigmine treatment started early after MI can improve BRS, HRV and parasympathetic and sympathetic tone in experimental rats. These data may have potential clinical implications because autonomic markers have prognostic significance after MI.
Assuntos
Colinérgicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Brometo de Piridostigmina/farmacologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Ecocardiografia/métodos , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
A Miastenia gravis adquirida pode desenvolver-se em qualquer raça canina e é considerado umdos principais distúrbios imunomediados que afetam o sistema neuromuscular dos cães, caracterizadaprincipalmente por fraqueza muscular e fadiga, que pioram com o exercício físico. Oprognóstico é reservado, principalmente quando associado à megaesôfago, devido ao risco depneumonia por aspiração que pode levar ao óbito. O diagnóstico torna-se muitas vezes desafiantedevido à similaridade com outras alterações neuromusculares. O diagnóstico definitivo é feitopela identificação de anticorpos antirreceptores de acetilcolina presentes no soro sanguíneo, maspode ser terapêutico, confirmado pela remissão dos sinais clínicos após tratamento com fármacosanticolinesterásicos. Este trabalho tem como objetivo relatar o caso de um cão com Miasteniagravis generalizada adquirida, ressaltando a importância do diagnóstico terapêutico feito combrometo de piridostigmina, bem como o acompanhamento de seus aspectos clínicos até completaremissão da doença.
The acquired myasthenia gravis can develop in any breed of dog and is considered one of the mostcommon immune-mediated disorders that affect the neuromuscular system of dogs, mainly characterizedby muscle weakness and fatigue that worsens during exercise. The prognosis is guarded,especially when associated with megaesophagus, due to risk of aspiration pneumonia that can leadto death. The diagnosis often becomes challenging due to the similarity to other neuromusculardisorders. The definitive diagnosis is done through the identification of antibodies against acetylcholinereceptors present in blood serum, but may be accomplished by remission of clinical signsafter administration of an anticholinesterase drug. This paper aims to reporting a case of a dogwith acquired generalized myasthenia gravis emphasizing the importance of therapeutic diagnosingmade by use of pyridostigmine bromide, and the monitoring of its clinical features until completeremission of the disease..
Assuntos
Animais , Cães , Cães , Miastenia Gravis/veterinária , Doenças NeuromuscularesRESUMO
A Miastenia gravis adquirida pode desenvolver-se em qualquer raça canina e é considerado umdos principais distúrbios imunomediados que afetam o sistema neuromuscular dos cães, caracterizadaprincipalmente por fraqueza muscular e fadiga, que pioram com o exercício físico. Oprognóstico é reservado, principalmente quando associado à megaesôfago, devido ao risco depneumonia por aspiração que pode levar ao óbito. O diagnóstico torna-se muitas vezes desafiantedevido à similaridade com outras alterações neuromusculares. O diagnóstico definitivo é feitopela identificação de anticorpos antirreceptores de acetilcolina presentes no soro sanguíneo, maspode ser terapêutico, confirmado pela remissão dos sinais clínicos após tratamento com fármacosanticolinesterásicos. Este trabalho tem como objetivo relatar o caso de um cão com Miasteniagravis generalizada adquirida, ressaltando a importância do diagnóstico terapêutico feito combrometo de piridostigmina, bem como o acompanhamento de seus aspectos clínicos até completaremissão da doença.(AU)
The acquired myasthenia gravis can develop in any breed of dog and is considered one of the mostcommon immune-mediated disorders that affect the neuromuscular system of dogs, mainly characterizedby muscle weakness and fatigue that worsens during exercise. The prognosis is guarded,especially when associated with megaesophagus, due to risk of aspiration pneumonia that can leadto death. The diagnosis often becomes challenging due to the similarity to other neuromusculardisorders. The definitive diagnosis is done through the identification of antibodies against acetylcholinereceptors present in blood serum, but may be accomplished by remission of clinical signsafter administration of an anticholinesterase drug. This paper aims to reporting a case of a dogwith acquired generalized myasthenia gravis emphasizing the importance of therapeutic diagnosingmade by use of pyridostigmine bromide, and the monitoring of its clinical features until completeremission of the disease.(AU).
Assuntos
Animais , Cães , Miastenia Gravis/veterinária , Cães , Doenças NeuromuscularesRESUMO
The cardiovascular electrophysiologic basis for the action of pyridostigmine, an acetylcholinesterase inhibitor, has not been investigated. The objective of the present study was to determine the cardiac electrophysiologic effects of a single dose of pyridostigmine bromide in an open-label, quasi-experimental protocol. Fifteen patients who had been indicated for diagnostic cardiac electrophysiologic study underwent two studies just before and 90-120 min after the oral administration of pyridostigmine (45 mg). Pyridostigmine was well tolerated by all patients. Wenckebach nodal anterograde atrioventricular point and basic cycle were not altered by pyridostigmine. Sinus recovery time (ms) was shorter during a 500-ms cycle stimulation (pre: 326 ± 45 vs post: 235 ± 47; P = 0.003) but not during 400-ms (pre: 275 ± 28 vs post: 248 ± 32; P = 0.490) or 600-ms (pre: 252 ± 42 vs post: 179 ± 26; P = 0.080) cycle stimulation. Pyridostigmine increased the ventricular refractory period (ms) during the 400-ms cycle stimulation (pre: 238 ± 7 vs post: 245 ± 9; P = 0.028) but not during the 500-ms (pre: 248 ± 7 vs post: 253 ± 9; P = 0.150) or 600-ms (pre: 254 ± 8 vs post: 259 ± 8; P = 0.255) cycle stimulation. We conclude that pyridostigmine did not produce conduction disturbances and, indeed, increased the ventricular refractory period at higher heart rates. While the effect explains previous results showing the anti-arrhythmic action of pyridostigmine, the clinical impact on long-term outcomes requires further investigation.