Adrenaline; the effects in presence of beta blocker in isolated mammalian heart

There is no doubt that the effects of the catecholamines of the heart are mainly due to the stimulation of beta-adrenoceptors but in the mid 1960' s the first evidence was presented that a-adrenoceptors mediating positive inotrpoism exists also in the myocardium beside well established beta -adrenoceptors. In our observation adrenaline shows a positive inotropic response. The response of adrenaline in presence of metoprolol [beta1blocker] showed negative inotropic effect

Methylation of adrenergic 1 receptor is a potential epigenetic mechanism controlling antihypertensive response to metoprolol.

Although metoprolol is used to treat hypertension, clinical responses are variable and unpredictable. Evidence suggests that adrenergic 1 receptor (ADRB1, designated Adrb1 in rodents) gene polymorphisms influence the level of blood pressure response to this drug therapy, but their presence can not predict the response of the individual patient. The question exists whether epigenetic modifications, such as DNA methylation could cause changes in the gene’s expression that are a determining factor in metoprolol’s efficacy. The aim of this study was to verify whether DNA methylation could change the expression of the ADRB1 gene, and epigenetic modification could explain why individuals with identical ADRB1 gene polymorphisms have different antihypertensive responses to metoprolol. H9c2 rat myocardial cells in vitro were randomly divided into 5-aza-2'-deoxycytidine (decitabine)-treated (0.5 to 10.0 μM) and control groups. For the in vivo experiments, 45 spontaneously hypertensive rats (SHRs) were divided into metoprolol-treated and control groups, and after a 4-week intervention myocardia were harvested. Genomic methylation-sensitive PCR was used to assess the methylation status of the Adrb1 promoter after DNA extraction from H9c2 cells and SHR myocardia. Real-time fluorescent quantitative RT-PCR was used to determine levels of Adrb1 mRNA. In H9c2 cells, the least degree of methylation was observed in the 5.0 μM decitabine treated group. Prolonged exposure of cells to 5.0 μM decitabine resulted in downregulating methylation of the Adrb1 promoter. Increased levels of Adrb1 mRNA of the 5.0 μM group demonstrated that this concentration resulted in the highest expression. Accordingly, DNA methylation resulted in the downregulation of Adrb1 transcription. In vivo, the lower level of methylation of the Adrb1 promoter from SHR myocardial samples demonstrated a better antihypertensive effect by metoprolol. The expression of Adrb1 mRNA in the effective group of SHRs was significantly upregulated. In conclusion, as shown in both H9c2 cells and SHRs, downregulated methylation of the Adrb1 promoter is likely to improve the antihypertensive efficacy of metoprolol.

Associação de betabloqueadores e treinamento físico na insuficiência cardíaca de camundongos / Association of physical training with beta-blockers in heart failure in mice / Asociación de betabloqueantes y entrenamiento físico en la insuficiencia cardíaca de ratones

FUNDAMENTO: O tratamento da insuficiência cardíaca (IC) conta atualmente com diversos tipos de intervenções. Dentre elas, destacam-se a terapia com betabloqueadores (BB) e o treinamento físico (TF). Contudo, os efeitos da associação dessas terapias são pouco estudados. OBJETIVO: Verificar os efeitos do tratamento com BB, metoprolol (M) e carvedilol (C) associados ao TF na IC em camundongos. MÉTODOS: Utilizamos modelo genético de IC induzida em camundongos por hiperatividade simpática. Inicialmente, dividimos os animais com IC em: sedentários (S); treinados (T); tratados com M (138 mg/kg) (M) ou C (65 mg/kg) (C). Na segunda parte, dividimos os grupos em S; treinado e tratado com M (MT) e treinado e tratado com C (CT). O TF consistiu em treinamento aeróbico em esteira por 8 semanas. A tolerância ao esforço foi avaliada por teste progressivo máximo e a fração de encurtamento foi avaliada (FE) por ecocardiografia. O diâmetro dos cardiomiócitos e a fração de colágeno foram avaliados por meio de análise histológica. Os dados foram comparados por ANOVA de um caminho com post hoc de Duncan. O nível de significância foi considerado p < 0,05. RESULTADOS: Destacando FE e remodelação cardíaca, verificamos que, isoladamente, T, M e C apresentaram melhora das variáveis. Na associação, após o período de intervenção, observamos aumento da tolerância ao esforço em MT e CT (43,0 por cento e 33,0 por cento, respectivamente). Houve também redução do diâmetro dos cardiomiócitos (10,0 por cento e 9,0 por cento, respectivamente) e da fração de colágeno (52,0 por cento e 63,0 por cento), após a intervenção. Porém, somente CT melhorou significantemente a FE. CONCLUSÃO: A associação do TF às terapias com M ou C proporcionou benefícios sobre a função e remodelação cardíaca em camundongos com IC.

BACKGROUND: Currently there are several types of interventions for the treatment of heart failure (HF). Among these are beta-blocker therapy (BB) and physical training (PT). However, the effects of the combination of these therapies are poorly studied. OBJECTIVE: To investigate the effects of BB treatment with metoprolol (M) and carvedilol (C) associated with PT in mice with HF. METHODS: We used a genetic model of sympathetic hyperactivity-induced heart failure in mice. Initially, we divided the HF animals into three groups: sedentary (S); trained (T); treated with M (138 mg/kg) (M); or C (65 mg/kg) (C). In the second part, we divided the groups into three subgroups: sedentary (S); trained and treated with M (TM); and trained and treated with C (CT). The PT consisted of aerobic training on a treadmill for 8 weeks. Exercise tolerance was assessed by maximal graded test, and fractional shortening (FS) was assessed by echocardiography. Cardiomyocyte diameter and collagen volume fraction were evaluated by histological analysis. Data were compared by one way ANOVA and post hoc Duncan test. The significance level was set at p < 0.05. RESULTS: As to FS and cardiac remodeling, we found that, in isolation, T, M, and C showed an improvement of the variables analyzed. As to therapy combination, after the intervention period, we observed an increase in exercise tolerance in MT and CT (43.0 percent and 33.0 percent respectively). There was also a reduction in cardiomyocyte diameter (10.0 percent and 9.0 percent respectively) and in collagen volume fraction (52.0 percent and 63.0 percent) after the intervention. However, only CT significantly improved FS. CONCLUSION: The association of PT with M or C therapies provided benefits on cardiac function and remodeling in HF mice.

FUNDAMENTO: El tratamiento de la insuficiencia cardiaca (IC) cuenta actualmente con diversos tipos de intervenciones. De entre ellas podemos destacar la terapia con betabloqueantes (BB) y el entrenamiento físico (EF). Con todo, los efectos de la asociación de estas terapias son poco estudiados. OBJETIVO: Verificar los efectos del tratamiento con BB, metoprolol (M) y carvedilol (C) asociados al EF en la IC en ratones. MÉTODOS: Utilizamos modelo genético de IC inducida en ratones por hiperactividad simpática. Inicialmente, dividimos los animales con IC en: sedentarios (S); entrenados (E); tratados con M (138 mg/kg) (M) o C (65 mg/kg) (C). En la segunda parte, dividimos los grupos en S; entrenado y tratado con M (ME) y entrenado y tratado con C (CE). El EF consistió en entrenamiento aeróbico en estera por 8 semanas. La tolerancia al esfuerzo se evaluó por prueba progresivo máxima y la fracción de acortamiento se evaluó (FE) por ecocardiografía. El diámetro de los cardiomiocitos y la fracción de colágeno fueron evaluados por medio de análisis histológico. Los dados fueron comparados por ANOVA de un camino con post hoc de Duncan. El nivel de significancia se consideró como p < 0,05. RESULTADOS: Destacando FE y remodelación cardíaca, verificamos que, aisladamente, E, M y C presentaron mejora de las variables. En la asociación, tras el período de intervención, observamos aumento de la tolerancia al esfuerzo en ME y CE (el 43 por ciento y el 33 por ciento, respectivamente). Hubo también reducción del diámetro de los cardiomiocitos (el 10 por ciento y el 9 por ciento, respectivamente) y de la fracción de colágeno (el 52 por ciento y el 63 por ciento), tras la intervención. Sin embargo, solamente CE mejoró significantemente la FE. CONCLUSIÓN: La asociación del EF a las terapias con M o C proporcionó beneficios sobre la función y remodelación cardíaca en ratones con IC.

Miocardiopatía hipertrófica potencialmente obstructiva y la utilidad del eco-estrés en su valoración funcional: relato de un caso / Hypertrophic potentially obstructive myocardiopathy and the utility of the echo-stress in its functional evaluation

Se propone el empleo del eco-estrés farmacológico o por ejercicio físico para la valoración funcional de la miocardiopatía hipertrófica en sus diferentes variedades (la septal asimétrica y medioventricular en especial, así como también en el control "de salud" del deportista en actividades isométricas y alta competición que desarrollan severas hipertrofias), ya sea para el estudio hemodinámico por Doppler y búsqueda de gradientes intraventriculares ausentes en el reposo, como así también para el análisis de la contractilidad sectorial en la detección de isquemia miocárdica. Hipótesis de trabajo ésta, que surgió del caso clínico presentado, de una paciente con cardiopatía hipertrófica obstructiva con leve gradiente en reposo, con angor de esfuerzo, estudios de perfusión radioisotópicos positivos y coronariografía sin lesiones significativas de vasos subepicárdicos, que en el apremio con dobutamina presentó un gradiente medio ventricular mayor de 120 mm Hg. Dado lo amigable de la técnica, su poca invasividad y bajo costo fue posible la semicuantificación seriada de los diferentes parámetros diagnósticos y reproducir en el laboratorio cardiológico su vida diaria sintomática. También nos permitió el testeo de la terapéutica indicada

Effect of beta blocker versus alpha combined alpha and beta blocker on blood pressure response under static exercise and cold pressor test

The effect of a single oral dose of beta-1 blocker [Metoprolol] versus combined alpha- and beta-blocker [Labetalol] was evaluated in two groups of patients: Control [C] normotensive and hypertensive [H] groups with mild to moderate elevation of blood pressure. Each group consisted of 10 subjects. The study comprised monitoring the heart rate [HR] and blood pressure [BP] response to two tests: Hand grip test [HCT] and cold pressor test [CPT]. These tests were performed before and after the drugs on separate sittings. The BP and HR response to HGT before administration of drugs was linear for the two groups, while the CPT showed insignificant rise of HR. The results at rest before and after medications in both groups showed a decrease in HR and BP. It was statistically insignificant in C group only after Labetalol used. In C group Metoprolol was more effective in lowering the pressor response than Labetalol, while in the H group Labetalol was potent in reducing BP, specially during CPT

Effect of thyroid hormones excess on left ventricular function in thyrotoxic patients: Effects of metoprolol versus carbimazole

To determine the role of beta adrenoreceptors in the pathophysiology of thyroid hormones excess on left ventricular [LV] function, 12 patients with thyrotoxicosis were studied before and after using beta adrenoreceptor blocker metoprolol [M] versus antithyroid drug carbimazole [C]. LV functions were assessed by Doppler echocardiography. M and C were equally effective in slowing the heart rate. Both drugs equally prolonged preejection/ejection time ratio, while C, but not M, significantly slowed the velocity of LV circumferential fiber shortening suggesting direct effect of thyroid hormones on myocardial contractility. However, both drugs showed similar effect on LV diastolic function by prolonging time to peak LV filling and increasing early to peak mitral flow velocity ratio [E/A]. However, the increase in E/A was due to decrease in A velocity with atrial contraction suggesting increased atrial contractility in thyrotoxicosis. In conclusion, thyroid hormones excess increased myocardial contractility by direct effect, and increased heart rate, atrial contraction and LV relaxation by increasing cardiac beta adrenoreceptor activity

Efeito do propranolol e metoprolol nas respostas cárdio-respiratórias e metabólicas ao exercício / Effects of propranolol and metoprolol on cardiorespiratory And metabolic responses to exercise.

PurposeTo study the effects of intravenous propranolol and metoprolol on cardiorespiratory and metabolic responses to exercise. MethodsTwo groups of anaesthetized dogs (sodium pentobarbital, 33 mg/kg) were studied at rest and moderate exercise (induced by electrical stimulation) before and after metoprolol (0.4 mg/ Kg, n = 7) or propranolol (0.2 mg/kg, n = 10). Haemodynamic, metabolic and respiratory variables were measured. ResultsThere was a decrease in heart rate both at rest and during exercise after metoprolol and propranolol administration. The cardiac output, stroke volume and peripheral vascular resistance presented decreased responses to exercise after both drugs. O2 consumption and CO2 production were not altered signifcantly at rest but increased in a lesser degree during exercise. Propranolol administration reduced ventilation during rest and exercise, although the ventilatory response to exercise remained the same. Metoprolol administration did not affect ventilation at rest but reduced the ventilatory response to exercise leading to an increase of the PaCO2 Conclusion Propranolol and metoprolol effects on cardiovascular and metabolic variables measured at rest and during exercise were the same. The ventilatory effect with metoprolol administration was different from the observed with propranolol

Influência de betabloqueadores com atividade simpaticomimética intrínseca sobre pressäo arterial e lípides sanguíneos em portadores de hipertensäo arterial essencial / Effect of beta blockers with intrinsic sympathomimetic activity on blood pressure and blood lipids in patients with essential hypertension

Com a finalidade do comparar os efeitos de um betabloqueador com atividade simpaticomimética intrínseca (ASI) aos de um sem ASI, foram selecionados hipertensos com idade superior a 50 anos estudados durante quatro semanas e compreendendo três grupos: A) mepindolol (com ASI) 5mg/dia, 10 pacientes; B) metoprolol "duriles" (sem ASI) 200 mg/dia, 9 pacientes; C) placebo, 10 pacientes. Realizaram-se avaliaçäo clínica, prova ergométrica e dosagem de lípides sangüíneos antes e após o tratamento. O estudo da influência das drogas foi realizado pela análise de perfil. Em repouso, as três substâncias administradas reduziram igualmente a pressäo sistólica (PS), pressäo diastólica (PD) e freqüência cardíaca (FC). As médias de PS, PD e FC, em repouso, pós-tratamento foram respectivamente: 154,0, 95,5, 73,7 (grupo A); 148,8, 94,4, 70,1 (grupo B); 153,0, 96,0, 77,8 (grupo C). Na prova ergométrica houve reduçäo da PS, FC e duplo produto (DP) nos três grupos. A PD näo sofreu influência das drogas. As médias de PS, PD, FC e DP na carga máxima comum para os três grupos, na fase pós-tratamento, foram respectivamente: 198,0, 115,5, 124,3, 246,9 (grupo A); 198,8, 114,4, 144,6, 283,2 (grupo B); 202,2, 119,0, 143,5, 283,4 (grupo C). Em relaçäo ao perfil lipídico houve apenas uma discreta elevaçäo dos níveis séricos de triglicérides e de VLDL-colesterol após o tratamento. Em concluäo, o emprego do mepindolol e do metroprolol "duriles" foi igualmente útil na reduçäo dos níveis de pressäo arterial de hipertensos...

Beta blockade for patients of mitral stenosis in sinus rhythm.

Twenty patients of isolated mitral stenosis in normal sinus rhythm (age 22 +/- 4 yrs) in whom symptoms of systemic and pulmonary congestion were controlled on diuretics were the subjects of the present study. The effects of addition of Metoprolol 50 mg po bid for 4 weeks on subjective and objective indices of exercise tolerance were evaluated. Metoprolol produced greater than 50% subjective improvement in 80% of these patients. The increase in time to dyspnoea and total work done on treadmill after 90-120 mins, and after 12 hrs of a dose of metoprolol, were both significant (p less than 0.01). In none of the patients, resting heart rate less than 50/mt, resting and exercise systolic BP less than 90 and less than 105 mmHg, respectively, or any important untoward effects were observed. Metoprolol's beneficial effects and safety can be judged in these patients at two hours after first dose in out patients clinic.

Ação do metroprolol duriles na insuficiência coronária crônica / Effect of metoprolol duriles in chronic coronary insufficiency

Com o objetivo de estudar o efeito beta-bloqueador durante o teste ergométrico, foram selecionados 30 pacientes, 27 do sexo masculino e 3 do feminino, com idades entre 43 e 62 anos (média 53,8 anos) que apresentavam resposta isquêmica ao eletrocardiograma de esforço e/ou sintomas e sinais de insuficiência coronária crônica (angina estável e lesäo de pelo menos 70% em uma das artérias coronárias pela cinecoronariografia) e com níveis de pressäo arterial sistólica entre 110 e 160 mmHg e da diastólica entre 75 e 90 mmHg. O estudo constou de três períodos de quatro semanas cada: fase de controle, fase de beta-bloqueador (administraçäo de 200 mg diárias de metoprolol de liberaçäo prolongada) e fase de placebo. Foram realizados testes ergométricos no ínicio de cada uma dessas três fases e no final da investigaçäo. Em 28 dos 30 casos, foi estudado o comportamento das seguintes variáveis: freqüência cardíaca, pressäo arterial máxima, pressäo arterial mínima e duplo-produto em repouso e no momento de carga máxima da prova de esforço, bem como o trabalho executado, a quantidade de nitritos utilizados pelos pacientes nas diferentes fases da investigaçäo e os valores de 0,1 mv/watts durante o exercício físico realizado. O tratamento estatístico dos dados obtidos permitiu verificar que: 1) na fase de beta-bloqueador, durante a prova de esforço, houve aumento da freqüência cardíaca média, significantemente menor que o observado nas fases de controle e placebo; 2) durante a fase de beta-bloqueador, o aumento da pressäo arterial máxima durante a prova ergométrica näo foi significantemente menor que o observado nas outras fases; 3) para a pressäo arterial mínima, durante o teste ergométrico, näo ocorreram diferenças significativas nas três fases; 4) os valores do duplo-produto, durante a prova de esforço, mostraram que, na fase de beta-bloqueador, ocorreu aumento significantemente menor que o obtido nas outras fases; 5) em relaçäo ao trabalho executado, observou-se tolerância maior ao exercício físico na fase de beta-bloqueador; 6) o uso de nitritos foi significantemente menor na fase de beta-bloqueador em relaçäo às fases de controle e placebo; 7) os valores de 0,1 mv/watts näo diferiram nas três fases. Os resultados obtidos permitem confirmar a eficácia do metoprolol na terapêutica dos portadores de coronariopatia crônica, mesmo durante programas especiais de condicionamento físico