Bradycardic and Antiarrhythmic Effects of the D-Limonene in Rats / Efeitos Bradicárdicos e Antiarrítmicos do D-Limoneno em Ratos

Abstract Background: D-limonene (DL) is a monoterpene and is the major component in the essential oil of citrus fruit. It presents antihyperglycemic and vasodilatation activities. Objectives: This study evaluated the cardiovascular effects and potential antiarrhythmic of DL in rats. Methods: Hemodynamic and electrocardiographic (ECG) parameters were measured in male Wistar rats, which under anesthesia had been cannulated in the abdominal aorta and lower vena cava and had electrodes subcutaneously implanted. In the in vitro approach, the heart was removed and perfused using the Langendorff technique. The significance level adopted was 5% (p < 0.05). Results: DL, in doses of 10, 20, and 40 mg/kg (i.v), produced intense and persistent bradycardia associated with hypotension. Bradycardia with prolonged QTc was observed in the ECG in vivo recording. In the in vivo model of arrhythmia induced by Bay K8644, DL (10 mg/kg) decreased the arrhythmia score from 15.33 ± 3.52 to 4.0 ± 2.64 u.a (p < 0.05, n = 4). In isolated perfused hearts, DL (10-3 M) promoted significant reductions in heart rate (from 228.6 ± 8.5 ms to 196.0 ± 9.3 bpm; p < 0.05) and left ventricular development pressure (from 25.2 ± 3.4 to 5.9 ± 1.8 mmHg; n = 5, p < 0.05). Conclusions: DL produces bradycardia and antiarrhythmic activity in rat heart.

Resumo Fundamento: O D-limoneno (DL) é um monoterpeno e o principal componente do óleo essencial de frutas cítricas. Ele apresenta atividades anti-hiperglicêmicas e vasodilatadoras. Objetivos: Este estudo avaliou os efeitos cardiovasculares e antiarrítmicos potenciais do DL em ratos. Métodos: Os parâmetros hemodinâmicos e eletrocardiográficos (ECG) foram mensurados em ratos Wistar machos que, sob anestesia, tiveram a aorta abdominal e a veia cava inferior canuladas e receberam eletrodos implantados subcutaneamente. Na abordagem in vitro, o coração foi removido e perfundido utilizando a técnica de Langendorff. O nível de significância adotado foi de 5% (p < 0,05). Resultados: DL, nas doses de 10, 20 e 40 mg/kg (i.v), produziu bradicardia intensa e persistente associada à hipotensão. A bradicardia com QTc prolongado foi observada no registro in vivo do ECG. No modelo in vivo de arritmia induzida por Bay K8644, DL (10 mg / kg) houve diminuição do escore da arritmia de 15,33 ± 3,52 para 4,0 ± 2,64 u.a (p < 0,05, n = 4). Em corações perfundidos isolados, o DL (10-3 M) promoveu reduções significativas na frequência cardíaca (de 228,6 ± 8,5 ms para 196,0 ± 9,3 bpm; p < 0,05) e na pressão desenvolvida do ventrículo esquerdo (de 25,2 ± 3,4 para 5,9 ± 1,8 mmHg; n = 5, p < 0,05). Conclusões: O DL produz bradicardia e atividade antiarrítmica no coração de ratos.

Colchicine to Reduce Atrial Fibrillation in the Postoperative Period of Myocardial Revascularization / Colchicina para Redução de Fibrilação Atrial em Pós-Operatório de Revascularização Miocárdica

Abstract Background: The high prevalence of atrial fibrillation (AF) in the postoperative period of myocardial revascularization surgery increases morbidity and mortality. Objective: To assess the efficacy of colchicine to prevent AF in the postoperative period of myocardial revascularization surgery, the impact of AF on hospital length of stay and death, and to identify its risk factors. Methods: Between May 2012 and November 2013, 140 patients submitted to myocardial revascularization surgery were randomized, 69 to the control group and 71 to the colchicine group. Colchicine was used at the dose of 1 mg orally, twice daily, preoperatively, and of 0.5 mg, twice daily, until hospital discharge. A single dose of 1 mg was administered to those admitted 12 hours or less before surgery. Results: The primary endpoint was AF rate in the postoperative period of myocardial revascularization surgery. Colchicine group patients showed no reduction in AF incidence as compared to control group patients (7.04% versus 13.04%, respectively; p = 0.271). There was no statistically significant difference between the groups regarding death from any cause rate (5.6% versus 10.1%; p = 0,363) and hospital length of stay (14.5 ± 11.5 versus 13.3 ± 9.4 days; p = 0.490). However, colchicine group patients had a higher infection rate (26.8% versus 8.7%; p = 0.007). Conclusion: The use of colchicine to prevent AF after myocardial revascularization surgery was not effective in the present study. Brazilian Registry of Clinical Trials number RBR-556dhr.

Resumo Fundamento: A alta prevalência de fibrilação atrial (FA) no pós-operatório de cirurgia de revascularização miocárdica ocasiona maior morbidade e mortalidade. Objetivos: Avaliar a eficácia da colchicina como profilaxia para FA no pós-operatório de cirurgia de revascularização miocárdica, o impacto da FA sobre o tempo de internação hospitalar e óbito e identificar fatores de risco para o seu aparecimento. Métodos: Entre maio de 2012 e novembro de 2013, 140 pacientes submetidos à cirurgia de revascularização miocárdica foram randomizados, 69 no grupo controle e 71 no grupo colchicina. A colchicina foi utilizada na dose de 1 mg via oral, duas vezes ao dia, no pré-operatório, e 0,5 mg, duas vezes ao dia, até a alta hospitalar. Dose única de 1 mg foi administrada aos internados 12 horas ou menos antes da cirurgia. Resultados: O desfecho primário foi a taxa de FA no pós-operatório de cirurgia de revascularização miocárdica. Os pacientes do grupo colchicina não apresentaram redução na incidência de FA em comparação aos do grupo controle (7,0% versus 13,0%, respectivamente; p = 0,271). Não houve diferença estatisticamente significativa entre os grupos em relação à taxa de óbito por qualquer causa (5,6% versus 10,1%; p = 0,363) e ao tempo de internação (14,5 ± 11,5 versus 13,3 ± 9,4 dias; p = 0,490). Porém, o grupo colchicina apresentou maior taxa de infecção (26,8% versus 8,7%; p = 0,007). Conclusões: O uso da colchicina para profilaxia da FA no pós-operatório de revascularização miocárdica não se mostrou eficaz neste estudo. Registro Brasileiro de Ensaios Clínicos número RBR-556dhr.

Role of mitochondrial ATP-sensitive potassium channel-mediated PKC-ε in delayed protection against myocardial ischemia/reperfusion injury in isolated hearts of sevoflurane-preconditioned rats

This study aimed to determine the role of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels and protein kinase C (PKC)-ε in the delayed protective effects of sevoflurane preconditioning using Langendorff isolated heart perfusion models. Fifty-four isolated perfused rat hearts were randomly divided into 6 groups (n=9). The rats were exposed for 60 min to 2.5% sevoflurane (the second window of protection group, SWOP group) or 33% oxygen inhalation (I/R group) 24 h before coronary occlusion. The control group (CON) and the sevoflurane group (SEVO) group were exposed to 33% oxygen and 2.5% sevoflurane for 60 min, respectively, without coronary occlusion. The mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD) was given 30 min before sevoflurane preconditioning (5-HD+SWOP group). Cardiac function indices, infarct sizes, serum cardiac troponin I (cTnI) concentrations, and the expression levels of phosphorylated PKC-ε (p-PKC-ε) and caspase-8 were measured. Cardiac function was unchanged, p-PKC-ε expression was upregulated, caspase-8 expression was downregulated, cTnI concentrations were decreased, and the infarcts were significantly smaller (P<0.05) in the SWOP group compared with the I/R group. Cardiac function was worse, p-PKC-ε expression was downregulated, caspase-8 expression was upregulated, cTnI concentration was increased and infarcts were larger in the 5-HD+SWOP group (P<0.05) compared with the SWOP group. The results suggest that mitoKATP channels are involved in the myocardial protective effects of sevoflurane in preconditioning against I/R injury, by regulating PKC-ε phosphorylation before ischemia, and by downregulating caspase-8 during reperfusion.

Impacto do uso de psicotrópicos na dispersão do intervalo QT em pacientes adultos / Impact of Psychotropic Drugs on QT Interval Dispersion in Adult Patients

Fundamento: A dispersão do intervalo QT induzida por fármacos tem sido associada a arritmias ventriculares potencialmente fatais. Pouco se conhece sobre o uso de psicotrópicos, isolados ou em combinação com outros fármacos, na dispersão do QT. Objetivo: Avaliar o impacto do uso psicotrópicos na dispersão do intervalo QT em pacientes adultos. Métodos: Estudo de coorte observacional, envolvendo 161 pacientes hospitalizados em um departamento de emergência de hospital terciário, estratificados em usuários e não usuários de psicotrópicos. Dados demográficos, clínicos, laboratoriais e de fármacos em uso foram coletados à admissão, bem como o eletrocardiograma de 12 derivações, com a mensuração do intervalo e da dispersão do QT. Resultados: A dispersão do intervalo QT foi significativamente maior no grupo de usuário de psicotrópicos comparado ao grupo não usuário (69,25 ± 25,5 ms vs. 57,08 ± 23,4 ms; p = 0,002). O intervalo QT corrigido pela fórmula de Bazzett também se mostrou maior no grupo de usuário de psicotrópicos, com significância estatística (439,79 ± 31,14 ms vs. 427,71 ± 28,42 ms; p = 0,011). A análise por regressão linear mostrou associação positiva entre o número absoluto de psicotrópicos utilizados e a dispersão do intervalo QT, com r = 0,341 e p < 0,001. Conclusão: Na população amostral estudada, o uso de psicotrópicos se mostrou associado ao aumento da dispersão do intervalo QT, e esse incremento se acentuou em função do maior número de psicotrópicos utilizados. .

Background: Drug-induced increase in QT dispersion has been associated with potentially fatal ventricular arrhythmias. Little is known about the use of psychotropic substances, alone or in combination with other drugs on QT dispersion. Objectives: To evaluate the impact of psychotropic drugs on QT interval dispersion in adults. Methods: An observational cohort study was designed involving 161 patients hospitalized from an emergency department at a tertiary hospital, divided into psychotropic users or non-users. Demographic, clinical, laboratory data and drugs used on a regular basis were collected on admission, in addition to 12-lead electrocardiogram with QT dispersion measurement. Results: QT dispersion was significantly higher in the psychotropic user group compared to non-users (69.25 ± 25.5 ms vs. 57.08 ± 23.4 ms; p = 0.002). The QT interval corrected by Bazzett formula was also higher in the psychotropic drugs user group, with statistical significance. (439.79 ± 31.14 ms vs. 427.71 ± 28.42 ms; p = 0.011). A regression analysis model showed a positive association between the number of psychotropic drugs used and QT interval dispersion, with r = 0.341 and p < 0.001. Conclusions: The use of psychotropic drugs was associated with increased QT dispersion and this increase was accentuated, as the number of psychotropic drugs used was higher. .

Interações medicamentosas em cardiologia: Fármacos antiárritmicos / Drugs interactions in cardiology: Antiarrhythmics drugs

As arritmias cardíacas são geradas por diferentes mecanismoseletrofisiológicos que atuam isoladamente ou interagem entresi para a formação e condução do impulso anormal. Com baseno conhecimento da eletrofisiologia celular e dos mecanismosgeradores de arritmias, diversos fármacos antiarrítmicos foramdesenvolvidos com objetivo de propiciar terapias cada vez maiseficazes e seguras. A necessidade de se agrupar os antiarrítmicos deacordo com seu mecanismo de ação e efeitos no impulsocardíaco, resultou na classificação de Vaughan- Williams que,apesar de amplamente difundida, não contempla algumasmedicações classicamente utilizadas como antiarrítmicos, taiscomo a adenosina e os digitálicos. Os antiarrítmicos são, emgeral, metabolizados pelo fígado por meio dos citocromos.Fármacos que interagem no mesmo sítio de ação em que sãometabolizados podem resultar em potencialização ou inibiçãodos efeitos antiarrítmicos. A redução ou o aumento do nívelsérico do antiarrítmico causado pelo fármaco utilizado concomitantemente,em decorrência da alteração na velocidade demetabolização, da redução na absorção ou somatório de efeitos,pode aumentar o potencial para efeitos colaterais deletérios eefeitos pró-arrítmicos e resultar em efeitos tóxicos potencialmentegraves. O objetivo deste capítulo é revisar os diversosmecanismos de interação medicamentosa que podem ocorrerenvolvendo as classes de antiarrítmicos...

Cardiac arrhythrnias are generated by different electrophysiologicalmechanisms that act alone or interact for the formation andconduction of the abnormal impulse. Based on the knowledge ofcellular electrophysiology and arrhythmia mechanisms, severalantiarrhythrnics were developed in order to provide therapiesincreasingly effective and safe. The need of grouping the antiarrhythmicagents according to their mechanism of action andeffects on cardiac impulse have led to the development of theVaughan- Williams c1assification. Although widespread used,this c1assification does not include some drugs c1assically usedas antiarrhythmics such as adenosine and digitalis.Antiarrhythmic agents are generaUy metabolized by the livervia the cytochrome. Drugs that interact at the same site of actionthat are metabolized may result in potentiation or inhibition ofantiarrhythmic effects. The reduction or increase in serum levelscaused by antiarrhythmic drug used concomitantly, due to thechange in the metabolism, reduction in absorption or summationeffects may increase the potential for deleterious side effects andproarrhythmic effects and result in potentiaUy serious toxic effects.The purpose of this chapter is to review the variousmechanisms of drug interactions that may occur involving theantiarrhythmic drugs...

Principios básicos de las nuevas estrategias farmacológicas antiarrítmicas en fibrilación auricular / Basic mechanisms of the new antiarrhythmic drugs in atrial fibrillation

La fibrilación auricular (FA) es la arritmia crónica sostenida más frecuente en la población general. A pesar de los últimos avances tecnológicos y en el entendimiento de sus mecanismos, derivados de modelos experimentales, así como de los procedimientos de ablación en pacientes con FA, los fármacos antiarrítmicos siguen siendo la principal estrategia para la cardioversión y mantenimiento del ritmo sinusal. Nuevas generaciones de fármacos antiarrítmicos han llegado a la práctica clínica, y otros se encuentran en fase de experimentación. Los nuevos fármacos actúan de forma más específica sobre corrientes iónicas auriculares, y al mismo tiempo involucradas en el mantenimiento de la arritmia. Paralelamente, cada vez se da más importancia a la necesidad de actuar sobre el sustrato arritmogénico auricular y los factores que lo promueven, implicados en el mantenimiento a largo plazo de la arritmia (terapias upstream). La presente revisión tiene como objetivo exponer las actuales líneas de desarrollo en fármacos antiarrítmicos y terapias para prevención o retraso del remodelado auricular, con base a los conocimientos mecanísticos que hoy en día se involucran en el mantenimiento de la FA.

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. Despite of new technological breakthroughs and the understanding of the mechanisms underlying AF, based on animal models and ablation procedures in patients, the antiarrhythmic drugs remain the main therapeutic strategy to restore and maintain the sinus rhythm. New antiarrhythmic drugs are already available in the clinical practice and many others are under development. The new antiarrhythmic drugs have the capability to block atrial-specific ionic currents, which are involved in the maintenance of the arrhythmia. Parallel, increasing evidence supports the use of compounds to regulate the arrhythmogenic atrial substrate involved in the long-term maintenance of the arrhythmia (upstream therapies). This article reviews the new antiarrhythmic drugs and upstream therapies, based on the current knowledge of the mechanisms involved in the maintenance of AF.

Polyphenol (-)-Epigallocatechin Gallate during Ischemia Limits Infarct Size Via Mitochondrial K(ATP) Channel Activation in Isolated Rat Hearts

Polyphenol (-)-epigallocatechin gallate (EGCG), the most abundant catechin of green tea, appears to attenuate myocardial ischemia/reperfusion injury. We investigated the involvement of ATP-sensitive potassium (K(ATP)) channels in EGCG-induced cardioprotection. Isolated rat hearts were subjected to 30 min of regional ischemia and 2 hr of reperfusion. EGCG was perfused for 40 min, from 10 min before to the end of index ischemia. A nonselective K(ATP) channel blocker glibenclamide (GLI) and a selective mitochondrial K(ATP) (mK(ATP)) channel blocker 5-hydroxydecanoate (HD) were perfused in EGCG-treated hearts. There were no differences in coronary flow and cardiodynamics including heart rate, left ventricular developed pressure, rate-pressure product, +dP/dt(max), and -dP/dt(min) throughout the experiments among groups. EGCG-treatment significantly reduced myocardial infarction (14.5+/-2.5% in EGCG 1 micrometer and 4.0+/-1.7% in EGCG 10 micrometer, P<0.001 vs. control 27.2+/-1.4%). This anti-infarct effect was totally abrogated by 10 micrometer GLI (24.6+/-1.5%, P<0.001 vs. EGCG). Similarly, 100 micrometer HD also aborted the anti-infarct effect of EGCG (24.1+/-1.2%, P<0.001 vs. EGCG ). These data support a role for the K(ATP) channels in EGCG-induced cardioprotection. The mK(ATP) channels play a crucial role in the cardioprotection by EGCG.

Regulation of Antiarrhythmic Drug Propafenone Effects on the C-type KV1.4 Potassium Channel by PHo and K+

The effects of the antiarrhythmic drug propafenone at c-type kv1.4 channels in Xenopus laevis oocytes were studied with the two-electrode voltage-clamp techinique. Defolliculated oocytes (stage V-VI) were injected with transcribed cRNAs of ferret Kv1.4 delta N channels. During recording, oocytes were continuously perfused with control solution or propafenone. Propafenone decreased the currents during voltage steps. The block was voltage-, use-, and concentration- dependent manners. The block was increased with positive going potentials. The voltage dependence of block could be fitted with the sum of monoexponential and a linear function. Propafenone accelerated the inactivate of current during the voltage step. The concentration of half-maximal block (IC(50)) was 121 micrometer/L. With high, normal, and low extracellular potassium concentrations, the changes of IC(50) value had no significant statistical differences. The block of propafenone was PH- dependent in high-, normal- and low- extracellular potassium concentrations. Acidification of the extracellular solution to PH 6.0 increased the IC50 values to 463 micrometer/L, alkalization to PH 8.0 reduced it to 58 micrometer/L. The results suggest that propafenone blocks the kv1.4 delta N channel in the open state and give some hints for an intracellular site of action.

Positive inotropic effect of Murraya koenigii (Linn.) Spreng extract on an isolated perfused frog heart.

Ethanolic extract of fresh leaves of M. koenigii (MKEE) showed a dose dependent positive inotropic effect on isolated frog heart. The responses to MKEE (62.5-1000 microg) were not affected in either way by theophylline, imidazole, propranolol and sildenafil. The change in potassium and sodium concentration did not alter MKEE-induced positive inotropic effect. Lignocaine did not alter the responses to MKEE significantly. Responses to MKEE were significantly inhibited when calcium concentration was reduced to half (from 1.58 to 0.79 mM) and were significantly potentiated when calcium concentration was doubled (from 1.58 to 3.16 mM). Verapamil was found to inhibit the responses significantly. The results suggest that M. koenigii induced positive inotropic effect possibly by increasing availability of calcium from extra cellular sites.

Analisis ecocardiografico del efecto de diferentes inhibidores del intercambiador Na+/H+ sobre la estructura y funcion sistolica del ventriculo izquierdo en ratas espontaneamente hipertensas / Echocardiographic analysis of the effect of different Na+/H+ exchanger inhibitors on left

El presente estudio fue proyectado para analizar mediante ecocardiograma los efectos del HOE 642 (cariporide) (HOE) y del BIIB 723 (BIIB) sobre la estructura y función sistólica del ventrículo izquierdo en ratas espontáneamente hipertensas (SHR)- 8 con 30 mg/kg/día de HOE, 8 con 30 mg/kg/día de BIIB durante 30 días y 4 sin tratamiento (grupo control) durante esos 30 días. Los distintos parámetros analizados no mostraron cambios durante ese período en las ratas controles. Si bien el HOE determinó un leve descenso de la presión arterial (C: 184 ± 1.75 mm Hg; 30d:176.20 ± 2.60 mm Hg, p <0.01), no detectada con BIIB,ambas drogas provocaron un aumento del estrés sistólico pico (HOE C:166 ± 29 kdinas/cm2; 30d: 204 ± 34kdinas/cm2, p <0.04. BIIB C: 164 ± 25.90 kdinas/cm2; 30d: 234 ± 29.30 kdinas/cm2, p<0.02).Tanto HOE comoBIIB redujeron significativamente la masa ventricular izquierda (MVI) (HOE C: 612.50±50 mg; 30d:452 ± 37 mg,p <0.01; BIIB C: 544 ± 16mg; 30 d: 374 ± 25 mg, p<0.01). El porcentaje de acortamiento endocárdico no semodificó luego del tratamiento con HOE (C: 62.30 ± 2.75; 30d 65.50 ± 2.40%, ns) y BIIB (C: 63.20 ± 2.39%;30d 67.20 ± 1.62%, ns). Los resultados analizados permiten concluir que ambos inhibidores determinaron similarreducción de la MVI. Esa reducción se acompañó de mejoría en los índices de evaluación de la función sistólica ventricular izquierda, pese al incremento del estrés sistólico pico. Estas evidencias sugieren que independientemente del inhibidor utilizado se encuentra un aumento del inotropismo, previamente comprometidodurante el desarrollo de la hipertrofia

The aim of this study was to analyze by echocardiogram, the action of two Na+/H+ exchange, inhibitors, HOE 642 (HOE) and BIIB 723 (BIIB) on left ventricular (LV) mass and LV systolic function. We studied 16 spontaneously hypertensive rats (SHR), 8 treated with HOE 30 mg/kg/day, 8 with 30 mg/kg/day of BIIB during 30 days and 4 SHR as controls during those 30 days. Results are expressed as mean values ± SEM. The systolic blood pressure and theechocardiograpic parameters examined did not evidence changes during that period in the controls rats. Eventhough HOE determined a slight decrease in blood pressure (HOE C: 184 ± 1.75 mm Hg; HOE 30d: 176.20 ±2.60 mm Hg - p <0.01) which was not detected with BIIB, both drugs provoked an increase of peak systolic stress (HOE C: 166 ± 29 kdynes/cm2; HOE 30d: 204 ± 34 kdynes/cm2, p <0.04; BIIB C: 164 ± 25.90 kdynes/cm2; BIIB 30d: 234 ± 29.30 kdynes/cm2, p <0.02). HOE and BIIB reduced LV mass after 30 days of administration (HOE C: 612.50 ± 50 mg; 30d: 452 ± 37 mg, p <0.01. BIIB C: 544 ± 16mg; 30d: 374 ± 25 mg, p <0.01). LV endocardial shortening was similar independently of the NHE inhibitors used (HOE C: 62.30 ± 2.75%; 30d: 65.50 ± 2.40%, ns. BIIB C: 63.20 ± 2,39%; 30d 67,20 ± 1.62%, ns). These data demonstrate that long-treatment with HOE or BIIB produced similar LV mass regression without changes in endocardial fractional shortening in spite of the increase of peak systolic stress. This finding could represent an increased inotropism previously depressed by the development of hypertrophy

Acute effect of amiodarone on cardiovascular reflexes of normotensive and renal hypertensive rats

The aim of the present study was to evaluate the effect of amiodarone on mean arterial pressure (MAP), heart rate (HR), baroreflex, Bezold-Jarisch, and peripheral chemoreflex in normotensive and chronic one-kidney, one-clip (1K1C) hypertensive rats (N = 9 to 11 rats in each group). Amiodarone (50 mg/kg, iv) elicited hypotension and bradycardia in normotensive (-10 ± 1 mmHg, -57 ± 6 bpm) and hypertensive rats (-37 ± 7 mmHg, -39 ± 19 bpm). The baroreflex index (deltaHR/deltaMAP) was significantly attenuated by amiodarone in both normotensive (-0.61 ± 0.12 vs -1.47 ± 0.14 bpm/mmHg for reflex bradycardia and -1.15 ± 0.19 vs -2.63 ± 0.26 bpm/mmHg for reflex tachycardia) and hypertensive rats (-0.26 ± 0.05 vs -0.72 ± 0.16 bpm/mmHg for reflex bradycardia and -0.92 ± 0.19 vs -1.51 ± 0.19 bpm/mmHg for reflex tachycardia). The slope of linear regression from deltapulse interval/deltaMAP was attenuated for both reflex bradycardia and tachycardia in normotensive rats (-0.47 ± 0.13 vs -0.94 ± 0.19 ms/mmHg and -0.80 ± 0.13 vs -1.11 ± 0.13 ms/mmHg), but only for reflex bradycardia in hypertensive rats (-0.15 ± 0.02 vs -0.23 ± 0.3 ms/mmHg). In addition, the MAP and HR responses to the Bezold-Jarisch reflex were 20-30 percent smaller in amiodarone-treated normotensive or hypertensive rats. The bradycardic response to peripheral chemoreflex activation with intravenous potassium cyanide was also attenuated by amiodarone in both normotensive (-30 ± 6 vs -49 ± 8 bpm) and hypertensive rats (-34 ± 13 vs -42 ± 10 bpm). On the basis of the well-known electrophysiological effects of amiodarone, the sinus node might be the responsible for the attenuation of the cardiovascular reflexes found in the present study.

Utilização de fármacos antiarrítmicos em pacientes com cardioversor-desfibrilador automático / Antiarrhythmic drug effects in patients with automatic implantable cardioverter defibrillators

O cardioversor desfibrilador automático é a principal forma de tratamento de pacientes portadores de arritmias ventriculares malignas e com alto risco para morte súbita. Pelo fato de esses pacientes apresentarem alto risco de recorrência da taquicardia ventricular, o tratamento medicamentoso incluindo antiarrítmicos torna-se necessário. Os principais objetivos dessa forma de tratamento são: redução da frequência de surgimento da taquicardia ventricular e, assim, prolongar a vida da bateria e tornar o tratamento mais bem tolerado pelo paciente; redução da frequência cardíaca durante a taquicardia, permitindo que a função antitaquicardia seja efetiva em restabelecer o ritmo cardíaco normal e reduzir a frequência de aparecimento de taquicardia supraventricular, diminuindo a possibilidade de choques inapropriados pelo gerador. Embora pareça intuitivo, são escassos os estudos que avaliam de maneira prospectiva os efeitos da medicação antiarrítmica sobre a função do cardioversor elétrico e a frequência de aparecimento de taquicardia, bem como sobre a qualidade de vida dos pacientes. Esse tipo de tratamento farmacológico não é desprovido de efeitos colaterais, já que alguns agentes antiarrítmicos podem interagir com o desfibrilador, interferindo em suas funções, como a elevação do limiar de desfibrilação elétrica, ou então facilitando o surgimento de outras taquicardias não-clínicas, pelos seus efeitos pró-arrítmicos. Por essas razões, é aconselhável cautela quando de opta pela terapêutica combinada. Devem ser realizadas averiguações do limiar de desfibrilação elétrica sempre que houver qualquer mudança do regime terapêutco para se atingir margem de segurança efetiva para a desfibrilação ventricular

Estabilidad del inyectable de fosfato de disopiramida (13 mg/mL) / Stability of disopyramide phosphate injectable product (13 mg/mL)

Entre los fármacos utilizados actualmente en el tratamiento de las afecciones cardiovasculares, se encuentran el fosfato de disopiramida, un agente antiarrítmico tipo I, estabilizante del potencial de membrana en reposo. Una de las formas farmacéuticas en que este se presenta es la de inyectable, con una dosificasión de 13 mg/mL para la base, por lo que en este trabajo se realizó el estudio acelerado de estabilidad y el estudio de vida útil de 3 lotes de este innyectable. En las condiciones ensayadas, el medicamento resultó estable, por lo que se propuso una fecha de vencimiento de 2 años

Efecto de la fenitoína prenatal en fetos de rata: estudio morfológico y morfométrico de la glándula submandibular / Effect of prenatal phenytoin on rat fetuses: and morphometrical study of the submandibular gland

La fenitoína (difenil hidantoína) es una droga anticonvulsiva y antiarrítmica, que posee acción teratógena en animales y humanos, causando importantes alteraciones, aún cuando se administra en dosis no teratógenas. Con el objetivo de estudiar morfológica y morfométricamente los efectos de la droga sobre la glándula submandibular fetal, ratas Wistar fueron inyectadas el 10ª día de preñez, con 70, 100 ó 150 mg/kg de fenitoína. Las dosis más altas provocaron la muerte intrauterina de todos los fetos. El peso de los fetos de las ratas inyectadas con 70 mg/kg de fenitoína fue menor que el de los controles. El examen histopatológico de la glándulas submandibular reveló una glándula inmadura, constituida por acinos y conductos mayores y con luz disminuida. Las células de los acinos y conductos eran mayores, con núcleos más grandes. El tejido conjuntivo era más escaso en los fetos del grupo tratado. Morfométricamente, fue posible confirmar los hallazgos histopatológicos. Los resultados sugieren que la exposición prenatal a la fenitoína, en dosis no teratógenas, actúa en la embriogénesis, causando alteraciones en el desarrollo (menor peso, cordón umbilical más corto y glándula submandibular menos diferenciada), mostrando el feto tratado aspectos de inmaturidad

El intercambiador Na+/Ca2+ como responsable del atontamiento miocardio / The Na+/Ca2+ exchanger as responsible of myocardial stunning

Nuestro objetivo fue examinar la participación de los intercambiadores Na+/H+ (NHE) y Na+/Ca+2 (NCX) sobre las alteraciones sistólicas propias del atontamiento miocárdio. Se utilizó el modelo de corazón aislado isovolúmico de rata el cual fue sometido a 20 minutos de isquemia global (Is) y 30 minutos de perfusión (R). Este protocolo se repitió en prasencia de 1microM de HOE 642, bloqueante específico del NHE-1 y de KB-R7943, bloqueante del modo inverso del NCX (entrando Ca+2 y sacando Na de la célula) administrados antes de la Is, y/o en la R. En los controles isquémicos la contractilidad, evaluada a través de la +dP/dtmax se recuperó aproximadamente un 60 porciento. La recuperación postisquémica fue total cuando el bloqueo de NHE fue efectuado antes de la Is o al comienzo de la R y mejoró significativamente cuando en Is y R bloqueó el NCX ( 95 + o - 7 porciento). La contractura isquémica disminuyó com ambos tratamientos cuando fueron realizados previos a la Is. El aumento de la PDF observado en la R (24 + o - 6 y 12 + o - 2 mmHg) y por el bloqueo del NCX realizado durante Is y R (12 + o - 6 mmHg). Estos resultados indican que la activación del modo inverso del NCX secundaria a una activación del NHE (que incrementa el Na+ intracelular) durante la isquemia y reperfusión es el mecanismo culpable de la sobrecarga de Ca+2 involucrado en la disminuición de la contractilidad que caracteriza al miocardio atontado.

Cuantificacion de amiodarona en suero mediante precipitacion de proteinas seguida de cromatografia liquida de alta resolucion con deteccion ultravioleta / Measurement of serum amiodarone by protein precipitation followed by high performance liquid chromatography with ultraviolet detection

Nos propusimos desarrollar un método para la medición de amiodarona en suero mediante cromatografia líquida de alta resolución con detección ultravioleta, optimizando las condiciones analíticas descritas en la literatura y determinar las condiciones óptimas de almacenamiento de la muestra, para la instalación de un servicio nacional de referencia. la preparación de la muestra consistió en la adición de 2 partes de acetonitrilo a 1 parte de suero, agitación por 45s, incubación a 24§C por 5 min, centrifugación a 6000 x g durante 2 min e inyección de 20 mu L del sobrenadante al cromatógrafo. Utilizando una columna mu Bondapak CN RP (3.9 x 150 mm) a 45§C, con una fase móvil compuesta por KH2PO4 10 mM/metanol/acetonitrilo (40:37:223 v/v/v) a pH 3,5, bombeada a 0,6 mL/min, obtuvimos un tiempo de retención de 4,9 min. La detección se realizó a 242 nm, y la cuantificación mediante comparación con estándares externos; el límite de detección fue de 0,11 mu g/mL. La relación masa/respuesta fue lineal (r2 > 0,99) para inyecciones con masa nominal de 2,96 a 18930 ng, lo cual excede lo requerido para el monitoreo de amiodarona sérica (0,3 a 6,0 mu g/ml). La recuperación fue de 99,26 por ciento más o menos 2,84 por ciento. El almacenamiento a -16§C de muestras precipitadas evita la degradación de la droga. Este método resultó más eficiente, sencillo y económico que otros ya descritos, manteniendo la sensibilidad, especificidad y linealidad requeridas para ser considerado un método óptimo para la cuantificación de amiodarona en suero.