Temperature effects on the cardiorespiratory control of American bullfrog tadpoles based on a non-invasive methodology.

Temperature effects on cardiac autonomic tonus in amphibian larval stages have never been investigated. Therefore, we evaluated the effect of different temperatures (15, 25 and 30°C) on the cardiorespiratory rates and cardiac autonomic tonus of premetamorphic tadpoles of the bullfrog, Lithobates catesbeianus To this end, a non-invasive method was developed to permit measurements of electrocardiogram (ECG) and buccal movements (fB; surface electromyography of the buccal floor). For evaluation of autonomic regulation, intraperitoneal injections of Ringer solution (control), atropine (cholinergic muscarinic antagonist) and sotalol (ß-adrenergic antagonist) were performed. Ringer solution injections did not affect heart rate (fH) or fB across temperatures. Cardiorespiratory parameters were significantly augmented by temperature (fH: 24.5±1.0, 54.5±2.0 and 75.8±2.8 beats min-1 at 15, 25 and 30°C, respectively; fB: 30.3±1.1, 73.1±4.0 and 100.6±3.7 movements min-1 at 15, 25 and 30°C, respectively). A predominant vagal tone was observed at 15°C (32.0±3.2%) and 25°C (27.2±6.7%) relative to the adrenergic tone. At 30°C, the adrenergic tone increased relative to the lower temperature. In conclusion, the cholinergic and adrenergic tones seem to be independent of temperature for colder thermal intervals (15-25°C), while exposure to a hotter ambient temperature (30°C) seems to be followed by a significant increase in adrenergic tone and may reflect cardiovascular adjustments made to match oxygen delivery to demand. Furthermore, while excluding the use of implantable electrodes or cannulae, this study provides a suitable non-invasive method for investigating cardiorespiratory function (cardiac and respiratory rates) in water-breathing animals such as the tadpole.

Abordagem das arritmias na Doença de Chagas Crônica / Approach of arrhythmias in chronic Chagas Disease

As arritmias na cardiopatia chagásica (CCH) são responsáveis por incapacitação física e morte em indivíduos adultos em faixa etária precoce e produtiva, decorrendo daí a necessidade de sua abordagem criteriosa e, às vezes, mais agressiva para se obter controle completo. As arritmias cardíacas mais encontradas na CCH são as bradiarritmias e as taquicardias. Entre as bradicardias estão as alterações sinoatriais e os bloqueios atrioventriculares, cujo tratamento padrão é o emprego de implante de marcapasso definitivo. Entre as taquiarritmias, encontram-se as supraventriculares ­ extrassístoles atriais, taquicardia atrial ectópica, "flutter" atrial e fibrilação atrial ­ que provocam morbidades como progressão para disfunção ventricular esquerda e fenômenos tromboembólicos, e as ventriculares, cujo desfecho pode ser a morte súbita instantânea. A abordagem deve ser, inicialmente, por meio de eletrocardiograma de 12 derivações, pela gravação ambulatorial (Holter), ecocardiograma, teste ergométrico, e por fim, o estudo eletrofisiológico e a ressonância nuclear magnética. O tratamento farmacológico pode ser conduzido com o uso dos fármacos existentes em nosso mercado, como amiodarona, propafenona e sotalol. O tratamento invasivo, pode consistir em ablação por cateter, embora com resultados ainda abaixo de índices confortadores, devido à possibilidade de recidivas. O uso de cardiodesfibrilador implantável é a última alternativa, que também tem suas limitações

Arrhythmias in Chagas cardiomyopathy (CCM) are responsible for physical disability and death in adults in early and productive age group, from which arises the need for a judicious and sometimes more aggressive approach to achieve the complete control. The arrhythmias most common in CCM are bradyarrhythmias and tachycardias. Among the bradycardias are the sinoatrial changes and atrioventricular blocks, whose standard treatment is the use of permanent pacemaker implantation. Among tachyarrhythmias are the supraventricular ones - atrial extrasystoles, ectopic atrial tachycardia, atrial flutter and atrial fibrillation - causing morbidity and progression of left ventricular dysfunction and thromboembolic events, and the ventricular ones, whose outcome can be the instantaneous sudden death. The approach should be initially through 12-lead electrocardiogram, by ambulatory ECG recording (Holter), echocardiogram, stress testing, and finally the electrophysiological study and magnetic resonance imaging. Pharmacological treatment can be conducted with the use of marketed drugs such as amiodarone, propafenone and sotalol. The invasive treatment may consist of catheter ablation, although the results are still below comforting rates due to the possibility of recurrence. The use of implantable cardioverter defibrillator is the last alternative, which also has its limitations

Role of brain nitric oxide in the cardiovascular control of bullfrogs.

The goal of the present study was to determine if nitric oxide (NO) acting on the brain of bullfrog (Lithobates catesbeianus) is involved in arterial pressure and heart rate (HR) control by influencing sympathetic activity. We investigated the effect of intracerebroventricular injections of L-NMMA (a nonselective NO synthase inhibitor) on mean arterial blood pressure (MAP), HR and cutaneous vascular conductance (CVC) of pelvic skin after intravenous injection of α or ß adrenergic blockers, prazosin or sotalol, respectively. Arterial pressure was directly measured by a telemetry sensor inserted in the aortic arch of animals. L-NMMA increased MAP, but did not change HR. This hypertensive response was inhibited by the pre-treatment with prazosin, but accentuated by sotalol. The effect of L-NMMA on MAP was also inhibited by i.v. injections of the ganglionic blocker, hexamethonium. Thus, NO acting on the brain of bullfrog seems to present a hypotensive effect influencing the sympathetic activity dependent on α and ß adrenergic receptors in the periphery.

Systemic propranolol acts centrally to reduce conditioned fear in rats without impairing extinction.

BACKGROUND: Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. With an auditory fear conditioning task in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar-pressing. METHODS: One day after receiving auditory fear conditioning, rats were injected with saline, propranolol, or peripheral beta-receptor blocker sotalol (both 10 mg/kg, IP). Twenty minutes after injection, rats were given either 6 or 12 extinction trials and were tested for extinction retention the following day. The effect of propranolol on the firing rate of neurons in prelimbic (PL) prefrontal cortex was also assessed. RESULTS: Propranolol reduced freezing by more than 50%, an effect that was evident from the first extinction trial. Suppression was also significantly reduced. Despite this, propranolol had no effect on the acquisition or retention of extinction. Unlike propranolol, sotalol did not affect fear expression, although both drugs significantly reduced heart rate. This suggests that propranolol acts centrally to reduce fear. Consistent with this, propranolol reduced the firing rate of PL neurons. CONCLUSION: Propranolol reduced the expression of conditioned fear, without interfering with extinction learning. Reduced fear with intact extinction suggests a possible use for propranolol in reducing anxiety during extinction-based exposure therapies, without interfering with long-term clinical response.

In vitro effects of acute amiodarone and dronedarone on epicardial, endocardial, and M cells of the canine ventricle.

Amiodarone (AM) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias. Dronedarone (DR) is a new compound with a pharmacological profile similar to that of AM, but iodine free. We previously demonstrated that chronic AM treatment reduces transmural dispersion of repolarization (TDR) in the canine heart. We used standard microelectrode technique to evaluate the effects of acute AM (100 microM) and DR (30 microM) on epicardial (EPI), endocardial (ENDO), and M region tissues obtained from the left ventricular wall of the canine heart. Amiodarone (100 microM, 120 min of exposure) produced little change in the action potential duration of ENDO and EPI tissues, but it shortened the action potential of M cells, especially at slow rates, leading to a decrease in TDR. Similar results were observed with DR. Acute AM (100 microM) and DR (30 microM) eliminated d-sotalol-induced early afterdepolarizations (EADs) and triggered activity in 3 of 3 and 2 of 6 M cell preparations, respectively. The reduction of TDR and the elimination of EAD-induced triggered activity differentiates AM and DR from other class III agents. These effects may explain the efficacy and low arrhythmogenicity of acute AM and suggest a potential safe use of DR as an antiarrhythmic agent.

Role of dipolar and nondipolar components of the T wave in determining the T wave residuum in an isolated rabbit heart model.

INTRODUCTION: Repolarization heterogeneity has been shown to constitute a substrate for malignant ventricular arrhythmias. Noninvasive measurement of abnormal repolarization through assessment of QT interval dispersion from the resting standard 12-lead ECG initially had shown promise in assessing arrhythmia risk but was challenged recently. The relative T wave residuum (TWR) has been proposed recently to reflect regional repolarization dispersion more accurately. We analyzed the role played by the dipolar and nondipolar components in determining TWR. METHODS AND RESULTS: Singular value decomposition was applied to the repolarization signals obtained from isolated rabbit hearts using a 5 x 8 array multielectrode recording system during premature beats (N = 11) and after d-sotalol (N = 9) exposure. Both the dipolar and nondipolar components of the T wave increased significantly during premature stimulation and after d-sotalol exposure. The relative TWR decreased significantly during premature stimulation but did not change after d-sotalol. Changes in the dipolar and nondipolar components of the second half of the T wave were significantly greater than those corresponding to the first half during premature stimulation, and a significant correlation was observed between the nondipolar components of the second half of the T wave and the T(peak-end) interval. CONCLUSION: Conditions exist during which both the dipolar and nondipolar components can change simultaneously. Under these conditions, the relative TWR may not reflect regional heterogeneity of repolarization with accuracy. The nondipolar components of the second half of the T wave can be linked to assessment of the transmural dispersion of repolarization.

Eficacia y seguridad del d,1 sotalol en el tratamiento ambulatorio de pacientes con fibrilación y flutters atriales / d,1 Sotalol in the treatment of atrial fibrilation and atrial flutter

El objetivo de este estudio fue: (1) evaluar la eficacia del d,1 sotalol para mantener el ritmo sinusal (RS) normal en pacientes con FA o FLA refractarios, (2) evaluar la eficacia del d,1 sotalol en la prevención de recurrencias de episodios paroxísticos de FA o FLA, (3) evaluar el control de la respuesta ventricular media (RVM) en aquellos pacientes con episodios paroxísticos o refractarios de fibrilación atrial (FA) o flutter atrial (FLA) que no respondieron exitosamente a otros antiarrítmicos, (4) determinar predictores de eficacia del medicamento y (5) evaluar la seguridad del d,1 sotalol en nuestros pacientes. Se incluyeron doscientos enfermos con FA o FLA crónica y paroxístico y fueron refractarios a uno hasta seis esquemas de antiarrítmicos antes de recibir d,1 sotalol: 54 por ciento de mujeres con edad promedio de 47 ñ 16 años, seguimiento de 7 ñ 7 meses (1 a 14); 79 de los enfermos tuvo la arritmia por más de un año. Hubo 37.5 por ciento de FA crónico (FAC) y 8 por ciento de FLA paroxístico (FLAP). El 82 por ciento permació en clase funcional (CF) I (NYHA) y el 82 por ciento tuvo una cardiopatía estructural, con diámetro atrial izquierdo de 44 ñ 10 mm, del atrio derecho de 37 ñ 7 mm y fracción de eyección de 58 ñ 8 por ciento. El ET (éxito total) se alcanzó en 58 por ciento de los pacientes (40 por ciento con FA y 18 por ciento con FLA), el EP (éxito parcial) fue del 38 por ciento (Fa en 18 por ciento y 20 por ciento con FLA) y hubo fracaso en 4 por ciento de los pacientes. Rspondieron mejor los pacientes con FA que aquellos con FLA (ET vs EP p<0.07). Los pacientes con una cardiopatía estructural respondieron peor al d,1 sotalol (p=0,10) que aquellos sin cardiopatía, especialmente si existía dilatación de las cámaras cardíacas. El d,1 sotalol es un agente terapéutico seguro, moderadamente eficaz, barato y alterno a otros antiarrítmicos en la cardioversión farmacológica de FA y/o FLA a RS y en el mantenimiento del mismo

[Brazilian multicenter study of sotalol effectiveness in ventricular arrhythmias]. / Estudo multicêntrico Brasileiro da eficácia do sotalol em arritmias ventriculares.

PURPOSE: To evaluate the effects of sotalol in patients with nonsustained ventricular tachyarrhythmia (NSVT). METHODS: Ninety patients were enrolled. Patients were submitted to a double-blind crossover randomized study (placebo x 320 ms/po/d/sotalol; 4 weeks, after a wash-out control period. Holter recordings were performed in control (Ct), placebo (Pb) and drug (Dg) periods. Eligible patients had > 50/h isolated ventricular premature beats (VPB), in control, with or without pairs (P) or nonsustained VT (NSVT; > 3 beats, > 100bpm). Drug efficacy criteria were; > or = 75% reduction in isolated VPB, reduction > or = 90% of P and NSVT. The effects of the Dg were evaluated in the global population, in patients with Chagas' disease, idiopathic arrhythmias and ischemic/hypertensive patients. RESULTS: Differences between control and placebo were NS. Isolated VPB; Dg was effective in 42% (38/90 patients) with a mean of Pb and Dg respectively of 11,770 +/- 13,818 and 1,043 +/- 1,554 (p < 0.001). Pairs: drug was effective in 48% (32/67 patients) with a mean of Pb and Dg respectively of 439 +/- 586 and 27 +/- 52 (p < 0.001). NSVT: drug effectiveness was 53% (19/36 patients) with a mean of Pb and Dg respectively of 445 +/- 1,148 and 2.5 +/- 5.8 (p < 0.102). In patients with Chagas' disease, the reduction in VPB was 33% (13/39 patients), in pairs was 42+ (14/34) and in NSVT was 64% (12/22). In idiopathic patients the reduction of VPB was 53% (17/32 patients), in pairs was 50% (10/20) and in NSVT was 36% (4/11). In ischemic and hypertensive patients the reduction of VPB was 47% (7/15 patients) and 73% in pairs (8/11). CONCLUSION: In the present study, sotalol was effective in the control of nonsustained ventricular tachyarrhythmia, with minimal side-effects.

[Antiarrhythmic drug effectiveness. Proposal for a new approach based on pharmacological hourly effects]. / Efficácia das drogas antiarrítmicas. Proposta para uma nova forma de avaliação baseada nos efeitos farmacológicos horários.

PURPOSE: To use a new approach in order to assess the antiarrhythmic drugs, based in the hourly autonomic effects and antiarrhythmic efficacy of sotalol. METHODS: Sixteen patients were evaluated in a randomized double-blind placebo-controlled study. Patients were classified in group 1 (anti-arrhythmic efficacy) and group 2 (no antiarrhythmic efficacy). The following parameters were analyzed: 1) clinical variables as age, gender, cardiac disease and ventricular ectopies density; 2) drug effects on pNN50 in 24-hour and on mean hourly cardiac cycle length; 3) percentage of hourly ventricular ectopies distribution and its correlation with pNN50 and with mean hourly cardiac cycle length in all patients; 4) drug effects on mean hourly cardiac cycle length in groups 1 and 2; 5) correlation between hourly pNN50 and ventricular ectopies density after sotalol administration in groups 1 and 2; 6) hourly drug efficacy in groups 1 and 2 and correlation with pNN50. RESULTS: Efficacy of the drug was present in 8 (50%) patients. Sotalol significantly increased 24-hour pNN50 (placebo 5.01 +/- 2.02%; after drug, 11.70 +/- 5.59%-p < 0.001), also increasing mean hourly cardiac cycle length during the day and night, in all patients (placebo 758.25 +/- 75.68 ms; after drug 967.71 +/- 80.17 ms-p < 0.000). It was noted that patients under placebo had different autonomic tonus; group 1 showed higher sympathetic activity as compared to group 2. Hourly drug efficacy was seen in 23 of 24-hour recordings in group 1 while it was not seen at any time in group 2. CONCLUSION: Sotalol significantly increased parasympathetic cardiac activity. The anti-arrhythmic response was related to the autonomic tonus seen before and after drug administration.

Efeitos do sotalol na atividade elétrica de fibras de Purkinje / Sotalol effects in electric activity of Purkinje fibers

Os efeitos eletrofisiológicos do sotalol, um bloqueador beta-adrenérgico, foram estudados em fibras de Purkinje do miocárdio de cäo, sendo utilizadas tanto preparaçöes com potencial de repouso (PR) normal (PR > -85 mV), como despolarizadeas "in vitro" pela elevaçäo do K+ na soluçäo de perfusäo (PR entre -64 e 78 mV). Os resultados mostraram que o sotalol (1 a 100 micronM) näo deprime a fase de despolarizaçäo rápida do potencial de açäo (PA), uma vez que a amplitude do PA e o valor de Vmax mantiveram-se constantes, mesmo quando as preparaçöes despolarizadas eram estimuladas com freqüências elevadas (3 a 4 Hz). O sotalol produziu um aumento dose-dependente da duraçäo do PA, o que acentuou-se em baixas freqüências de estimulaçäo. O aumento percentual na duraçäo do PA foi similar nas prepaçöes controles e despolarizadas. O período refratário efetivo aumentou na mesma proporçäo que a duraçäo do PA. A resposta lenta isolada, produzida em soluçäo de Tyrode com alto K+ + bário (1 mM), näo foi afetada em presença do sotalol. Tais dados mostram que o efeito antiarrítmico da classe III do sotalol também ocorre no miocárdio despolarizado, e é similar aquele observado nas fibras com PA normal

Molecular mechanisms controlling norepinephrine-mediated release of serotonin from rat pineal glands.

This study describes various elements of the mechanism controlling norepinephrine (NE)-mediated release of serotonin (5HT) from rat pineal glands. After radiolabelling the endogenous pool of pineal 5HT with 3H-5HT, individual pineal glands were exposed to depolarizing buffers or those containing NE. Although 3H-5HT was not released by 50mM potassium, efflux of the indoleamine was increased by NE. Alpha-adrenergic receptors mediate the effects of NE as indicated by the fact that phenylephrine but not isoproterenol, a beta receptor agonist, also enhanced 3H-5HT release. This hypothesis is supported further by the fact that prazosin and phentolamine (alpha-antagonists) but not sotolal (beta-antagonist), inhibited the stimulatory effects of NE on 5HT release. In order to determine the intracellular second messenger involved in the 5HT release process, pineals were incubated with 8-bromo cAMP or the phorbol ester, PMA. PMA simulated the effects of NE and phenylephrine on 3H-5HT efflux, while cAMP had no effect. Furthermore, calcium-, phospholipid-dependent protein kinase activities in pineal homogenates were responsive to NE. These findings suggest that 5HT secretion from rat pinealocytes occurs rapidly in response to NE signals that act through alpha-adrenergic receptors in concert with phospholipid dependent protein kinase(s). These molecular processes are different from those involved in melatonin metabolism and may represent a general mechanism for regulating 5HT release in the brain.

[Effects of sotalol on ventricular function]. / Efecto del sotalol sobre la función ventricular.

There were studied 31 patients 20 of them sanes and 11 with sustained systemic arterial hypertension to whom it was administered propranolol and sotalol in different periods. By means of phonomechanocardiographic study it was observed that the contractile heart function didn't present alterations in the sane patients, with the administration of the two drugs. Sotalol produced significative changes with depression of contractility in hypertense patients, even though there were no alterations of the "pump" function. It is probably on account that hypertensive cardiopathy per se has a minor functional myocardiac reserve and the negative inotropic effect is made evident with greater clearness. The fall of the elevation velocity of radial pulse (EVRP) in the two groups, suggests the increase of vascular resistances by the peripheric beta blockade.

[Renin-angiotensin-aldosterone system in the treatment of essential hypertension with a beta-adrenergic blocker: sotalol]. / El sistema renina-angiotensina-aldosterona en el tratamiento de la hipertensión arterial esencial con el bloqueador adrenérgico beta: sotalol.

The administration of beta blockers has been useful in the treatment of essential hypertension. The anti-hypertensive effect of the beta-blocker sotalol was evaluated in 28 patients with essential hypertension. In all of the patients a determination of urinary aldosterone and plasma renin activity, before and after, three months of treatment with sotalol was done. In the pre-treatment tests, five patients (18%) had elevated renin values, in 13 (6%) renin was normal, and in 10 (36%) the renin activity in plasma was low. Treatment with sotalol caused normalization or significant lowering of diastolic pressure in the majority of cases with high or normal plasma renin. Patients with low plasma renin activity had less satisfactory results with the drug. Since there was no correlation between the lowering of arterial pressure and the degree of depletion of renin, we can conclude that anti-hypertensive mechanism of sotalol does not come from the decrease in secretion of renin. However our results suggest that patients with high renin respond better to treatment with sotalol, than cases with low renin levels.