Changes in gap junction proteins Connexin30. 2 and Connexin40 expression in the sinoatrial node of rats with dexmedetomidine-induced sinus bradycardia

Abstract Background Dexmedetomidine (Dex) is widely used, and its most common side effect is bradycardia. The complete mechanism through which Dex induces bradycardia has not been elucidated. This research investigates the expression of gap junction proteins Connexin30.2 (Cx30.2) and Connexin40 (Cx40) within the sinoatrial node of rats with Dex-induced sinus bradycardia. Methods Eighty rats were randomly assigned to five groups. Saline was administered to rats in Group C. In the other four groups, the rats were administered Dex to induce bradycardia. In groups D1and D2, the rats were administered Dex at a loading dose of 30 μg.kg−1 and 100 μg.kg−1 for 10 min, then at 15 μg.kg−1.h−1 and 50 μg.kg−1.h−1 for 120 min separately. The rats in group D1A and D2A were administered Dex in the same way as in group D1and D2; however, immediately after the administration of the loading dose, 0.5 mg atropine was administered intravenously, and then at 0.5 mg.kg−1.h−1 for 120 min. The sinoatrial node was acquired after intravenous infusion was completed. Quantitative real-time polymerase chain reaction and western blot analyses were performed to measure mRNA and protein expression of Cx30.2 and Cx40, respectively. Results The expression of Cx30.2 increased, whereas the expression of Cx40 decreased within the sinoatrial node of rats with Dex-induced sinus bradycardia. Atropine reversed the effects of Dex on the expression of gap junction proteins. Conclusion Dex possibly altered the expression of gap junction proteins to slow down cardiac conduction velocity in the sinoatrial node.

Critical analysis of autoregressive and fast Fourier transform markers of cardiovascular variability in rats and humans

The autonomic nervous system plays an important role in physiological and pathological conditions, and has been extensively evaluated by parametric and non-parametric spectral analysis. To compare the results obtained with fast Fourier transform (FFT) and the autoregressive (AR) method, we performed a comprehensive comparative study using data from humans and rats during pharmacological blockade (in rats), a postural test (in humans), and in the hypertensive state (in both humans and rats). Although postural hypotension in humans induced an increase in normalized low-frequency (LFnu) of systolic blood pressure, the increase in the ratio was detected only by AR. In rats, AR and FFT analysis did not agree for LFnu and high frequency (HFnu) under basal conditions and after vagal blockade. The increase in the LF/HF ratio of the pulse interval, induced by methylatropine, was detected only by FFT. In hypertensive patients, changes in LF and HF for systolic blood pressure were observed only by AR; FFT was able to detect the reduction in both blood pressure variance and total power. In hypertensive rats, AR presented different values of variance and total power for systolic blood pressure. Moreover, AR and FFT presented discordant results for LF, LFnu, HF, LF/HF ratio, and total power for pulse interval. We provide evidence for disagreement in 23 percent of the indices of blood pressure and heart rate variability in humans and 67 percent discordance in rats when these variables are evaluated by AR and FFT under physiological and pathological conditions. The overall disagreement between AR and FFT in this study was 43 percent.

O exercício físico atenua o déficit autonômico cardíaco induzido pelo bloqueio da síntese do óxido nítrico / El ejercicio físico atenúa el déficit autonómico cardiaco inducido por el bloqueo de la síntesis de óxido nítrico / Physical exercise attenuates the cardiac autonomic deficit induced by nitric oxide synthesis blockade

FUNDAMENTO: O bloqueio da síntese do óxido nítrico (NO) é caracterizado pelo aumento da atividade simpática cardíaca, e o treinamento físico promove a redução da atividade simpática. OBJETIVO: Investigamos o efeito do bloqueio da síntese do NO sobre o controle autonômico cardiovascular em ratos submetidos ao exercício aeróbio durante dez semanas. MÉTODOS: Ratos wistar foram divididos em quatro grupos: controle tratados com ração e água ad libitum durante dez semanas (RC); controle tratados com N G-nitro-L-arginine methyl ester (L-NAME) na última semana (RCL); treinados durante dez semanas em esteira motorizada (RT); treinados por dez semanas e tratados com L-NAME na última semana (RTL). O controle autonômico cardiovascular foi investigado em todos os grupos com a utilização de duplo bloqueio com metilatropina e propranolol, e análise da variabilidade. RESULTADOS: Os grupos RCL e RTL apresentaram hipertensão. O grupo RCL apresentou taquicardia e predomínio do tônus simpático na determinação da FC após o bloqueio autonômico farmacológico. O grupo RT apresentou bradicardia e menor freqüência cardíaca (FC) intrínseca em relação aos demais. A avaliação da variabilidade da FC mostrou menores valores absolutos e normalizados na banda de baixa freqüência (BF) no grupo RCL. Por sua vez, o grupo RTL apresentou elevação na banda de BF em valores absolutos. A análise da variabilidade da PAS mostrou que os grupos RCL e RTL apresentaram maiores valores na banda de BF. CONCLUSÃO: O exercício físico prévio impediu o déficit no controle autonômico cardíaco induzido pelo tratamento com L-NAME, no entanto não impediu o aumento na variabilidade da PAS.

BACKGROUND: The nitric oxide (NO) synthesis blockade is characterized by an increase in the cardiac sympathetic activity and the physical training promotes the decrease in the sympathetic activity. OBJECTIVE: We investigated the effect of the NO synthesis blockade on the autonomic cardiovascular control in rats submitted to aerobic exercises during a 10-week period. METHODS: Male Wistar rats were divided in four groups: control rats, treated with chow food and water ad libitum for 10 weeks (CR); control rats, treated with N G-nitro-L-arginine methyl ester (L-NAME) during the last week (CRL); rats trained during 10 weeks on an electrical treadmill (TR); rats trained for 10 weeks and treated with L-NAME during the last week (TRL). The autonomic cardiovascular control was investigated in all groups with the use of a double blockade with methylatropine and propranolol and analysis of variability. RESULTS: The CRL and TRL groups presented hypertension. The CRL group presented tachycardia and predominance of the sympathetic tonus in heat rate (HR) measurement after the pharmacological autonomic blockade. The TR group presented bradycardia and lower intrinsic HR when compared to the others. The evaluation of the HR variability showed lower absolute and normalized values in the low frequency (LF) band in the CRL group. On the other hand, the TRL presented an increase in the LF band in absolute values. The analysis of variability of the systemic arterial pressure (SAP) showed that the CRL and TRL groups presented higher values in the LF band. CONCLUSION: The previous physical exercise prevented the deficit in the autonomic cardiac control induced by the treatment with L-NAME, but did not prevent the increase in the SAP variability.

FUNDAMENTO: El bloqueo de la síntesis de óxido nítrico (NO) se caracteriza por el incremento de la actividad simpática cardiaca, y el entrenamiento físico promueve la reducción de la actividad simpática. OBJETIVO: Investigamos el efecto del bloqueo de la síntesis del NO sobre el control autonómico cardiovascular en ratones sometidos al ejercicio aerobio durante diez semanas. MÉTODOS: Se dividieron ratones wistar en cuatro grupos: control tratados con ración y agua ad libitum durante diez semanas (RC); control tratados con NG-nitro-L-arginina metil éster (L-NAME) en la última semana (RCL); entrenados durante diez semanas en cinta motorizada (RT); entrenados por diez semanas y tratados con L-NAME en la última semana (RTL). Se investigó el control autonómico cardiovascular en todos los grupos con la utilización de doble bloqueo con metilatropina y propranolol, y análisis de la variabilidad. RESULTADOS: Los grupos RCL y RTL presentaron hipertensión. El grupo RCL presentó taquicardia y predominio del tono simpático en la determinación de la FC tras el bloqueo autonómico farmacológico. El grupo RT presentó bradicardia y menor frecuencia cardiaca (FC) intrínseca en relación a los demás. La evaluación de la variabilidad de la FC mostró menores valores absolutos y normalizados en la banda de baja frecuencia (BF) en el grupo RCL. El grupo RTL presentó elevación en la banda de BF en valores absolutos. El análisis de la variabilidad de la PAS mostró que los grupos RCL y RTL presentaron mayores valores en la banda de BF. CONCLUSIÓN: El ejercicio físico previo impidió el déficit en el control autonómico cardiaco inducido por el tratamiento con L-NAME, pero no impidió el aumento en la variabilidad de la PAS.

Análisis de las propiedades antihipertensivas del ácido-3-nitropropionico: un compuesto proveniente de plantas del género Astragalus / Antihypertensive properties of 3-nitropropionic acid: a compound derived from the astragalus plant

El ácido 3-nitropropiónico (ANP) es un compuesto proveniente de plantas del género Astragalus que ocasionó relajación dependiente de la concentración en anillos precontraídos de aorta de conejo. La remoción del endotelio o la presencia de atropina, propranolol o bromofeniramina no afectaron el efecto vasodilatador del ANP, el cual fue claramente inhibido por el azul de metileno. Por otra parte, la administración i.v. aguda de ANP en ratas normotensas o crónica por vía oral en perros hipertensos renales, provocó disminución en la presión sanguínea y bradicardia. Finalmente, el ANP ocasionó efectos inotrópicos negativos en aurículas aisladas de cobayos que no fueron bloqueados por atropina e inhibió los incrementos en fuerza y frecuencia de contracción cardíaca provocados por el isoproterenol. Los resultados indican que el ANP posee propiedades vasodilatadoras y antihipertensivas. La actividad vasodilatadora parece ser consecuencia de activación de la guanilato ciclasa, ya que se inhibió con azul de metileno. El efecto hipotensor del ANP fue independiente de la especie del animal o ruta de administración empleada. La bradicardia apreciada en ratas y perros y los efectos inotrópicos y cronotrópico negativos observados en aurículas aisladas, sugieren que el efecto hipotensor del ANP es una mezcla de acciones vasodilatadoras y cardiodepresoras. Los efectos cardíacos del ANP parecen relacionarse con inhibición de las respuestas mediadas por receptores ß-adrenérgicos

Vagal and sympathetic control of heart rate during exercise by sedentary and exercise-trained rats

1. The present investigation was undertaken to study the vagal and sympathetic effects of an acute bout of exercise on ten sedentary (S) and nine trained (T) rats. The exercise training was performed 5 times a week for 13 weeks on a motor treadmill, at 1.0 mph, 15% grade for 60 min. 2. Heart rate (HR) was recorded at rest and during exercise, 15% grade at 0.5, 0.8 and 1.0 mph, for 3 min per stage. Vagal and sympathetic effects were studied after the administration of methylatropine (3 mg/kg) and propranolol (4 mg/kg). 3. Exercise training significantly attenuated cardiac acceleration at 0.8 (441 +/- 8 vs 486 +/- 9 bpm in S, P < 0.05) and 1.0 mph (466 +/- 12 vs 508 +/- 6 bpm in S, P < 0.05). The vagal effect was significantly increased in the T group at 0.8 (72 +/- 5 vs 32 +/- 10 bpm in S, P < 0.05) and 1.0 mph (46 +/- 8 vs 15 +/- 7 bpm in S, P < 0.05). The sympathetic effect was significantly decreased in the T group at 0.8 (73 +/- 9 vs 112 +/- 9 bpm in S, P < 0.05) and 1.0 mph (96 +/- 11 vs 125 +/- 7 bpm in S, P < 0.05). The intrinsic HR behavior was not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of vehicle composition on bioavailability of atropine sulfate in rabbit's eyes

The effects of vehicle composition on ocular disposition of atropine sulfate was studied using different ophthalmic drops, ointments and gels on rabbit's eyes. The bioavailability of the drug in eye tissues showed that, their distribution were greatly affected by the type of the vehicle. In addition, the uptake by different eye tissues was variable. The peak time of atropine sulfate was found to be 2 hours for ophthalmic drops and 3 hours in case of ointments and gels. The total bioavailability of atropine sulfate in eye tissues of rabbit and aqueous humor after 2 hours were 4350,4010 and 3675 ugm/gm using NaCMC, PVP and PEG ophthalmic drops. While that from ointments and gels after 3 hours were 4355, 4320, 4255 and 4205 ugm/gm for PVP gel, PEG base, hydrocarbon base and NaCMC gel respectively

Phentonium induces a transient increase of acetylcholine efflux from motor nerve terminals

Phenthonium (10-50 µM), a quaternary derivative of 1-hyoscyamine, increases the frequency of miniature end-plate potentials (205 fold) and blocks the nicotinic receptor-ionic channel in skeletal muscles. When tested on rat diaphragms previously incubated with [3H] choline, phenthonium (50µM) increased the spontaneous release of radiolabelled acetylcholine (ACh) from 11.6 ñ 6.4 to 110.5 ñ 40.2 x 10**3 dpm/g within 15 min. The effect was transient, declining to 24.6 ñ 14.7 after 50 min. Subsequent electrical stimulation still in the prsence of phenthonium increased the efflux to 164.7 ñ 45.3. The fractional release relative to the level before stimulation did not differ from controls. Phenthonium (20 µM) did not increase the spontaneous ACh release but doubled the efflux induced by nerve stimulation. The present results, compared to previous electrophysiological findeings, indicate that quantal and nonquantal release are increased by phenthonium. They also show that the transient effect is not due to ACh depletion in nerve terminals

Comparison of inhaled terbutaline and inhaled terbutaline plus ipratropium bromide in acute asthmatic children.

Twenty asthmatic children, aged 4 to 15 years, consisting of 14 boys and 6 girls, were studied during acute episodes of asthmatic attacks. A group of 10 children each received either inhaled terbutaline 0.5 mg or inhaled terbutaline 0.5 mg followed by ipratropium bromide 0.04 mg 15 minutes later through a 750-ml volumetric spacer. Significant increases in FEV1 over the baseline were observed from 2 minutes to 2 hours and from 2 minutes to 6 hours following the first and second regimen respectively. A slightly greater increase and longer duration in FEV1 were observed in the combined drug treatment and very slight decreases in systolic and diastolic blood pressure below the base-line were observed. Neither regimen showed any serious adverse effect on the heart rate and respiratory rate.

The effects of inhaled ipratropium bromide, fenoterol and their combination in COPD patients.

A double-blind, cross over, placebo controlled study was conducted to compare the response of lung function to metered doses inhaler of ipratropium bromide (IB, 40 micrograms, fenoterol hydrobromide (F), 100 micrograms, and a combination of the two (IBF). The drugs were administered on 4 consecutive days to 16 stable chronic airway obstructive patients (COPD), all of whom had shown minimal improvement after inhaling sympathomimetic drugs. Lung function response was measured for six hours after administration. All active medications caused greater improvement of FEV1 and FVC than the placebo did and none caused cardiovascular side effects. Improvement of FEV1 and FVC after IBF therapy was significantly better than after F at 1 hour and lasted up to six hour, whereas IBF was better than IB only after the third hour onwards. In addition, additive effects on FEV1 and FVC were seen in this period. IB caused greater response in FEV1 and FVC than F at both first and fifth hour. IB and IBF showed a rapid onset of action and had greater duration of action than F.