Resting spontaneous baroreflex sensitivity and cardiac autonomic control in anabolic androgenic steroid users

OBJECTIVES: Misuse of anabolic androgenic steroids in athletes is a strategy used to enhance strength and skeletal muscle hypertrophy. However, its abuse leads to an imbalance in muscle sympathetic nerve activity, increased vascular resistance, and increased blood pressure. However, the mechanisms underlying these alterations are still unknown. Therefore, we tested whether anabolic androgenic steroids could impair resting baroreflex sensitivity and cardiac sympathovagal control. In addition, we evaluate pulse wave velocity to ascertain the arterial stiffness of large vessels. METHODS: Fourteen male anabolic androgenic steroid users and 12 nonusers were studied. Heart rate, blood pressure, and respiratory rate were recorded. Baroreflex sensitivity was estimated by the sequence method, and cardiac autonomic control by analysis of the R-R interval. Pulse wave velocity was measured using a noninvasive automatic device. RESULTS: Mean spontaneous baroreflex sensitivity, baroreflex sensitivity to activation of the baroreceptors, and baroreflex sensitivity to deactivation of the baroreceptors were significantly lower in users than in nonusers. In the spectral analysis of heart rate variability, high frequency activity was lower, while low frequency activity was higher in users than in nonusers. Moreover, the sympathovagal balance was higher in users. Users showed higher pulse wave velocity than nonusers showing arterial stiffness of large vessels. Single linear regression analysis showed significant correlations between mean blood pressure and baroreflex sensitivity and pulse wave velocity. CONCLUSIONS: Our results provide evidence for lower baroreflex sensitivity and sympathovagal imbalance in anabolic androgenic steroid users. Moreover, anabolic androgenic steroid users showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased blood pressure in this population.

Serotoninergic Modulation of Basal Cardiovascular Responses and Responses Induced by Isotonic Extracellular Volume Expansion in Rats / Modulação Serotoninérgica de Respostas Cardiovasculares Basais e Induzidas pela Expansão Isotônica do Volume Extracelular em Ratos

Abstract Background: Isotonic blood volume expansion (BVE) induced alterations of sympathetic and parasympathetic activity in the heart and blood vessels, which can be modulated by serotonergic pathways. Objective: To evaluate the effect of saline or serotonergic agonist (DOI) administration in the hypothalamic paraventricular nucleus (PVN) on cardiovascular responses after BVE. Methods: We recorded pulsatile blood pressure through the femoral artery to obtain the mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and the sympathetic-vagal ratio (LF/HF) of Wistar rats before and after they received bilateral microinjections of saline or DOI into the PVN, followed by BVE. Results: No significant differences were observed in the values of the studied variables in the different treatments from the control group. However, when animals are treated with DOI followed by BVE there is a significant increase in relation to the BE control group in all the studied variables: MBP (114.42±7.85 vs 101.34±9.17); SBP (147.23±14.31 vs 129.39±10.70); DBP (98.01 ±4.91 vs 87.31±8.61); HR (421.02±43.32 vs 356.35±41.99); and LF/HF ratio (2.32±0.80 vs 0.27±0.32). Discussion: The present study showed that the induction of isotonic BVE did not promote alterations in MAP, HR and LF/HF ratio. On the other hand, the injection of DOI into PVN of the hypothalamus followed by isotonic BVE resulted in a significant increase of all variables. Conclusion: These results suggest that serotonin induced a neuromodulation in the PVN level, which promotes an inhibition of the baroreflex response to BVE. Therefore, the present study suggests the involvement of the serotonergic system in the modulation of vagal reflex response at PVN in the normotensive rats.

Resumo Fundamento: Expansão de volume extracelular (EVEC) promove alterações da atividade simpática e parassimpática no coração e vasos sanguíneos, os quais podem ser moduladas por vias serotoninérgicas. Objetivo: Avaliar o efeito da administração de salina ou agonista serotoninérgico (DOI) nos núcleos paraventriculares hipotalâmico (NPV) sobre respostas cardiovasculares após EVEC. Métodos: Foram obtidos registros da pressão arterial pulsátil, por meio da artéria femoral, para obtenção dos valores da pressão arterial média (PAM), sistólica (PAS), diastólica (PAD), frequência cardíaca (FC) e razão simpático-vagal (LF/HF) de ratos Wistar antes e após receberem microinjeções bilaterais no NPV de salina ou DOI seguida de EVEC. Resultados: Não foram observadas diferenças significativas dos valores das variáveis estudadas nos diferentes tratamentos do grupo controle. Entretanto, quando os animais são tratados com DOI seguida de EVEC ocorre aumento significativo em relação ao grupo controle com EVEC em todas as variáveis estudadas: PAM (114,42±7,85 vs 101,34±9,17), PAS (147,23±14,31 vs 129,39±10,70), PAD (98,01 ±4,91 vs 87,31±8,61), FC (421,02±43,32 vs 356,35±41,99) e LF/HF (2,32±0,80 vs 0,27±0,32). Discussão: O presente estudo mostrou que a indução de EVEC isotônica não promoveu alterações na PAM, PAD, PAS, FC e LF/HF. Por outro lado, os animais que receberam microinjeção de DOI no NPV seguida de EVEC apresentaram aumento significativo de todas as variáveis. Conclusão: Esses resultados sugerem que a serotonina exerce uma neuromodulação em nivel do NPV, e essa promove uma inibição da resposta barorreflexa frente à EVEC. Assim, o presente trabalho sugere o envolvimento serotoninérgico na neuromodulação no nivel do NPV na resposta reflexa vagal em ratos normotensos.

Association of exercise training and angiotensin-converting enzyme 2 activator improves baroreflex sensitivity of spontaneously hypertensive rats

The present study sought to determine cardiovascular effects of aerobic training associated with diminazene aceturate (DIZE), an activator of the angiotensin converting enzyme 2, in spontaneously hypertensive rats (SHRs). Male SHRs (280–350 g) were either subjected to exercise training or not (sedentary group). The trained group was subjected to 8 weeks of aerobic training on a treadmill (five times a week, lasting 60 min at an intensity of 50–60% of maximum aerobic speed). In the last 15 days of the experimental protocol, these groups were redistributed into four groups: i) sedentary SHRs with daily treatment of 1 mg/kg DIZE (S+D1); ii) trained SHRs with daily treatment of 1 mg/kg DIZE (T+D1); iii) sedentary SHRs with daily treatment of vehicle (S+V); and iv) trained SHRs with daily treatment of vehicle (T+V). After treatment, SHRs were anesthetized and subjected to artery and femoral vein cannulation prior to the implantation of ECG electrode. After 24 h, mean arterial pressure (MAP) and heart rate (HR) were recorded; the baroreflex sensitivity and the effect of double autonomic blockade (DAB) were evaluated in non-anesthetized SHRs. DIZE treatment improved baroreflex sensitivity in the T+D1 group as compared with the T+V and S+D1 groups. The intrinsic heart rate (IHR) and MAP were reduced in T+D1 group as compared with T+V and S+D1 groups. Hence, we conclude that the association of exercise training with DIZE treatment improved baroreflex function and cardiovascular regulation.

Neuropeptides in the posterodorsal medial amygdala modulate central cardiovascular reflex responses in awake male rats

The rat posterodorsal medial amygdala (MePD) links emotionally charged sensory stimuli to social behavior, and is part of the supramedullary control of the cardiovascular system. We studied the effects of microinjections of neuroactive peptides markedly found in the MePD, namely oxytocin (OT, 10 ng and 25 pg; n=6/group), somatostatin (SST, 1 and 0.05 μM; n=8 and 5, respectively), and angiotensin II (Ang II, 50 pmol and 50 fmol; n=7/group), on basal cardiovascular activity and on baroreflex- and chemoreflex-mediated responses in awake adult male rats. Power spectral and symbolic analyses were applied to pulse interval and systolic arterial pressure series to identify centrally mediated sympathetic/parasympathetic components in the heart rate variability (HRV) and arterial pressure variability (APV). No microinjected substance affected basal parameters. On the other hand, compared with the control data (saline, 0.3 µL; n=7), OT (10 ng) decreased mean AP (MAP50) after baroreflex stimulation and increased both the mean AP response after chemoreflex activation and the high-frequency component of the HRV. OT (25 pg) increased overall HRV but did not affect any parameter of the symbolic analysis. SST (1 μM) decreased MAP50, and SST (0.05 μM) enhanced the sympathovagal cardiac index. Both doses of SST increased HRV and its low-frequency component. Ang II (50 pmol) increased HRV and reduced the two unlike variations pattern of the symbolic analysis (P<0.05 in all cases). These results demonstrate neuropeptidergic actions in the MePD for both the increase in the range of the cardiovascular reflex responses and the involvement of the central sympathetic and parasympathetic systems on HRV and APV.

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

Effects of the administration of a catalase inhibitor into the fourth cerebral ventricle on cardiovascular responses in spontaneously hypertensive rats exposed to sidestream cigarette smoke

OBJECTIVE: Previous studies have demonstrated a relationship between brain oxidative stress and cardiovascular regulation. We evaluated the effects of central catalase inhibition on cardiovascular responses in spontaneously hypertensive rats exposed to sidestream cigarette smoke. METHODS: Male Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SH) (16 weeks old) were implanted with a stainless steel guide cannula leading into the fourth cerebral ventricle (4th V). The femoral artery and vein were cannulated for arterial pressure and heart rate measurement and drug infusion, respectively. The rats were exposed to sidestream cigarette smoke for 180 minutes/day, 5 days/week for 3 weeks (CO: 100-300 ppm). The baroreflex was tested using a pressor dose of phenylephrine (8 μg/kg, bolus) and a depressor dose of sodium nitroprusside (50 μg/kg, bolus). Cardiovascular responses were evaluated before and 5, 15, 30 and 60 minutes after injection of a catalase inhibitor (3-amino-1,2,4-triazole, 0.001 g/100 μL) into the 4th V. RESULTS: Vehicle administration into the 4th V did not affect the cardiovascular response, whereas administration of the central catalase inhibitor increased the basal HR and attenuated the bradycardic peak (p<0.05) to a greater extent in WKY rats exposed to sidestream cigarette smoke than in WKY rats exposed to fresh air. However, in spontaneously hypertensive rats, the effect of the catalase inhibitor treatment was stronger in the fresh air condition (p<0.05). CONCLUSION: Administration of a catalase inhibitor into the 4th V combined with exposure to sidestream cigarette smoke has a stronger effect in WKY rats than in SH rats. .

Pleiotropic effects of simvastatin in physically trained ovariectomized rats

This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats.

Avaliação da função autonômica em portadores de cardiomiopatia hipertrófica com e sem síncope / Evaluation of the autonomic function in patients with hypertrophic cardiomyopathy with and without syncope

FUNDAMENTO: Diversos mecanismos podem estar envolvidos no desencadeamento da síncope em pacientes com cardiomiopatia hipertrófica (CMH), incluindo colapsos hemodinâmicos que podem estar relacionados a um desequilíbrio autonômico. OBJETIVO: Avaliar e comparar a função autonômica de pacientes que apresentam CMH com síncope inexplicada (SI) com os que não apresentam síncope. MÉTODOS: Trinta e sete pacientes foram incluídos, sendo 16 com SI e 21 sem síncope. Sua função autonômica foi avaliada por sensibilidade barorreflexa (SB) espontânea e induzida por fenilefrina, pela variabilidade da frequência cardíaca (VFC) no domínio do tempo durante o Holter de 24 horas e no domínio da frequência (análise espectral), ambos em decúbito dorsal e no teste de inclinação (TI) a 70º. RESULTADOS: A SB espontânea mostrou-se semelhante em ambos os grupos (16,46 ± 12,99 vs. 18,31 ± 9,88 ms/mmHg, p = 0,464), assim como a SB induzida por fenilefrina (18,33 ± 9,31 vs. 15,83 ± 15,48 ms/mmHg, p = 0,521). Não foram observadas diferenças no SDNN (137,69 ± 36,62 vs . 145,95 ± 38,07 ms, p = 0,389). O grupo com síncope apresentou um RMSSD significativamente menor (24,88 ± 10,03 vs. 35,58 ± 16,43 ms, p = 0,042) e tendência a menor pNN50 (4,51 ± 3,78 vs . 8,83 ± 7,98%, p =0,085) e a menores valores do componente de alta frequência da análise espectral da VFC em repouso (637,59 ± 1.295,53 vs. 782,65 ± 1.264,14 ms2 , p = 0,075). Nenhuma diferença significativa foi observada em resposta ao TI (p = 0,053). A sensibilidade, especificidade e acurácia do TI na identificação da etiologia da SI em pacientes com CMH foram 6%, 66% e 40%, respectivamente. CONCLUSÃO: Observou-se tônus parassimpático mais baixo em pacientes com CMH e SI, mas a relevância clínica deste achado ainda não está clara. O TI não é uma ferramenta vantajosa para avaliar a origem da síncope em tais doentes, principalmente por causa da sua baixa especificidade.

BACKGROUND: Several mechanisms may be involved in the trigger of syncope in patients with hypertrophic cardiomyopathy (HCM), including hemodynamic collapses that might be related to an autonomic imbalance. OBJECTIVE: To evaluate and compare the autonomic function of patients presenting HCM with unexplained syncope (US) to those without syncope. METHODS: Thirty-seven patients were included, 16 with US and 21 without syncope. Their autonomic function was assessed by spontaneous and phenylephrine induced baroreflex sensitivity (BRS), by heart rate variability (HRV) in time domain during 24-hour Holter and in frequency domain (spectral analysis), both in supine position and at 70º head-up tilt (HUT). RESULTS: The spontaneous BRS was similar in both groups (16,46 ± 12,99 vs. 18,31 ± 9,88 ms/mmHg, p = 0,464), as was phenylephrine-induced BRS (18,33 ± 9,31 vs. 15,83 ± 15,48 ms/mmHg, p = 0,521). No differences were observed in SDNN (137,69 ± 36,62 vs . 145,95 ± 38,07 ms, p=0,389). The group presenting syncope had a significantly lower RMSSD (24,88±10,03 vs. 35,58 ± 16,43 ms, p = 0,042) and a tendency to lower pNN50 (4,51 ± 3,78 vs . 8,83 ± 7,98%, p =0,085) and lower values of the high frequency component of HRV spectral analysis at rest (637,59±1.295,53 vs. 782,65±1.264,14ms2, p=0,075). No significant difference was observed in response to HUT (p = 0,053). HUT sensitivity, specificity and accuracy in identifying the etiology of US in HCM patients were 6%, 66% and 40%, respectively. CONCLUSIONS: A lower parasympathetic tone was observed in HCM patients with US, but the clinical relevance of this finding remains unclear. HUT is not a valuable tool for evaluating the origin of syncope in these patients, mainly because of its poor specificity.

Pressão arterial, respostas metabólicas e autonômicas à insulina e infusão de intralipid® em pacientes chagásicos / Blood pressure, metabolic and autonomic responses to insulin and intralipid® infusion in chagasic patients / Presión arterial, respuestas metabólicas y autonómicas a la insulina e infusión de intralipid® en pacientes chagásicos

FUNDAMENTO: Infusão de intralipid e heparina resulta em aumento da pressão arterial e também em anormalidades autonômicas em indivíduos normais e hipertensos. OBJETIVO: Avaliar a sensibilidade a insulina e o impacto da infusão de intralipid e de heparina (ILH) sobre a resposta hemodinâmica, metabólica e autonômica em pacientes com a forma indeterminada da doença de Chagas. MÉTODOS: Doze pacientes com a forma indeterminada da doença de Chagas e 12 voluntários saudáveis foram avaliados. RESULTADOS: A pressão arterial basal e a frequência cardíaca foram semelhantes nos dois grupos. Os níveis plasmáticos de noradrenalina encontravam-se ligeiramente aumentados no grupo de pacientes chagásicos. Após o Teste de Tolerância a Insulina (TTI), houve um declínio significativo na glicose dos dois grupos. A Infusão de ILH resultou em aumento da pressão arterial em ambos os grupos, mas não houve nenhuma mudança significativa na noradrenalina plasmática. O componente de Baixa Frequência (BF) mostrou-se semelhante e aumentou de forma semelhante em ambos os grupos. O componente de Alta Frequência (AF) apresentou-se menor no grupo chagásico. CONCLUSÃO: Pacientes com forma indeterminada da doença de Chagas apresentaram aumento da atividade simpática no momento basal e uma resposta inadequada à insulina. Eles também tiveram um menor componente de alta frequência e sensibilidade barorreflexa prejudicada no momento basal e durante a infusão de intralipid e heparina.

BACKGROUND: Intralipid and heparin infusion results in increased blood pressure and autonomic abnormalities in normal and hypertensive individuals. OBJECTIVE: To evaluate insulin sensitivity and the impact of Intralipid and heparin (ILH) infusion on hemodynamic, metabolic, and autonomic response in patients with the indeterminate form of Chagas' disease. METHODS: Twelve patients with the indeterminate form of Chagas' disease and 12 healthy volunteers were evaluated. RESULTS: Baseline blood pressure and heart rate were similar in both groups. Plasma noradrenaline levels were slightly increased in the Chagas' group. After insulin tolerance testing (ITT), a significant decline was noted in glucose in both groups. ILH infusion resulted in increased blood pressure in both groups, but there was no significant change in plasma noradrenaline. The low-frequency component (LF) was similar and similarly increased in both groups. The high-frequency component (HF) was lower in the Chagas' group. CONCLUSION: Patients with the indeterminate form of Chagas' disease had increased sympathetic activity at baseline and impaired response to insulin. They also had a lower high-frequency component and impaired baroreflex sensitivity at baseline and during Intralipid and heparin infusion.

FUNDAMENTO: La Infusión de intralipid® y de heparina trae como resultado un aumento de la presión arterial y también de las anormalidades autonómicas en los individuos normales e hipertensos. OBJETIVO: Evaluar la sensibilidad a la insulina y el impacto de la infusión de intralipid® y de heparina (ILH) sobre la respuesta hemodinámica, metabólica y autonómica en pacientes con la forma indefinida de la Enfermedad de Chagas. MÉTODOS: Fueron evaluados doce pacientes con la forma indefinida de la Enfermedad de Chagas y 12 voluntarios sanos. RESULTADOS: La presión arterial basal y la frecuencia cardíaca fueron similares en los dos grupos. Los niveles plasmáticos de noradrenalina estaban ligeramente más elevados en el grupo de pacientes chagásicos. Después del Test de Tolerancia a la Insulina (TTI), se produjo una ostensible disminución en la glucosa de los dos grupos. La Infusión de ILH trajo como consecuencia el aumento de la presión arterial en ambos grupos, pero no hubo ningún cambio significativo en la noradrenalina plasmática. El componente de Baja Frecuencia (BF), fue similar y aumentó de forma parecida en ambos grupos. El componente de Alta Frecuencia (AF) se presentó con un menor nivel en el grupo chagásico. CONCLUSIONES: Los pacientes con una forma indeterminada de la Enfermedad de Chagas, presentaron un aumento en la actividad simpática al momento basal y una respuesta inadecuada a la insulina. También tuvieron un menor componente de alta frecuencia y de sensibilidad barorrefleja, que fue perjudicado en el momento basal y durante la infusión de intralipid® y heparina.

Malnutrition affects the pressor response to microinjection of L-glutamate into the RVLM of awake rats

Post-weaning protein malnutrition is often related to the development of cardiovascular and metabolic diseases in humans, as well to changed content of neurotransmitters in the central nervous system under experimental conditions. The rostral ventrolateral medulla (RVLM) is a bulbar region that contains sympathetic premotor neurons; the excitatory amino acid L-glutamate seems to be the main neurotransmitter at this level. The aim of the present study was to evaluate the possible change in the L-glutamate sensitivity of the RVLM neurons of malnourished animals. Male Fischer rats were divided into two groups: control (n = 15) and malnourished (n = 19). Four days before the experiments, guide cannulas were implanted bilaterally in direction of the RVLM for microinjection of L-glutamate. Twenty-four hours before the experiments, the femoral artery was cannulated for cardiovascular recordings. The results showed that the baseline heart rate increased in malnourished compared to control animals (412.18 ± 16.03 bpm vs. 370.74 ± 9.59 bpm, respectively). Malnourished animals presented a dissimilar concentration-dependent pressor response curve to L-glutamate and an attenuated baroreflex gain. Our results suggest that post-weaning protein restriction affects glutamatergic neurotransmission of the baroreflex at the RVLM level.

Comportamento dos quimiorreflexos central e periférico na insuficiência cardíaca / Behavior of central and peripheral chemoreflexes in heart failure / Comportamiento de los quimiorreflejos central y periférico en la insuficiencia cardíaca

A síndrome da insuficiência cardíaca (IC) pode ser definida como via final de qualquer forma de doença cardíaca. Os reflexos cardiovasculares simpatoinibitórios como o reflexo arterial barorreceptor estão significativamente suprimidos na IC. Pacientes com IC apresentam maior ventilação para determinada carga de trabalho quando comparados a indivíduos normais. Esse fato gera baixa eficiência ventilatória e relaciona-se com maior ventilação relativa à produção de gás carbônico, que é um preditor de mau prognóstico, além de ser um fator limitante ao exercício. Há evidências de que o desequilíbrio autonômico contribua para a patogênese e a progressão da insuficiência cardíaca. Os quimiorreflexos são os principais mecanismos de controle e regulação das respostas ventilatórias às mudanças de concentração do oxigênio e gás carbônico arterial. A ativação do quimiorreflexo causa aumento da atividade simpática, frequência cardíaca, pressão arterial e volume minuto. No entanto, o aumento do volume minuto e da pressão arterial, pelo feedback negativo provocam inibição da resposta simpática à ativação do quimiorreflexo. Apesar das alterações funcionais dos reflexos, seu comportamento em condições normais e patológicas, especialmente sua contribuição para o estado simpatoexcitatório encontrado na IC, não tem sido amplamente estudado. Dessa forma, esta revisão tem por objetivo integrar os conhecimentos a respeito dos quimiorreflexos central e periférico na síndrome da insuficiência cardíaca, bem como esclarecer a influência da terapêutica medicamentosa da insuficiência cardíaca nos quimiorreflexos.

The heart failure (HF) syndrome can be defined as the final pathway of any type of heart disease. The sympatho-inhibitory cardiovascular reflexes, such as the arterial baroreceptor reflex, are significantly decreased in HF. Patients with HF present higher ventilation for a certain workload when compared with normal individuals. This fact generates low ventilatory efficiency and is related to higher ventilation associated with the carbon dioxide production, which is a predictor of bad prognosis, in addition to being a limiting factor for the practice of exercises. There is evidence that the autonomic imbalance contributes to the pathogenesis and the progression of heart failure. The chemoreflexes are the main mechanisms of control and regulation of the ventilatory responses to the changes in concentrations of arterial oxygen and carbon dioxide. The chemoreflex activation causes an increase in the sympathetic activity, heart rate, arterial pressure and minute volume. However, the increase in the minute volume and the arterial pressure, due to negative feedback, cause inhibition of the sympathetic response at the chemoreflex activation. In spite of the functional alterations of the reflexes, their behavior in normal and pathological conditions, especially their contribution to the sympathoexcitatory state observed in HF has not been broadly studied. Therefore, this review aims at integrating the knowledge on central and peripheral chemoreflexes in HF syndrome, as well as clarifying the influence of the heart failure drug therapy on the chemoreflexes.

El síndrome de insuficiencia cardíaca (IC) puede ser definido como vía final de cualquier forma de enfermedad cardíaca. Los reflejos cardiovasculares simpáticoinhibitorios como el reflejo arterial barorreceptor están significativamente suprimidos en la IC. Pacientes con IC presentan mayor ventilación para determinada carga de trabajo cuando son comparados a individuos normales. Ese hecho genera baja eficiencia ventilatoria y se relaciona con mayor ventilación relativa a la producción de gas carbónico, que es un predictor de mal pronóstico, además de ser un factor limitante del ejercicio. Hay evidencias de que el desequilibrio autonómico contribuya a la patogénesis y la progresión de la insuficiencia cardíaca. Los quimiorreflejos son los principales mecanismos de control y regulación de las respuestas ventilatorias a los cambios de concentración del oxígeno y gas carbónico arterial. La activación del quimiorreflejo causa aumento de la actividad simpática, frecuencia cardíaca, presión arterial y volumen minuto. Mientras tanto, el aumento del volumen minuto y de la presión arterial, por el feedback negativo provocan inhibición de la respuesta simpática a la activación del quimiorreflejo. A pesar de las alteraciones funcionales de los reflejos, su comportamiento en condiciones normales y patológicas, especialmente su contribución al estado simpáticoexcitatorio encontrado en la IC, no ha sido ampliamente estudiado. De esa forma, esta revisión tiene por objetivo integrar los conocimientos respecto a los quimiorreflejos central y periférico en el síndrome de insuficiencia cardíaca, así como aclarar la influencia de la terapéutica medicamentosa de la insuficiencia cardíaca en los quimiorreflejos.

ATZ (3-amino-1,2,4-triazole) injected into the fourth cerebral ventricle influences the Bezold-Jarisch reflex in conscious rats

OBJECTIVES: Many studies have investigated the importance of oxidative stress on the cardiovascular system. In this study we evaluated the effects of central catalase inhibition on cardiopulmonary reflex in conscious Wistar rats. METHODS: Male Wistar rats were implanted with a stainless steel guide cannula in the fourth cerebral ventricle. The femoral artery and vein were cannulated for mean arterial pressure and heart rate measurement and for drug infusion, respectively. After basal mean arterial pressure and heart rate recordings, the cardiopulmonary reflex was tested with a dose of phenylbiguanide (PBG, 8 μg/kg, bolus). Cardiopulmonary reflex was evaluated before and μl15 minutes after 1.0 μl 3-amino-1,2,4-triazole (ATZ, 0.01g/100μl)0.01 g/100 μl) injection into the fourth cerebral ventricle. Vehicle treatment did not change cardiopulmonary reflex responses. RESULTS: Central ATZ significantly increased hypotensive responses without influencing the bradycardic reflex. CONCLUSION: ATZ injected into the fourth cerebral ventricle increases sympathetic inhibition but does not change the parasympathetic component of the cardiopulmonary reflex in conscious Wistar rats.

Strain differences in baroceptor reflex in adult Wistar Kyoto rats

OBJECTIVES: A subset of normotensive Sprague-Dawley rats show lower baroreflex sensitivity; however, no previous study investigated whether there are differences in baroreflex sensitivity within this subset. Our study compared baroreflex sensitivity among conscious rats of this specific subtype. METHODS: Male Wistar Kyoto (WKY) rats (16 weeks old) were studied. Cannulas were inserted into the abdominal aortic artery through the right femoral artery to measure mean arterial pressure (MAP) and heart rate (HR). Baroreflex gain was calculated as the ratio between change in HR and MAP variation (ÄHR/ÄMAP) in response to a depressor dose of sodium nitroprusside (SNP, 50 µg/kg, i.v.) and a pressor dose of phenylephrine (PE, 8 µg/kg, i.v.). Rats were divided into four groups: 1) low bradycardic baroreflex (LB), baroreflex gain (BG) between -1 and -2 bpm/mmHg tested with PE; 2) high bradycardic baroreflex (HB), BG < -2 bpm/mmHg tested with PE; 3) low tachycardic baroreflex (LT), BG between -1 and -2 bpm/mmHg tested with SNP and; 4) high tachycardic baroreflex (HT), BG < -2 bpm/mmHg tested with SNP. Significant differences were considered for p < 0.05. RESULTS: Approximately 37 percent of the rats showed a reduced bradycardic peak, bradycardic reflex and decreased bradycardic gain of baroreflex while roughly 23 percent had a decreased basal HR, tachycardic peak, tachycardic reflex and reduced sympathetic baroreflex gain. No significant alterations were noted with regard to basal MAP. CONCLUSION: There is variability regarding baroreflex sensitivity among WKY rats from the same laboratory.

Avaliação da função barorreflexa em ratos jovens espontaneamente hipertensos / Evaluation of baroreflex function in young spontaneously hypertensive rats / Evaluación de la función barorrefleja en ratas jóvenes espontáneamente hipertensas

FUNDAMENTO: A literatura tem descrito dados contraditórios em relação ao início da diminuição da função barorreflexa em ratos espontaneamente hipertensos. OBJETIVO:Este estudo foi realizado para avaliar a função barorreflexa em ratos jovens de 13 semanas espontaneamente hipertensos. MÉTODOS:Foram estudados ratos machos Wistar Kyoto (WKY) (n=15) e ratos espontaneamente hipertensos (REH) de 13 semanas (n=15). Cânulas foram inseridas na artéria aorta abdominal através da artéria femoral direita para medir a pressão arterial média (PAM) e a freqüência cardíaca (FC). A função barorreflexa foi calculada como a derivada da variação da FC em função da variação da PAM (ΔFC/ΔPAM), quando submetida a teste com uma dose depressora de nitroprussiato de sódio (50µg/kg) e com uma dose pressora de fenilefrina (8µg/kg) através de cânula inserida na veia femoral direita em ratos espontaneamente hipertensos e WKY. Diferenças com um valor de p < 0.05 foram consideradas estatisticamente significantes. RESULTADOS:Ratos espontaneamente hipertensos: ΔPAM=43,5 mmHg±5,2, ΔFC=-59,7 ppm±17,9 e ΔFC/ΔPAM=1,3 ppm/mmHg±0,1 testados com fenilefrina; Wistar Kyoto: ΔPAM=&56mmHg±3, ΔFC=*-114,9ppm±11,3 e ΔFC /ΔPAM =#1,9ppm/mmHg±0,3 testados com fenilefrina; ratos espontaneamente hipertensos: ΔPAM=-45,6mmHg±8,1, ΔFC=40,1ppm±11,6 e ΔFC/ΔPAM=0,9ppm/mmHg±0,5 testados com nitroprussiato de sódio; Wistar Kyoto: ΔPAM=-39,8mmHg±6,2, ΔFC=51,9ppm±21,8 e ΔFC/ΔPAM=1,4ppm/mmHg±0,7 testados com nitroprussiato de sódio (*p<0,05; #p<0,01; &p<0,001). CONCLUSÃO: Nossos resultados mostram que ratos espontaneamente hipertensos de 13 semanas apresentaram redução da função barorreflexa quando testados com fenilefrina.

BACKGROUND: The literature describes contradictory data regarding the onset of the baroreflex reduction in spontaneously hypertensive rats. OBJECTIVE:This investigation was undertaken to evaluate the baroreflex function in 13-week-old spontaneously hypertensive rats. METHODS:Male Wistar Kyoto (n=15) and spontaneously hypertensive rats (n=15) aged 13 weeks were studied. Cannulas were inserted in the abdominal aortic artery through the right femoral artery to measure mean arterial pressure and heart rate. Baroreflex function was calculated as the derivative of the variation of HR in function of the MAP variation (Δheart rate/Δmean arterial pressure) tested with a depressor dose of sodium nitroprusside (50µg/kg) and with a pressor dose of phenylephrine (8µg/kg) in the right femoral venous approach through an inserted cannula in awake spontaneously hypertensive rats and Wistar-Kyoto. Differences with p values < 0.05 were considered statistically significant. RESULTS:Spontaneously hypertensive rats: Δmean arterial pressure=43.5mmHg±5.2, Δheart rate=-59.7ppm±17.9 and Δheart rate/Δmean arterial pressure=1.3ppm/mmHg±0.1 tested with phenylephrine; Wistar Kyoto: Δmean arterial pressure=&56mmHg±3, Δheart rate=*-114.9ppm±11.3 and Δheart rate/Δmean arterial pressure=#1.9ppm/mmHg±0.3 tested with phenylephrine; spontaneously hypertensive rats: Δmean arterial pressure=-45.6mmHg±8.1, Δheart rate=40.1ppm±11.6 and Δheart rate/Δmean arterial pressure=0.9ppm/mmHg±0.5 tested with sodium nitroprusside; Wistar Kyoto: Δmean arterial pressure=-39.8mmHg±6.2, Δheart rate=51.9ppm±21.8 and Δheart rate/Δmean arterial pressure=1.4ppm/mmHg±0.7 tested with sodium nitroprusside (*p<0.05; #p<0.01; &p<0.001). CONCLUSION: Our results showed that 13-week-old spontaneously hypertensive rats presented reduced baroreflex function when tested with phenylephrine.

FUNDAMENTO: La literatura ha descrito datos contradictorios con relación al inicio de la disminución de la función barorrefleja en ratas espontáneamente hipertensas. OBJETIVO: Se realizó este estudio con el objetivo de evaluar la función barorrefleja en ratas jóvenes de 13 semanas, espontáneamente hipertensas. MÉTODOS: Se estudiaron ratas machos Wistar Kyoto (WKY) (n=15) y ratas espontáneamente hipertensas (REH) de 13 semanas de edad (n=15). Se insertaron cánulas en la arteria aorta abdominal -a través de la arteria femoral derecha- para medir la presión arterial media (PAM) y la frecuencia cardiaca (FC). Se calculó la función barorrefleja como la derivada de la variación de la FC en función de la variación de la PAM (ΔFC/ΔPAM). Dicho cálculo se efectuó tras prueba con una dosificación depresora de nitroprusiato de sodio (50µg/kg) y también con una dosificación para presión arterial de fenilefrina (8µg/kg) a través de una cánula insertada en la vena femoral derecha tanto de ratas espontáneamente hipertensas como de WKY. Se consideraron estadísticamente significantes diferencias con un valor de p < 0.05. RESULTADOS: Ratas espontáneamente hipertensas sometidas a prueba con fenilefrina: ΔPAM=43,5 mmHg±5,2, ΔFC=-59,7 ppm±17,9 y ΔFC/ΔPAM=1,3 ppm/mmHg±0,1; Wistar Kyoto probadas con fenilefrina: ΔPAM=&56mmHg±3, ΔFC=*-114,9ppm±11,3 y ΔFC /ΔPAM =#1,9ppm/mmHg±0,3. Ratas espontáneamente hipertensas probadas con nitroprusiato de sodio: ΔPAM=-45,6mmHg±8,1, ΔFC=40,1ppm±11,6 y ΔFC/ΔPAM=0,9ppm/mmHg±0,5; Wistar Kyoto sometidas a prueba con nitroprusiato de sodio: ΔPAM =-39,8mmHg±6,2, ΔFC=51,9ppm±21,8 y ΔFC /ΔPAM =1,4ppm/mmHg±0,7 (*p<0,05; #p<0,01; &p<0,001). CONCLUSIÓN: Nuestros resultados muestran que ratas espontáneamente hipertensas de 13 semanas de edad presentaron reducción de la función barorrefleja cuando probadas con fenilefrina.

A semi-automatic computerized method to measure baroreflex-mediated heart rate responses that reduces interobserver variability

Arterial baroreflex sensitivity estimated by pharmacological impulse stimuli depends on intrinsic signal variability and usually a subjective choice of blood pressure (BP) and heart rate (HR) values. We propose a semi-automatic method to estimate cardiovascular reflex sensitivity to bolus infusions of phenylephrine and nitroprusside. Beat-to-beat BP and HR time series for male Wistar rats (N = 13) were obtained from the digitized signal (sample frequency = 2 kHz) and analyzed by the proposed method (PRM) developed in Matlab language. In the PRM, time series were low-pass filtered with zero-phase distortion (3rd order Butterworth used in the forward and reverse direction) and presented graphically, and parameters were selected interactively. Differences between basal mean values and peak BP (deltaBP) and HR (deltaHR) values after drug infusions were used to calculate baroreflex sensitivity indexes, defined as the deltaHR/deltaBP ratio. The PRM was compared to the method traditionally (TDM) employed by seven independent observers using files for reflex bradycardia (N = 43) and tachycardia (N = 61). Agreement was assessed by Bland and Altman plots. Dispersion among users, measured as the standard deviation, was higher for TDM for reflex bradycardia (0.60 ± 0.46 vs 0.21 ± 0.26 bpm/mmHg for PRM, P < 0.001) and tachycardia (0.83 ± 0.62 vs 0.28 ± 0.28 bpm/mmHg for PRM, P < 0.001). The advantage of the present method is related to its objectivity, since the routine automatically calculates the desired parameters according to previous software instructions. This is an objective, robust and easy-to-use tool for cardiovascular reflex studies.

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.

Baroreflex function in conscious rats submitted to iron overload

Our hypothesis is that iron accumulated in tissue, rather than in serum, may compromise cardiovascular control. Male Fischer 344 rats weighing 180 to 220 g were divided into 2 groups. In the serum iron overload group (SIO, N = 12), 20 mg elemental iron was injected ip daily for 7 days. In the tissue iron overload group (TIO, N = 19), a smaller amount of elemental iron was injected (10 mg, daily) for 5 days followed by a resting period of 7 days. Reflex heart rate responses were elicited by iv injections of either phenylephrine (0.5 to 5.0 µg/kg) or sodium nitroprusside (1.0 to 10.0 µg/kg). Baroreflex curves were determined and fitted to sigmoidal equations and the baroreflex gain coefficient was evaluated. To evaluate the role of other than a direct effect of iron on tissue, acute treatment with the iron chelator deferoxamine (20 mg/kg, iv) was performed on the TIO group and the baroreflex was re-evaluated. At the end of the experiments, evaluation of iron levels in serum confirmed a pronounced overload for the SIO group (30-fold), in contrast to the TIO group (2-fold). Tissue levels of iron, however, were higher in the TIO group. The SIO protocol did not produce significant alterations in the baroreflex curve response, while the TIO protocol produced a nearly 2-fold increase in baroreflex gain (-4.34 ± 0.74 and -7.93 ± 1.08 bpm/mmHg, respectively). The TIO protocol animals treated with deferoxamine returned to sham levels of baroreflex gain (-3.7 ± 0.3 sham vs -3.6 ± 0.2 bpm/mmHg) 30 min after the injection. Our results indicate an effect of tissue iron overload on the enhancement of baroreflex sensitivity.

Effects of alpha-1 adrenergic receptor antagonist, terazosin, on cardiovascular functions in anaesthetised dogs.

Initially a dose-response curve of phenylephrine was constructed at dose strengths of 1-16 microg/kg in a cumulative manner. Phenylephrine caused a significant rise in the mean arterial pressure, left ventricular systolic pressure, left ventricular contractility, stroke volume and a significant decline in the heart rate. Terazosin was administered in three selected doses of 10, 100 and 300 microg/kg. Following each dose of terazosin, dose-response curve of phenylephrine was constructed. Terazosin, per se, decreased the basal mean arterial pressure, left ventricular systolic pressure, left ventricular contractility and stroke volume significantly in a dose dependent manner with an increase in the heart rate with no significant change in the cardiac output. The baroreflex sensitivity at all the three doses remained unchanged. In conclusion, the present findings support the view that terazosin reduces the blood pressure in a physiologically more favorable manner by maintaining the neural integrity of the cardiovascular system.

Baroreceptor mediated blood pressure regulation is not affected during dose dependent inhibition of prostatic contractions by terazosin.

Benign prostatic hyperplasia (BPH), common in aging males is often treated with alpha1-adrenoceptor (AR) antagonists. In view of known hypotensive effect of most of the alpha1-AR antagonists, this work examined the effect of a selected alpha1-AR antagonist, terazosin on the baroreceptor mediated regulation of blood pressure. The three doses of terazosin (10, 100, 300 microg/kg body weight) used in anesthetized dogs inhibited in a dose-dependent manner the prostatic contractions and rise in blood pressure induced by phenylphrine. Impairment of arterial baroreflex, an important neural regulatory mechanism for the maintenance of normal arterial pressure, by alpha1-AR antagonist (prazosin) has been suggested in an earlier study. Hence, the effects of terazosin in doses 10, 100 and 300 microg/kg on baroreflex sensitivity (calculated as the ratio of heart rate change to acute increase in blood pressure by phenylephrine) were investigated. Terazocin did not produce any change in the baroreflex sensitivity. Therefore, in the absence of any adverse effect on the baroreceptor mediated regulation of the blood pressure, terazosin can be treated as a safer drug for the symptomatic treatment of BPH.

Effect of Enflurane on the Baroreflex Control of Heart Rate in Decerebrate Rats

Volatile anesthetics alter the arterial baroreflex (BRX) but its mechanisms are poorly understood. This study was designed to determine the effect of 1 and 2 minimal alveolar concentrations (MAC) of enflurane on the BRX parameters in unanesthetized brain stem-intact and decerebrate rats. Under enflurane anesthesia, the femoral artery and both femoral vein were catheterized for pressor (phenylephrine) and depressor (nitroprusside) drug delivery and continuous blood pressure measurements. Decerebration was performed at midcollicular level. BRX tests were performed in 3 time periods; before enflurane (conscious brain-intact), during 1 or 2 MAC enflurane exposure 1 hour after a sham operation or a decerebration operation, and 2 hours after the termination of enflurane (zero enflurane). Mean arterial pressure (MAP) and heart rate (HR) were fitted to a sigmoid logistic equation, the Boltzman equation. The curve of best fit was obtained with a computer program. 1 MAC and 2 MAC of enflurane shifted MAP-HR baroreflex curves to the left in the all groups and significantly attenuated the baroreflex range. The slope of conscious intact period and zero enflurane period of each group did not change significantly, but during the enflurane period the slope was significantly lowered. Enflurane depressed the baroreflex sensitivity (slope) and the HR range in a similar dose-dependant manner in both brain stem-intact and decerebrate rats. Such results draw into question whether the suprapontine sites contribute to enflurane's actions on cardiovascular autonomic regulation.