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NEW FINDINGS: What is the central question of this study? Sino-aortic denervated (SAD) rats present normal levels of sympathetic activity and mean arterial pressure. However, neural mechanisms regulating the sympathetic activity in the absence of arterial baroreceptors remain unclear. Considering that respiration modulates the sympathetic activity, we hypothesize that changes in the respiratory network contribute to keep the sympathetic outflow in the normal range after removal of arterial baroreceptors. What is the main finding and its importance? Despite longer inspiration observed in SAD rats, the respiratory-sympathetic coupling is working within a normal range of variation. These findings suggest that in the absence of arterial baroreceptors the respiratory modulation of sympathetic activity is maintained within the normal range. The activity of presympathetic neurons is under respiratory modulation, and changes in the central respiratory network may impact on the baseline sympathetic activity and mean arterial pressure. It is well known that after removal of baroreceptor afferents [sino-aortic denervation (SAD)], rats present an unexpected normal level of mean arterial pressure. We hypothesized that changes in the respiratory pattern and in the respiratory modulation of the sympathetic activity contribute to keep the sympathetic outflow within a normal range of variation in the absence of arterial baroreceptors in rats. To study these mechanisms, we recorded perfusion pressure and the activities of phrenic and thoracic sympathetic nerves in male juvenile rats using the working heart-brainstem preparation. The time of inspiration significantly increased in SAD rats, and this change was not dependent on the carotid bodies or on the vagal afferents. However, no changes were observed in the perfusion pressure or in the baseline thoracic sympathetic nerves in all phases of the respiratory cycle in SAD rats. Our data show that despite longer inspiratory activity, the baseline sympathetic activity is maintained at a normal level in SAD rats. These findings indicate that the respiratory-sympathetic coupling is normal after SAD and suggest that the respiratory modulation of sympathetic activity is maintained within the normal range after the removal of arterial baroreceptors.

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KEY POINTS: The integrity of the baroreflex control of sympathetic activity in heart failure (HF) remains under debate. We proposed the use of the sequence method to assess the baroreflex control of renal sympathetic nerve activity (RSNA). The sequence method assesses the spontaneous arterial pressure (AP) fluctuations and their related changes in heart rate (or other efferent responses), providing the sensitivity and the effectiveness of the baroreflex. Effectiveness refers to the fraction of spontaneous AP changes that elicits baroreflex-mediated variations in the efferent response. Using three different approaches, we showed that the baroreflex sensitivity between AP and RSNA is not altered in early HF rats. However, the sequence method provided evidence that the effectiveness of baroreflex in changing RSNA in response to AP changes is markedly decreased in HF. The results help us better understand the baroreflex control of the sympathetic nerve activity. ABSTRACT: In heart failure (HF), the reflex control of the heart rate is known to be markedly impaired; however, the baroreceptor control of the sympathetic drive remains under debate. Applying the sequence method to a series of arterial pressure (AP) and renal sympathetic nerve activity (RSNA), we demonstrated a clear dysfunction in the baroreflex control of sympathetic activity in rats with early HF. We analysed the baroreflex control of the sympathetic drive using three different approaches: AP vs. RSNA curve, cross-spectral analysis and sequence method between AP and RSNA. The sequence method also provides the baroreflex effectiveness index (BEI), which represents the percentage of AP ramps that actually produce a reflex response. The methods were applied to control rats and rats with HF induced by myocardial infarction. None of the methods employed to assess the sympathetic baroreflex gain were able to detect any differences between the control and the HF group. However, rats with HF exhibited a lower BEI compared to the controls. Moreover, an optimum delay of 1 beat was observed, i.e. 1 beat is required for the RSNA to respond after AP changing, which corroborates with the findings related to the timing between these two variables. For delay 1, the BEI of the controls was 0.45 ± 0.03, whereas the BEI of rats with HF was 0.29 ± 0.09 (P < 0.05). These data demonstrate that while the gain of the baroreflex is not affected in early HF, its effectiveness is markedly decreased. The analysis of the spontaneous changes in AP and RSNA using the sequence method provides novel insights into arterial baroreceptor reflex function.

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NEW FINDINGS: What is the central question of this study? Classically, areas of the brainstem are involved in the cardiac baroreceptor reflex. However, forebrain areas, such as the hippocampus, may also modulate the cardiac baroreflex function. What is the main finding and its importance? According to the hippocampal subarea recruited dorsoventrally, the baroreflex function can be either facilitated or inhibited. These results are according to the new topographical division proposed for the hippocampus, i.e. it can be divided into functionally and anatomically different regions along its dorsoventral axis. From a neuroanatomical point of view, we may split the hippocampal formation into the dorsal (DH) and ventral hippocampus (VH). Although the basic intrinsic circuitry of the hippocampus seems to be maintained throughout its longitudinal axis, dorsal and ventral portions connect differently with cortical and subcortical areas and express different gene patterns, being functionally distinct. Differential stimulation of the DH or VH can evoke either an increase or a decrease in blood pressure, heart rate and sympathetic activity. However, to the best of our knowledge, specific involvement of the hippocampus and its different subareas in the baroreflex function remains to be investigated. In the present work, therefore, we evaluated the involvement of hippocampal subareas arranged on the dorsoventral axis in cardiac baroreflex modulation. Our results suggest that inhibition of hippocampal subareas by CoCl2 , a calcium-dependent synaptic neurotransmission blocker, differentially affects baroreflex sensitivity; administration of CoCl2 into the DH increased cardiac baroreflex function, whereas it diminished cardiac baroreflex function when administered into the VH. In contrast, administration of CoCl2 into intermediate portions of the hippocampus did not affect the baroreflex response. Our findings suggest that the hippocampus influences baroreflex function according to the hippocampal subarea recruited dorsoventrally.

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Arterial baroreflex function is important for blood pressure control during exercise, but its contribution to cardiovascular adjustments at the onset of cycling exercise remains unclear. Fifteen healthy male subjects (24 ± 1 yr) performed 45-s trials of low- and moderate-intensity cycling, with carotid baroreceptor stimulation by neck suction at -60 Torr applied 0-5, 10-15, and 30-35 s after the onset of exercise. Cardiovascular responses to neck suction during cycling were compared with those obtained at rest. An attenuated reflex decrease in heart rate following neck suction was detected during moderate-intensity exercise, compared with the response at rest (P < 0.05). Furthermore, compared with the reflex decrease in blood pressure elicited at rest, neck suction elicited an augmented decrease in blood pressure at 0-5 and 10-15 s during low-intensity exercise and in all periods during moderate-intensity exercise (P < 0.05). The reflex depressor response at the onset of cycling was primarily mediated by an increase in the total vascular conductance. These findings evidence altered carotid baroreflex function during the first 35 s of cycling compared with rest, with attenuated bradycardic response, and augmented depressor response to carotid baroreceptor stimulation.

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INTRODUCTION: The ability of continuous aerobic exercise training (AET) to increase baroreflex control and cardiac function in heart failure (HF) has been well described, but the comparison between continuous and interval AET on these functions is inconclusive. OBJECTIVES: To compare the effects of continuous and interval AET on cardiac function and baroreflex sensitivity (BrS) in an experimental model of HF. METHODS: Rats were divided into the following groups: continuous training (HF-CT), intense interval training (HF-IIT), moderate interval training (HF-MIT), sedentary group (HF-SED), and sham sedentary (SHAM-SED). Animals underwent surgery to induce HF by ligation of the interventricular coronary artery. Six weeks after surgery, AET was started (8weeks, 3sessions/week). Echocardiography studies to assess cardiac function were performed before and after AET. At the end of the training protocols, the BrS index was assessed by stepwise intravenous infusions of sodium nitroprusside and phenylephrine. RESULTS: All methods of exercise prevented the HF-induced increase in left ventricular diameter in diastole observed in the HF-SED rats (0.88±0.09 vs. 1.03±0.09cm; P<0.05), but only the HF-CT (28.5±6.3 vs. 39.2±12.7%; P<0.05) and HF-MIT (31.0±8.5 vs. 42.0±10.3%; P<0.05) groups exhibited an increase in ejection fraction. Nevertheless, the HF-CT group was the only group that showed a tachycardia reflex higher than that of the HF-SED group (0.87±0.34 vs. 0.20±0.05bpm/mmHg; P<0.05) and similar to that of the SHAM-SED group (1.04±0.11bpm/mmHg). CONCLUSIONS: These results suggest that continuous and moderate interval training induced similar improvements in cardiac function but that only continuous training induced higher BrS in HF rats.

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The goal of the current study was to evaluate the effects of electrical stimulation (ES) on the arterial baroreflex sensitivity (BRS) and cardiovascular autonomic control in rats with chronic heart failure (CHF). Male Wistar rats were designated to one of four groups: placebo sham (P-Sham, n=9), ES sham (ES-Sham, n=9), placebo CHF (P-CHF, n=9) or ES CHF (ES-CHF, n=9). The ES was adjusted at a low frequency (30 Hz), duration of 250 µs, with hold and rest time of 8s (4 weeks, 30 min/day, 5 times/week). It was applied on the gastrocnemius muscle with intensity to produce a visible muscle contraction. The rats assigned to the placebo groups performed the same procedures with the equipment turned off. The two-way ANOVA and the post hoc Student-Newman-Keuls tests (P<0.05) were used to data comparison. The BRS was higher in ES-Sham group compared to the P-Sham group and the ES-CHF group compared to the P-CHF group. ES was able to decrease heart rate sympatho-vagal modulation and peripheral sympathetic modulation in ES-CHF compared to P-CHF group. Interestingly, heart rate sympatho-vagal modulation was similar between ES-CHF and P-Sham groups. Thus, ES enhances heart rate parasympathetic modulation on heart failure (ES-CHF) compared to placebo (P-CHF), with consequent decrease of sympatho-vagal balance in the ES-CHF group compared to the P-CHF. The results show that a 4 week ES protocol in CHF rats enhances arterial BRS and cardiovascular autonomic control.

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Arterial baroreflex control of muscle sympathetic nerve activity (ABRMSNA) is impaired in chronic systolic heart failure (CHF). The purpose of the study was to test the hypothesis that exercise training would improve the gain and reduce the time delay of ABRMSNA in CHF patients. Twenty-six CHF patients, New York Heart Association Functional Class II-III, EF ≤ 40%, peak V̇o2 ≤ 20 ml·kg(-1)·min(-1) were divided into two groups: untrained (UT, n = 13, 57 ± 3 years) and exercise trained (ET, n = 13, 49 ± 3 years). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique. Arterial pressure was measured on a beat-to-beat basis. Time series of MSNA and systolic arterial pressure were analyzed by autoregressive spectral analysis. The gain and time delay of ABRMSNA was obtained by bivariate autoregressive analysis. Exercise training was performed on a cycle ergometer at moderate intensity, three 60-min sessions per week for 16 wk. Baseline MSNA, gain and time delay of ABRMSNA, and low frequency of MSNA (LFMSNA) to high-frequency ratio (HFMSNA) (LFMSNA/HFMSNA) were similar between groups. ET significantly decreased MSNA. MSNA was unchanged in the UT patients. The gain and time delay of ABRMSNA were unchanged in the ET patients. In contrast, the gain of ABRMSNA was significantly reduced [3.5 ± 0.7 vs. 1.8 ± 0.2, arbitrary units (au)/mmHg, P = 0.04] and the time delay of ABRMSNA was significantly increased (4.6 ± 0.8 vs. 7.9 ± 1.0 s, P = 0.05) in the UT patients. LFMSNA-to-HFMSNA ratio tended to be lower in the ET patients (P < 0.08). Exercise training prevents the deterioration of ABRMSNA in CHF patients.

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Baroreflex dysfunction has been considered an important mortality predictor after myocardial infarction (MI). However, the impact of baroreflex deficiency prior to MI on tonic autonomic control and cardiac function, and on the profile of proteins associated with intracellular calcium handling has not yet been studied. The aim of the present study was to analyze how the impairment of baroreflex induced by sinoaortic denervation (SAD) prior to MI in rats affects the tonic autonomic control, ventricular function and cardiomyocyte calcium handling proteins. After 15 days of following or SAD surgery, rats underwent MI. Echocardiographic, hemodynamic, autonomic and molecular evaluations were performed 90 days after MI. Baroreflex impairment led to additional damage on: left ventricular remodeling, diastolic function, vagal tonus and intrinsic heart rate after MI. The loss of vagal component of the arterial baroreflex and vagal tonus were correlated with changes in the cardiac proteins involved in intracellular calcium homeostasis. Furthermore, additional increase in sodium calcium exchanger expression levels was associated with impaired diastolic function in experimental animals. Our findings strongly suggest that previous arterial baroreflex deficiency may induce additional impairment of vagal tonus, which was associated with calcium handling proteins abnormalities, probably triggering ventricular diastolic dysfunction after MI in rats.