Baroreceptor Research Articles

Effects of baroreceptor reflex modification on efficacy of ablation for atrial fibrillation

Abstract Background The autonomic nervous system (ANS) plays a significant role in atrial fibrillation (AF). Catheter ablation (CA) is a well-established treatment method for AF and significantly affects ANS, including baroreceptors (BR) function. However, little is known about the changes in the BR function caused by radiofrequency (RF) or cryo-energy (CB) influence the efficacy of AF ablation. Purpose To assess one-year efficacy of CA of AF in relation to BR function modification and type of ablation energy used. Methods The study group consisted of 78 patients (25 females, mean age 58±9 years) with paroxysmal AF and first CA (39 patients (RF group) and 39 (CB group)). The BR function was assessed non-invasively using tilt testing and three parameters: event count (BREC) depicting overall BR activity, slope mean depicting BR sensitivity (BRS) and BR effectiveness index (BEI). The efficacy of CA was assessed at 3, 6, and 12 months after CA using 24-hour Holter ECG recordings and dedicated scale (University of Toronto Atrial Fibrillation Severity Scale (AFSS)). Results After CA, BR function decreased in the whole group (mean BREC 12.0±3.0-22.0 vs 6.0±3.0-18.0, p=0.004; mean BRS 4.8±3.6-6.8 vs 4.0±3.0-5.8, p=0.014; mean BEI 18.7±8.3-27.4 vs 12.0±5.1-21.0, p=0.009). BREC was significantly more decreased in the CB vs RF (mean 12.0±3.0-22.0 vs 6.0±3.0-18.0, p=0.004). Similar trend was noted for BRS and BEI. On repeated Holter ECG monitorings efficacy of CB and RF was similar (89.7% vs 82.9% p=0.502, 89.7 vs 85.7%; p=0.727 and 84.6 vs 80%; p=0.602, respectively). According to AFSS, the AF symptoms were significantly reduced in both groups (CB baseline vs 3, 6 a and 12 months, respectively (median): 6.0 (IQR 2.0 – 13.0) vs 2.5 (IQR 1.0 – 4.0), p<0.001; 6.0 (IQR 2.0 – 13.0) vs 1.5 (IQR 0.0 – 4.0), p<0.001; 6.0 (IQR 2.0 – 13.0) vs 1.5 (IQR 0.0 – 4.0), p=0.002; RF baseline vs 3, 6 and 12 months, respectively (median): 10.5 (IQR 5.0 – 14.0) vs 7.0 (IQR 1.0 – 12.0), p=0.173; 10.5 (IQR 5.0 – 14.0) vs: 6.0 (IQR 2.0 – 12.0), p=0.015; 10.5 (IQR 5.0 – 14.0) vs 6.5 (IQR 2.0 – 12.0), p=0.005). After the adjustment for baseline there was no significant differencies between both groups (Table). Conclusions CA significantly affected BR function. These changes were more pronounced following CB than RF CA. However, the efficacy of RF and CB was similar.

Association between ablation-induced baroreceptor reflex modification and procedure efficacy in patients with atrial fibrillation.

The autonomic nervous system (ANS) plays a significant role in atrial fibrillation (AF). Catheter ablation (CA) is a well-established treatment method for AF and significantly affects the ANS, including baroreceptor (BR) function. However, little is known about the changes in BR function caused by radiofrequency (RF) or cryoballoon energy (CB) and its impact on future AF recurrences. To assess 1-year efficacy of CA of AF in relation to BR function modification and type of ablation energy used. The study group consisted of 78 patients (25 females, mean age 58 ± 9 years) with paroxysmal AF and first CA (39 patients in the RF group and 39 in the CB group). The BR function was assessed non-invasively, using tilt testing before and after CA, and three BR parameters were calculated: event count (BREC) depicting overall BR activity, slope mean depicting BR sensitivity (BRS), and BR effectiveness index (BEI). The efficacy of CA was assessed during 1-year follow-up, which consisted of ambulatory visits and 24-h Holter ECG recordings at 3, 6, and 12 months after CA. The quality of life was assessed by using a dedicated scale [University of Toronto Atrial Fibrillation Severity Scale (AFSS)]. The two groups did not show differences in terms of clinical or demographic data. One-year follow-up was completed for 35 (89.7%) patients from the CB group and for 34 (87.2%) from the RF group. The rates of efficacy of CB and RF were similar [31/35 (88.6%) vs. 26/34 (76.5%), respectively]. After CA, the BR function decreased in both groups, with a significantly greater decrease in the CB group. The changes in BR parameters were similar in both responders and non-responders after CA in the whole group [BREC 10.0 (2.0-24.0) vs. 12.0 (4.0-21.5), p = 0.939; BRS 5.4 (3.7-6.5) vs. 4.8 (3.6-7.2), p = 0.809; BEI 24.8 (15.9-27.4) vs. 17.5 (8.9-27.5), p = 0.508, respectively]. According to the AFSS, the AF symptoms were significantly reduced in both groups to a similar extent. CA for AF significantly decreased the BR function, especially in patients undergoing CB. There was no correlation between CA-induced changes in BR parameters and ablation outcome.

Firing properties of single axons with cardiac rhythmicity in the human cervical vagus nerve.

Microneurographic recordings of the human cervical vagus nerve have revealed the presence of multi-unit neural activity with measurable cardiac rhythmicity. This suggests that the physiology of vagal neurones with cardiovascular regulatory function can be studied using this method. Here, the activity of cardiac rhythmic single units was discriminated from human cervical vagus nerve recordings using template-based waveform matching. The activity of 44 cardiac rhythmic neurones (22 with myelinated axons and 22 with unmyelinated axons) was isolated. By consideration of each unit's firing pattern with respect to the cardiac and respiratory cycles, the functional identification of each unit was attempted. Of note is the observation of seven cardiac rhythmic neurones with myelinated axons whose activity was recruited or enhanced by slow, deep breathing, was maximal during the nadir of respiratory sinus arrhythmia, and showed an expiratory peak. This is characteristic of cardioinhibitory efferent neurones, which are responsible for respiratory sinus arrhythmia. The remaining 15 cardiac rhythmic neurones with myelinated axons were categorised as cardiopulmonary receptors or arterial baroreceptors based on the position of their peak in firing with respect to the R-wave of the cardiac cycle. This latter method is not viable for neurones with unmyelinated axons due to their slow and unknown conduction velocities. With the exception of three neurones whose expiratory modulation implicates them as cardiac-projecting efferent neurones, this population is likely dominated by arterial baroreceptors. In conclusion, the activity of single units with cardiovascular function has been discriminated within the human cervical vagus, enabling their systematic study. KEY POINTS: Recordings of the electrical activity of the vagus nerve have recently been made at the level of the neck in humans. Examination of the gross activity of this nerve reveals subpopulations of neurones whose activity fluctuates in time with the heart's beat, suggesting that the neurones that monitor or modify cardiac function can be studied using this method. Here, the activity of individual cardiac rhythmic neurones was isolated from human vagus nerve recordings using template-based spike sorting. The relationship between this activity and the cardiac and respiratory cycles was used as a means of classifying each neurone. Neuronal firing patterns that are consistent with that of neurones that modify cardiac function, including heart-slowing 'cardioinhibitory' neurones, as well as neurones that inform the brain of cardiovascular status were observed. This approach enables, for the first time, the systematic study of the function of these neurones in humans in both health and disease.

Interoceptive signals shape the earliest markers and neural pathway to awareness at the visual threshold

Variations in interoceptive signals from the baroreceptors (BRs) across the cardiac and respiratory cycle can modulate cortical excitability and so affect awareness. It remains debated at what stages of processing they affect awareness-related event-related potentials (ERPs) in different sensory modalities. We investigated the influence of the cardiac (systole/diastole) and the respiratory (inhalation/exhalation) phase on awareness-related ERPs. Subjects discriminated visual threshold stimuli while their electroencephalogram, electrocardiogram, and respiration were simultaneously recorded. We compared ERPs and their intracranial generators for stimuli classified correctly with and without awareness as a function of the cardiac and respiratory phase. Cyclic variations of interoceptive signals from the BRs modulated both the earliest electrophysiological markers and the trajectory of brain activity when subjects became aware of the stimuli: an early sensory component (P1) was the earliest marker of awareness for low (diastole/inhalation) and a perceptual component (visual awareness negativity) for high (systole/exhalation) BR activity, indicating that BR signals interfere with the sensory processing of the visual input. Likewise, activity spread from the primary visceral cortex (posterior insula) to posterior parietal cortices during high and from associative interoceptive centers (anterior insula) to the prefrontal cortex during low BR activity. Consciousness is thereby resolved in cognitive/associative regions when BR is low and in perceptual centers when it is high. Our results suggest that cyclic fluctuations of BR signaling affect both the earliest markers of awareness and the brain processes underlying conscious awareness.

Advancing cardiovascular neuromodulation: Aortic baroreceptor afferents act as targets for blood pressure control in hypertension.

Aortic baroreceptor afferents act as targets for blood pressure control in hypertension.

Variability of baroreceptor reflex assessed by tilt table test in a patient undergoing pulmonary vein isolation.

The autonomic nervous system (ANS) plays a significant role in atrial fibrillation (AF). Catheter ablation (CA) affects the ANS balance. The assessment of baroreceptor (BR) function is an established method to measure parasympathetic activity; however, it has been rarely used in patients undergoing CA of AF. This study is to assess changes in BR function caused by CA and to compare these changes between two different types of CA: point-by-point radiofrequency (RF) versus cryoballoon (CB). In this observational, prospective, single center study, 78 patients (25 females, mean age 58 ± 9) with paroxysmal AF and first CA were included: 39 patients (RF group) and 39 (CB group). The BR function was assessed non-invasively using tilt testing and three parameters: event count (BREC) depicting overall BR activity, slope mean depicting BR sensitivity (BRS), and BR effectiveness index (BEI). The groups did not differ in clinical or demographic data. Before CA, tilting caused a marked decrease in BR function parameters in the whole study group (BREC (29 ± 14.0-50.0 vs 28 ± 9.0-44.0, p < 0.068), BRS (10.2 ± 7.1-13.2 vs 5.8 ± 4.9-8.5; p < 0.001), and BEI (52.9 ± 39.9-65.5 vs 39.6 ± 23.6-52.1; p < 0.001), supine vs tilting, respectively). These changes were similar in the both groups. After CA, BR function decreased in the whole group (BREC 12.0 ± 3.0-22.0 vs 6.0 ± 3.0-18.0, p = 0.004; BRS 4.8 ± 3.6-6.8 vs 4.0 ± 3.0-5.8, p = 0.014; BEI 18.7 ± 8.3-27.4 vs 12.0 ± 5.1-21.0, p = 0.009). BREC was significantly more decreased in the CB vs RF. Similar trend was noted for BRS and BEI. CA significantly affects BR function. These changes were more pronounced following CB rather than RF CA.

Functional symmetry of the aortic baroreflex in female spontaneously hypertensive rats.

Altered baroreflex function is well documented in hypertension; however, the female sex remains far less studied compared with males. We have previously demonstrated a left-sided dominance in the expression of aortic baroreflex function in male spontaneously hypertensive rats (SHRs) and normotensive rats of either sex. If lateralization in aortic baroreflex function extends to hypertensive female rats remains undetermined. This study, therefore, assessed the contribution of left and right aortic baroreceptor afferents to baroreflex modulation in female SHRs. Anesthetized female SHRs (total n = 9) were prepared for left, right and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of reflex mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR) and femoral vascular resistance (FVR). All rats were also matched for the diestrus phase of the estrus cycle. Reflex (%) reductions in MAP, HR, MVR and FVR were comparable for both left-sided and right-sided stimulation. Bilateral stimulation evoked slightly larger ( P = 0.03) reductions in MVR compared with right-sided stimulation; however, all other reflex hemodynamic measures were similar to both left-sided and right-sided stimulation. These data show that female SHRs, unlike male SHRs, express similar central integration of left versus right aortic baroreceptor afferent input and thus show no laterization in the aortic baroreflex during hypertension. Marginal increases in mesenteric vasodilation following bilateral activation of the aortic baroreceptor afferents drive no superior depressor responses beyond that of the unilateral stimulation. Clinically, unilateral targeting of the left or right aortic baroreceptor afferents may provide adequate reductions in blood pressure in female hypertensive patients.

Differential frequency-dependent reflex summation of the aortic baroreceptor afferent input.

Reflex summation in the expression of left and right aortic baroreflex control of hemodynamic functions was investigated. In anesthetized Sprague-Dawley rats, mean arterial pressure (MAP), heart rate (HR), and mesenteric vascular resistance (MVR) were recorded following left, right, and bilateral stimulation of the aortic depressor nerve (ADN). Stimulation frequency was varied between low (1Hz), moderate (5Hz), and high (20Hz). At 1Hz, left and right ADN stimulation evoked similar depressor, bradycardic and MVR responses, whereas bilateral stimulation induced larger MAP, HR, and MVR reductions compared with stimulations of either side. The sum of the separate and combined stimulation effects on MAP, HR, and MVR was similar, indicating an additive summation. A similar additive summation was observed with HR responses at 5 and 20Hz. Left-sided and bilateral stimulation produced greater depressor and MVR responses than right-sided stimulation, with responses of the bilateral stimulation mimicking those of the left side. The bilateral MAP or MVR response was smaller than the sum of the separate responses, suggesting an inhibitory summation. In conclusion, reflex summation of the left and right aortic baroreceptor afferent input is differentially expressed in relation to the frequency of the input signal. Summation of baroreflex control of HR is always additive and independent of stimulation frequency. Summation of baroreflex control of MAP is additive when the frequency input is small and inhibitory when the frequency input is moderate to high, with MAP changes mainly driven by parallel baroreflex-triggered changes in vascular resistance.

Aortic baroreceptor afferent activity during systemic inflammation

Objective: Neuroimmune interactions have been extensively explored to find new therapeutic targets for inflammatory diseases. We postulated that baroreceptors (essential for arterial pressure control) might be susceptible to systemic inflammation. Thus, the present study investigated the effect of early-stage systemic inflammation on aortic baroreceptor afferent activity. Hypothesis: Aortic depressor nerve activity is increased during systemic inflammation. Methods: Anesthetized (urethane; 1 g/kg; i.p.) male Sprague-Dawley rats (7-8 weeks old) were used, and lipopolysaccharide (LPS; 1.5 mg/kg; i.v.) injected to induce systemic inflammation. The femoral artery and vein were cannulated for pulsatile arterial pressure recording and LPS administration, respectively. Following 30 min since injections of either saline (control; n = 10) or LPS (n = 16), pulsatile arterial pressure and aortic depressor nerve activity were recorded. Nerve activity recordings were rectified and integrated on a time basis. Body temperature was measured via rectal thermometer. The results are presented as mean ± standard error of the mean. Results: Compared to saline-treated rats, there was an increase in aortic depressor nerve activity (LPS: 1.04 ± 0.02 vs saline: 0.98 ± 0.01 a.u.; p = 0.007); this was accompanied by increases in diastolic arterial pressure (LPS: 83 ± 2 vs saline: 73 ± 4 mmHg; p = 0.031), mean arterial pressure (LPS: 102 ± 3 vs saline: 91 ± 4 mmHg; p = 0.035) but not systolic pressure (LPS: 140 ± 6 vs saline: 122 ± 6 mmHg; p = 0.057; strong trend) or heart rate (LPS: 425 ± 11 bpm vs saline: 393 ± 14; p = 0.085). Importantly, in the LPS-injected rats, a reduction in body temperature was noted compared to saline-treated rats (LPS: 36.7 ± 0.1 vs saline: 37.2 ± 0.2°C; p = 0.005), an indicative of systemic inflammation. Conclusions: Since the diastolic and mean arterial pressures increased after LPS administration, it remains unclear whether the elevated aortic depressor nerve activity reflects this increased pressure or results from the inflammatory mediated sensitization. However, our preliminary data support the notion that aortic baroreceptor afferents participate in the neuroimmune communication response in the early stages of inflammation. Funding sources: FAPESP (protocols #2021/03764-8 and #2021/05554-0). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Differential central integration of left versus right baroreceptor afferent input in spontaneously hypertensive rats.

The blood pressure (BP) regulatory impact of the arterial baroreflex has been well established in health and disease. Under normotensive conditions, we have previously demonstrated functional differences in the central processing of the left versus right aortic baroreceptor afferent input. However, it is unknown if lateralization in aortic baroreflex function remains evident during hypertension. We therefore, investigated the effects of laterality on the expression of baroreflex-driven cardiovascular reflexes in a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR). Anesthetized male SHRs (total n = 9) were instrumented for left, right, and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, and 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR), and femoral vascular resistance (FVR). Left right, and bilateral ADN stimulation evoked frequency-dependent decreases in MAP, HR, MVR, and FVR. Left and bilateral ADN stimulation evoked greater reflex reductions in MAP, HR, MVR, and FVR compared with right-sided stimulation. Reflex bradycardia to bilateral stimulation was larger relative to both left-sided and right-sided stimulation. Reflex depressor and vascular resistance responses to bilateral stimulation mimicked those of the left-sided stimulation. These data indicate a left-side dominance in the central integration of aortic baroreceptor afferent input. Furthermore, reflex summation due to bilateral stimulation is only evident on the reflex bradycardic response, and does not drive further reductions in BP, suggesting that reflex depressor responses in the SHRs are primarily driven by changes in vascular resistance. Together, these results indicate that lateralization in aortic baroreflex function is not only evident under normotensive conditions but also extends to hypertensive conditions.

Multiple sensor theory in cardiovascular mechanosensory units.

Multiple sensor theory (MST) has advanced our understanding of how lung mechanosensors operate. That is, single lung units contain multiple homogeneous or heterogeneous sensors. Each detects sensor-specific mechanical information and interacts with other sensors lying within the unit sending integrated information to the brain to evoke reflexes. MST explains numerous controversial issues in the respiratory system. Recent studies in baroreceptors (BRs), along with reinterpretation of recordings appearing in the literature, indicate MST also operates in the cardiovascular (CV) system. This review outlines evidence supporting MST in the CV system and provides examples to apply the theory. Longstanding controversies surrounding the CV sensors are also considered.

SARS-CoV-2 and Hypertension: Evidence Supporting Invasion into the Brain Via Baroreflex Circuitry and the Role of Imbalanced Renin-Angiotensin-Aldosterone-System.

Hypertension is considered one of the most critical risk factors for COVID-19. Evidence suggests that SARS-CoV-2 infection produces intense effects on the cardiovascular system by weakening the wall of large vessels via vasa-vasorum. In this commentary, we propose that SARS-CoV-2 invades carotid and aortic baroreceptors, leading to infection of the nucleus tractus solitari (NTS) and paraventricular hypothalamic nucleus (PVN), and such dysregulation of NTS and PVN following infection causes blood pressure alteration at the central level. We additionally explored the hypothesis that SARS-CoV-2 favors the internalization of membrane ACE2 receptors generating an imbalance of the renin-angiotensin-aldosterone system (RAAS), increasing the activity of angiotensin II (ANG-II), disintegrin, and metalloproteinase 17 domain (ADAM17/TACE), eventually modulating the integration of afferents reaching the NTS from baroreceptors and promoting increased blood pressure. These mechanisms are related to the increased sympathetic activity, which leads to transient or permanent hypertension associated with SARS-CoV-2 invasion, contributing to the high number of deaths by cardiovascular implications.

PS-B05-3: CARDIOVASCULAR RESPONSES EVOKED BY LOW ENERGY CONTINUOUS VERSUS INTERMITTENT STIMULATION OF THE AORTIC BARORECEPTOR AFFERENTS IN HYPERTENSION

Objectives: Device-based neurostimulation of the carotid baroreceptors is a novel approach to control hypertension. We have previously demonstrated the significance of aortic baroreceptor afferent nerves as a viable alternative neuromodulation target to carotid baroreceptors in lowering mean arterial pressure (MAP) in hypertension. We have also shown that appreciable reductions in MAP do not necessarily require the use of ultrahigh stimulation parameters. In this study, we aimed to investigate if energy consumption for neuromodulation of aortic baroreceptor afferents could be lowered further by using intermittent as opposed to continuous stimulation. Design and method: In male anesthetized spontaneously hypertensive rats (SHRs), the effects of continuous (20 sec) versus intermittent (5 sec ON/3 sec OFF and 5 sec ON/5 sec OFF for 20 sec) stimulation of the left aortic depressor nerve (ADN) on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance were assessed using low (5 Hz) and high (15 Hz) frequencies delivered at 0.4 mA and 0.2 ms. Results: Continuous and intermittent low frequency stimulation produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. Conclusions: Low charge intermittent stimulation of the aortic baroreceptor afferents maintains the required reductions in MAP levels in hypertension and intermittent delivery of the electrical stimulus can further lower energy consumption for neuromodulation. Clinically, these findings may provide useful insight for studies using baroreflex modulation in resistant hypertension and other cardiovascular diseases.

Abstract 051: Exploiting Angiotensin Sensitive Vagal Afferents To Understand And Alleviate Hypertension: A Closed Loop System For Blood Pressure Control

Cardiovascular homeostasis is maintained by neural signals arising from arterial baroreceptors (BRs) that apprise the brain of vascular stretch. Here, we test the overall hypothesis that angiotensin-II (AngII) type 1a receptor expressing neurons within the nodose ganglia (NDG AT1aR ) serve as BR that undergo plasticity during chronic elevations in BP. We found that NDG AT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (cNTS), and synthesize Piezo-1/-2. AT1aR-GCaMP6s mice were used to determine whether NDG AT1aR couple their firing to elevated BP. Two-photon intravital imaging revealed that phenylephrine (PE; i.v.) increased GCaMP6s fluorescence within NDG AT1aR (ΔF/F max = 0.65±0.05*, Time ΔF/Fmax = 92s) and this response was delayed in mice given DOCA-salt (Time ΔF/Fmax = 124s) or chronic AngII (Time ΔF/Fmax = 155s). To determine if optical perturbation of NDG AT1aR affects the baroreflex, expression of excitatory channelrhodpsin2 (ChR2) or inhibitory halorhodopsin (Halo) was directed to AT1aR cells. Optical excitation of NDG AT1aR at their axon terminals in the cNTS elicited frequency-dependent decreases in BP (ΔSBP @ 0.5, 1, 2, 3 Hz = -6.74±3.42 # , -9.75±2.33 # , -23.24±4.39 # , -25.27±4.38 # ) and HR (ΔHR @ 0.5, 1, 2, 3 Hz = -7.81±3.14 # , -14.86±3.22 # , -23.39±5.02 # , -23.66±4.13 # ). Conversely, optical inhibition of NDG AT1aR at axon terminals in the cNTS blunted pressor responses to PE (ΔHR PE(Min) = -36.15±5.31, ΔHR PE+Light(Min) = -23.11±3.33 + ). ChR2-expressing mice were then subjected to DOCA-salt. Optical excitation elicited hypotensive (ΔSBP Min = -21.11±4.05 + ) and bradycardic (ΔHR Min = -235.6±46.69 + ) responses; however, the duration of these effects was altered. We developed a closed loop system to target NDG AT1aR at axon terminals in the cNTS of ChR2-expressing mice to determine if these neurons can be exploited to alleviate hypertension. Mice were subjected to acute and chronic stimuli to elevate BP and stimulated by the system until BP returned below threshold. Collectively, these studies reveal the structure and function of NDG AT1aR and suggest that such neurons may be exploited to discern and relieve hypertension. ( p &lt; 0.05, * time by treatment, # time by frequency, or + time by light interaction)

Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.

Investigation of selective vagal afferents subserving baroreflex function and blood pressure control: implications for understanding and alleviating hypertension

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors (BRs) that apprise the brain of blood volume and pressure within the carotid sinus and aortic arch. Here, we test the overall hypothesis that neurons within the nodose ganglia that express the angiotensin type 1a receptor (referred to as NDGAT1aR) serve as BR that undergo plasticity during chronic elevations in blood pressure (BP). Towards this end, mice that express Cre‐recombinase at the AT1aR locus were delivered a Cre‐dependent AAV to express tdTomato within NDGAT1aR. These studies revealed that NDGAT1aR receive input from the aortic arch and carotid sinus, project to the caudal nucleus of the solitary tract (cNTS), and synthesize mechanosensitive ion channels, Piezo‐1/‐2. To determine whether NDGAT1aR couple their firing to elevated BP, we generated mice with the expression of the fluorescent Ca2+ indicator, GCaMP6s, directed to the AT1aR locus. Two‐photon (2P) intravital imaging revealed that phenylephrine (PE; i.v.) significantly increased GCaMP6s fluorescence within NDGAT1aR. To determine if optogenetic perturbation of NDGAT1aR at their soma or axon terminals within the cNTS affect the baroreflex, we directed the expression of excitatory (channelrhodpsin2; ChR2) or inhibitory (halorhodopsin; Halo) opsins to the AT1aR locus. Optical excitation of NDGAT1aR at their soma or axons terminals in the cNTS, elicited robust and frequency‐dependent decreases in BP and heart rate. Conversely, optical inhibition of afferents in the cNTS originating from NDGAT1aR blunted pressor responses to PE. The implication is that NDGAT1aR are sufficient and necessary to elicit appropriate compensatory responses to vascular mechanosensation induced by vasoconstriction. Opsin‐ or GCaMP6s‐expressing mice were then subjected to the DOCA‐salt model of hypertension. Optical excitation elicited hypotensive and bradycardic responses; however, the duration of these effects was altered, consistent with hypertension‐induced impairment of BR. Similarly, the increased GCaMP6s fluorescence observed after administration of PE was significantly delayed in mice that were subjected to DOCA‐salt or chronic delivery of angiotensin II. Finally, AT1aR‐flox mice were delivered AAV expressing Cre and/or tdTomato into the nodose ganglia to probe the function of AT1aR(s) themselves, in mediating the baroreflex. Preliminary results indicate deleting AT1aR(s) from the nodose ganglia alters pressor responses to vasoactive drugs. Collectively, these results reveal the structure and function of NDGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.

A single baroreceptor unit consists of multiple sensors

Arterial baroreceptors (BRs) play a vital role in the regulation of the cardiopulmonary system. What is known about how these sensors operate at the subcellular level is limited, however. Until recently, one afferent axon was considered to be connected to a single baroreceptor (one-sensor theory). However, in the lung, a single airway mechanosensory unit is now known to house many sensors (multiple-sensor theory). Here we tested the hypothesis that multiple-sensor theory also operates in BR units, using both morphological and electrophysiological approaches in rabbit aortic arch (in whole mount) labeled with Na+/K+-ATPase, as well as myelin basic protein antibodies, and examined microscopically. Sensory structures presented in compact clusters, similar to bunches of grapes. Sensory terminals, like those in the airways, formed leaf-like or knob-like expansions. That is, a single myelinated axon connected with multiple sensors forming a network. We also recorded single-unit activities from aortic baroreceptors in the depressor nerve in anesthetized rabbits and examined the unit response to a bolus intravenous injection of phenylephrine. Unit activity increased progressively as blood pressure (BP) increased. Five of eleven units abruptly changed their discharge pattern to a lower activity level after BP attained a plateau for a minute or two (when BP was maintained at the high level). These findings clearly show that the high discharge baroreceptor deactivates after over-excitation and unit activity falls to a low discharge sensor. In conclusion, our morphological and physiological data support the hypothesis that multiple-sensory theory can be applied to BR units.

Transient effects of carotid baroreflex stimulation via the neck chamber device on central venous pressure.

We examined in 11 young subjects (age 29.7±3.6 years, mean±SEM) whether carotid baroreceptor stimulation via the neck chamber device may affect central venous pressure (CVP), thus potentially involving other reflexogenic areas in the examined responses. Application of progressively greater neck chamber subatmospheric pressures caused a progressive lengthening in RR interval, which reached a peak at the maximal value of negative neck chamber pressure applied. This was accompanied by significant and progressively greater reduction in CVP values when the data were calculated considering the early changes occurring within the first 2 seconds of the stimulus. There was a weak correlation between the early changes in CVP and the RR interval responses when all stimuli were pooled together (r = 0.32, P < .05). The results of the present study suggest that the neck chamber technique employed to assess carotid baroreceptor‐heart rate sensitivity can transiently affect via the CVP reduction cardiopulmonary receptors activity, which may participate at the integrated reflex responses.

Renal denervation based on experimental rationale.

Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system, the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla in the brain stem play critical roles in the regulation of sympathetic outflow to peripheral organs. Information from the peripheral circulation, including serum concentrations of sodium and angiotensin II, is conveyed to the PVN via adjacent structures with a weak blood-brain barrier. In addition, signals from baroreceptors, chemoreceptors and cardiopulmonary receptors as well as afferent input via the renal nerves are all integrated at the level of the PVN. The brain renin-angiotensin system and the balance between nitric oxide and reactive oxygen species in these brain areas also determine the final sympathetic outflow. Additionally, brain inflammatory responses have been shown to modulate these processes. Renal denervation interrupts both the afferent inputs from the kidney to the PVN and the efferent outputs from the PVN to the kidney, resulting in the suppression of sympathetic outflow and eliciting beneficial effects on both hypertension and heart failure.

Immediate changes in cardiac autonomic tone and stroke volume during microgravity simulation using head-down tilt

Objectives: Gravity plays an important role in the day-to-day functioning of the cardiovascular system (CVS) in the human body. The absence of gravity severely affects CVS functioning. Out of existing simulation models of microgravity, the 6° head-down tilt (HDT) is frequently used analog to replicate the physiological effects of microgravity on earth. Materials and Methods: The present study has been designed to determine the specificity of 6° HDT usage as a microgravity simulation. The heart rate variability (HRV), blood pressure (BP), cardiac output (CO), and stroke volume (SV) responses to 5 min exposures were investigated for 4°, 6°, and 8° HDT. It was hypothesized that the graded HDT around 6° will demonstrate reversal of autonomic parameters. The study was conducted on 28 male subjects aged 20–30 years. Results: The study reveals that there was a significant rise in diastolic and mean BP at 6° and 8° HDT as compared to baseline. It was also observed that the high-frequency power in HRV was increased at 6° HDT (P = 0.026), with a concomitant reduction in the low-frequency power (P = 0.03) of HRV. The CO was increased at 6° and 8° HDT as compared to baseline (P = 0.037 and 0.021, respectively). There were no significant changes observed in any of the recorded parameters at 4° HDT. The cardiopulmonary volume receptors might have sensed the blood volume change in HDT as in microgravity simulation the blood passively shifts to cephalad. To overcome the low blood volume problem, the heart tried to pump extra blood through increased CO. At 8° HDT, it was observed that the cardiac sympathetic activity and CO were increased, which is not observed during microgravity exposures. Conclusion: The study suggests that 6° head-down-tilt is the best tilt level for producing microgravity on earth to study immediate cardiovascular parameters as it is a balanced compromise of increased vagal activity and CO without activation of cardiac sympathetic activity. Therefore, our data provide physiological evidence in support of 6° HDT microgravity simulation for the study of immediate cardiovascular responses.