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Hypertension (Dallas, Tex. : 1979) Dec 2019We investigated the impact of hypertension on circulatory responses to exercise and the role of the exercise pressor reflex in determining the cardiovascular...
We investigated the impact of hypertension on circulatory responses to exercise and the role of the exercise pressor reflex in determining the cardiovascular abnormalities characterizing patients with hypertension. After a 7-day drug washout, 8 hypertensive (mean arterial pressure [MAP] 130±4 mm Hg; 65±3 years) and 8 normotensive (MAP 117±2 mm Hg; 65±2 years) individuals performed single-leg knee-extensor exercise (7 W, 15 W, 50%, 80%-W) under control conditions and with lumbar intrathecal fentanyl impairing feedback from µ-opioid receptor-sensitive leg muscle afferents. Femoral artery blood flow (Q), MAP (femoral artery), leg vascular conductance, and changes in cardiac output were continuously measured. While the increase in MAP from rest to control exercise was significantly greater in hypertension compared with normotension, the exercise-induced increase in cardiac output was comparable between groups, and Q and leg vascular conductance responses were ≈18% and ≈32% lower in the hypertensive patients (<0.05). The blockade-induced decreases in MAP were significantly larger during exercise in hypertensive (≈11 mm Hg) compared with normotensive (≈6 mm Hg). Afferent blockade attenuated the central hemodynamic response to exercise similarly in both groups resulting in a ≈15% lower cardiac output at each workload. With no effect in normotensive, afferent blockade significantly raised the peripheral hemodynamic response to exercise in hypertensive, resulting in ≈14% and ≈23% higher Q and leg vascular conductance during exercise. Finally, Q and MAP during fentanyl-exercise in hypertensive were comparable to that of normotensive under control conditions (>0.2). These findings suggest that exercise pressor reflex abnormalities largely account for the exaggerated MAP response and the impaired peripheral hemodynamics during exercise in hypertension.
Topics: Aged; Arterial Pressure; Blood Flow Velocity; Blood Pressure Determination; Cardiovascular Abnormalities; Case-Control Studies; Exercise; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Muscle Contraction; Pressoreceptors; Reference Values; Regional Blood Flow; Severity of Illness Index; Stroke Volume
PubMed: 31607174
DOI: 10.1161/HYPERTENSIONAHA.119.13366 -
Journal of Applied Physiology... Sep 2018Previous studies have shown that muscle sympathetic nerve activity (MSNA) is reduced during low- and mild-intensity dynamic leg exercise. It has been suggested that such...
Previous studies have shown that muscle sympathetic nerve activity (MSNA) is reduced during low- and mild-intensity dynamic leg exercise. It has been suggested that such inhibition is mediated by loading of the cardiopulmonary baroreceptors and that this effect is overridden by muscle metaboreflex activation with higher-intensity exercise. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Therefore, we tested the hypothesis that cardiopulmonary baroreflex-mediated inhibition of MSNA is attenuated during high-intensity muscle metaboreflex activation. In nine young men, MSNA (right peroneal nerve), mean arterial pressure (MAP), and thoracic impedance were recorded. Graded isolation of muscle metaboreflex activation was achieved via postexercise ischemia (PEI) following low (PEI-L)-, moderate (PEI-M)-, and high (PEI-H)-intensity isometric handgrip performed at 20, 30, and 40% maximum voluntary contraction, respectively. Lower-body positive pressure (LBPP, +10 Torr) was applied at rest and during PEI, to load the cardiopulmonary baroreceptors. Handgrip exercise elicited intensity-dependent increases in MSNA and MAP that were maintained during PEI, indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency (BF: -36.7 ± 4.7%, mean ± SE, P < 0.05), whereas MAP was unchanged. When LBPP was applied during PEI, MSNA BF decreased significantly at PEI-L (-40.0 ± 9.2%, P < 0.05) and PEI-M (-27.0 ± 6.3%, P < 0.05), but not at PEI-H (+1.9 ± 7.1%, P > 0.05). These results suggest that low- and moderate-intensity muscle metaboreflex activation does not modulate the inhibition of MSNA by cardiopulmonary baroreceptor loading, whereas high-intensity metaboreflex activation can override cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow. NEW & NOTEWORTHY The interaction between the sympathoinhibitory influence of cardiopulmonary baroreflex and sympathoexcitatory effect of skeletal muscle metaboreflex is not completely understood. In the current study, light- to moderate-intensity muscle metaboreflex activation did not modulate the suppression of muscle sympathetic nerve activity by cardiopulmonary baroreceptor loading, whereas high-intensity muscle metaboreflex activation attenuated the cardiopulmonary baroreflex-mediated inhibition of muscle sympathetic nerve activity. These results provide important information concerning the neural reflex mechanisms regulating sympathetic vasomotor outflow during exercise.
Topics: Arterial Pressure; Baroreflex; Electric Impedance; Exercise; Hand Strength; Hemodynamics; Humans; Male; Muscle Contraction; Muscle, Skeletal; Peroneal Nerve; Pressoreceptors; Sympathetic Nervous System; Young Adult
PubMed: 29672226
DOI: 10.1152/japplphysiol.00161.2018 -
Journal of Computational Neuroscience Feb 2017The baroreceptor neurons serve as the primary transducers of blood pressure for the autonomic nervous system and are thus critical in enabling the body to respond...
The baroreceptor neurons serve as the primary transducers of blood pressure for the autonomic nervous system and are thus critical in enabling the body to respond effectively to changes in blood pressure. These neurons can be separated into two types (A and C) based on the myelination of their axons and their distinct firing patterns elicited in response to specific pressure stimuli. This study has developed a comprehensive model of the afferent baroreceptor discharge built on physiological knowledge of arterial wall mechanics, firing rate responses to controlled pressure stimuli, and ion channel dynamics within the baroreceptor neurons. With this model, we were able to predict firing rates observed in previously published experiments in both A- and C-type neurons. These results were obtained by adjusting model parameters determining the maximal ion-channel conductances. The observed variation in the model parameters are hypothesized to correspond to physiological differences between A- and C-type neurons. In agreement with published experimental observations, our simulations suggest that a twofold lower potassium conductance in C-type neurons is responsible for the observed sustained basal firing, where as a tenfold higher mechanosensitive conductance is responsible for the greater firing rate observed in A-type neurons. A better understanding of the difference between the two neuron types can potentially be used to gain more insight about pathophysiology and treatment of diseases related to baroreflex function, e.g. in patients with autonomic failure, a syndrome that is difficult to diagnose in terms of its pathophysiology.
Topics: Autonomic Nervous System Diseases; Humans; Models, Neurological; Neurons; Pressoreceptors; Synaptic Transmission
PubMed: 27704337
DOI: 10.1007/s10827-016-0624-6 -
Circulation Research Jul 2021[Figure: see text].
[Figure: see text].
Topics: Animals; Aortic Coarctation; Arterial Pressure; Cell Line; Cell Nucleus; Chromatin Assembly and Disassembly; Disease Models, Animal; Endocrine Cells; Female; Homeostasis; Integrin beta1; Kidney; Lamin Type A; Male; Mechanotransduction, Cellular; Mice, Knockout; Pressoreceptors; Renin; Stress, Mechanical; Mice
PubMed: 33993729
DOI: 10.1161/CIRCRESAHA.120.318711 -
Experimental Physiology Nov 2016What is the central question of this study? The arterial baroreflex regulates arterial pressure within a narrow range of variation. After sino-aortic denervation (SAD),...
What is the central question of this study? The arterial baroreflex regulates arterial pressure within a narrow range of variation. After sino-aortic denervation (SAD), rats show a large increase in arterial pressure variability, but mean arterial pressure levels remain similar to those of control rats. Considering that breathing influences the control of arterial pressure, the question is: to what extent does SAD cause changes in breathing? What is the main finding and its importance? Removal of arterial baroreceptors produced changes in breathing in rats, marked by a reduction in respiratory frequency, but not hypertension. These findings are indicative of a possible interaction of respiratory and autonomic neural mechanisms in the regulation of arterial pressure after SAD. Sino-aortic denervated (SAD) rats exhibit a mean arterial pressure (MAP) similar to that of control rats. Given that respiration modulates MAP, we hypothesized that conscious SAD rats show respiratory changes associated with the normal MAP. In this study, we evaluated the cardiovascular and respiratory activities and arterial blood gases in control and SAD rats. Male juvenile Wistar rats (postnatal day 19-21) were submitted to SAD, sham surgery or selective removal of the carotid bodies (CBX), and the three groups were evaluated 10 days after the surgery (SAD, n = 21; Sham, n = 18; and CBX, n = 13). The MAP in Sham, SAD and CBX groups was similar (P > 0.05), but the variability of MAP was significantly higher in SAD than in Sham and CBX rats (P < 0.0001). The duration of expiration and inspiration increased in SAD rats compared with Sham and CBX rats, which resulted in a reduced respiratory frequency and minute ventilation (P < 0.05). The arterial partial pressure of O and the haemoglobin saturation were reduced in SAD and CBX compared with Sham rats, whereas the arterial partial pressure of CO was increased in SAD compared with Sham rats. The short- and long-term respiratory variability were significantly higher in SAD than in Sham and CBX rats (P < 0.05). In addition, the reductions in MAP during deep breaths were greater in SAD than in Sham and CBX rats (P < 0.0001). The data show that SAD rats exhibit respiratory changes, which may be one of the compensatory mechanisms associated with the maintenance of normal levels of MAP in the absence of arterial baroreceptors.
Topics: Animals; Aorta; Arterial Pressure; Arteries; Baroreflex; Carbon Dioxide; Carotid Body; Denervation; Exhalation; Inhalation; Male; Oxygen; Pressoreceptors; Rats; Rats, Wistar; Sinoatrial Node
PubMed: 27615272
DOI: 10.1113/EP085897 -
American Journal of Physiology. Heart... Nov 2018Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of...
Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.
Topics: Animals; Arterial Pressure; Atrial Natriuretic Factor; Autonomic Nervous System; Baroreflex; Computer Simulation; Dogs; Electric Stimulation Therapy; Heart; Heart Rate; Humans; Hypertension; Kidney; Models, Animal; Models, Cardiovascular; Norepinephrine; Pressoreceptors; Sympathectomy; Time Factors
PubMed: 30004810
DOI: 10.1152/ajpheart.00302.2018 -
The Journal of Clinical Investigation Jul 2020The baroreceptor reflex is a powerful neural feedback that regulates arterial pressure (AP). Mechanosensitive channels transduce pulsatile AP to electrical signals in...
The baroreceptor reflex is a powerful neural feedback that regulates arterial pressure (AP). Mechanosensitive channels transduce pulsatile AP to electrical signals in baroreceptors. Here we show that tentonin 3 (TTN3/TMEM150C), a cation channel activated by mechanical strokes, is essential for detecting AP changes in the aortic arch. TTN3 was expressed in nerve terminals in the aortic arch and nodose ganglion (NG) neurons. Genetic ablation of Ttn3 induced ambient hypertension, tachycardia, AP fluctuations, and impaired baroreflex sensitivity. Chemogenetic silencing or activation of Ttn3+ neurons in the NG resulted in an increase in AP and heart rate, or vice versa. More important, overexpression of Ttn3 in the NG of Ttn3-/- mice reversed the cardiovascular changes observed in Ttn3-/- mice. We conclude that TTN3 is a molecular component contributing to the sensing of dynamic AP changes in baroreceptors.
Topics: Animals; Aorta, Thoracic; Blood Pressure; HEK293 Cells; Humans; Hypertension; Membrane Proteins; Mice; Mice, Knockout; Neurons; Nodose Ganglion; Pressoreceptors; Tachycardia
PubMed: 32484458
DOI: 10.1172/JCI133798 -
Life Sciences Aug 2021Diabetes promotes renal sympathetic hyperactivity, autonomic imbalance, and cardiovascular and renal dysfunction. Bilateral renal denervation (BRD) has emerged as a...
UNLABELLED
Diabetes promotes renal sympathetic hyperactivity, autonomic imbalance, and cardiovascular and renal dysfunction. Bilateral renal denervation (BRD) has emerged as a treatment for diabetes; however, the mechanisms that underlie the beneficial effects of BRD are unknown.
AIMS
The present study evaluated the effects of BRD on autonomic, cardiovascular, metabolic, and renal function in streptozotocin-diabetic rats.
MAIN METHODS
Wistar rats were separated into three experimental groups: control (CTR), diabetic (DM), and diabetic that underwent BRD (DM BRD). BRD was performed two weeks after STZ-diabetes induction, the experiments were performed four weeks after DM induction. This study evaluated sympathetic vasomotor nerve activity in different territories (renal, lumbar and splanchnic), arterial baroreceptor reflex, metabolic and renal function.
KEY FINDINGS
BRD significantly reduced glycemia, glycosuria, albuminuria, and SGLT2 gene expression in the kidney in DM rats. Renal sympathetic nerve activity (rSNA) was significantly increased and splanchnic sympathetic nerve activity (sSNA) was significantly decreased in DM rats, without changes in lumbar sympathetic nerve activity (lSNA). BRD was able to normalize sSNA and significantly increase lSNA in DM rats compared to control rats. Additionally, cardiac baroreceptor sensitivity was impaired in DM rats, and BRD significantly improved baroreflex sensitivity.
SIGNIFICANCE
Our data suggest that renal nerves play an important role in autonomic, cardiovascular, and renal dysfunction in STZ-DM rats. Thus, sympathetic renal hyperactivity should be considered a possible therapeutic target in diabetic patients.
Topics: Animals; Baroreflex; Blood Pressure; Cardiovascular System; Catheterization; Denervation; Diabetes Mellitus, Experimental; Heart; Heart Rate; Hematocrit; Kidney; Male; Pressoreceptors; Rats; Rats, Wistar; Sodium-Glucose Transporter 2; Streptozocin; Sympathetic Nervous System
PubMed: 33933461
DOI: 10.1016/j.lfs.2021.119534 -
Experimental Physiology Dec 2020What is the central question of this study? What ex vivo preparation of the rat's cavoatrial junction is efficient for characterising atrial mechanoreceptors? What is...
NEW FINDINGS
What is the central question of this study? What ex vivo preparation of the rat's cavoatrial junction is efficient for characterising atrial mechanoreceptors? What is the main finding and its importance? Of four different ex vivo preparations, static pressure, flow, open and euthermic, the optimal preparation was the euthermic one and involved direct recording from the right cardiac vagal branch with a Langendorff style perfusion at 37°C. Type A receptors were most common, and appeared insensitive to stretch and sensitive to atrial contraction. Type B and intermediate receptors were not isolated at 20°C but were observed closer to 37°C. The findings may suggest that type A and B receptors utilise different molecular transduction mechanisms.
ABSTRACT
Atrial volume receptors are a family of afferent neurons whose mechanically sensitive endings terminate in the atria, particularly at the cavoatrial junctions. These mechanosensors form the afferent limb of an atrial volume receptor reflex that regulates plasma volume. The prevailing functional classification of atrial receptors arose as a result of in vivo recordings in the cat and dog and were classified as type A, B or intermediate according to the timing of peak discharge during the cardiac cycle. In contrast, there have been far fewer studies of the common small laboratory mammals such as the rat. Using several ex vivo rat cavoatrial preparations, a total of 30 successful single cavoatrial mechanosensory recordings were obtained. These experiments show that the rat possesses type A, B and intermediate atrial mechanoreceptors as described for larger mammals. Recording these cavoatrial receptors proved challenging from the main vagus, but direct recording from the cardiac vagal branch greatly increased the yield of mechanically sensitive single units. In contrast to type A units, type B atrial mechanoreceptor activity was never observed at room temperature but required elevation of temperature to a more physiological range in order to be detected. The adequate stimulus for these receptors remains unclear; however, type A atrial receptors appear insensitive to direct atrial stretch when applied using a programmable positioner. The findings may suggest that type A and type B atrial receptors utilise different molecular transduction mechanisms.
Topics: Action Potentials; Animals; Blood Pressure; Female; Heart Atria; Heart Rate; Male; Mechanoreceptors; Myocardial Contraction; Neurons, Afferent; Pressoreceptors; Rats; Rats, Wistar; Vagus Nerve
PubMed: 33372723
DOI: 10.1113/EP088972 -
American Journal of Physiology. Heart... Sep 2014Sex differences in baroreflex (BRx) function are well documented. Hormones likely contribute to this dimorphism, but many functional aspects remain unresolved. Our lab... (Comparative Study)
Comparative Study
Sex differences in baroreflex (BRx) function are well documented. Hormones likely contribute to this dimorphism, but many functional aspects remain unresolved. Our lab has been investigating a subset of vagal sensory neurons that constitute nearly 50% of the total population of myelinated aortic baroreceptors (BR) in female rats but less than 2% in male rats. Termed "Ah," this unique phenotype has many of the nonoverlapping electrophysiological properties and chemical sensitivities of both myelinated A-type and unmyelinated C-type BR afferents. In this study, we utilize three distinct experimental protocols to determine if Ah-type barosensory afferents underlie, at least in part, the sex-related differences in BRx function. Electron microscopy of the aortic depressor nerve (ADN) revealed that female rats have less myelin (P < 0.03) and a smaller fiber cross-sectional area (P < 0.05) per BR fiber than male rats. Electrical stimulation of the ADN evoked compound action potentials and nerve conduction profiles that were markedly different (P < 0.01, n = 7 females and n = 9 males). Selective activation of ADN myelinated fibers evoked a BRx-mediated depressor response that was 3-7 times greater in female (n = 16) than in male (n = 17) rats. Interestingly, the most striking hemodynamic difference was functionally dependent upon the rate of myelinated barosensory fiber activation. Only 5-10 Hz of stimulation evoked a rapid, 20- to 30-mmHg reduction in arterial pressure of female rats, whereas rates of 50 Hz or higher were required to elicit a comparable depressor response from male rats. Collectively, our experimental results are suggestive of an alternative myelinated baroreceptor afferent pathway in females that may account for, at least in part, the noted sex-related differences in autonomic control of cardiovascular function.
Topics: Action Potentials; Afferent Pathways; Animals; Aorta; Baroreflex; Electric Stimulation; Female; Hemodynamics; Male; Mechanotransduction, Cellular; Nerve Fibers, Myelinated; Neural Conduction; Parasympathetic Nervous System; Phenotype; Pressoreceptors; Rats; Sex Characteristics; Sex Factors; Time Factors
PubMed: 25038145
DOI: 10.1152/ajpheart.00332.2014