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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 -
BMC Cardiovascular Disorders Mar 2021The study evaluated the cost of baroreflex activation therapy plus guideline directed therapy (BAT + GDT) compared to GDT alone for HF patients with reduced ejection... (Comparative Study)
Comparative Study
BACKGROUND
The study evaluated the cost of baroreflex activation therapy plus guideline directed therapy (BAT + GDT) compared to GDT alone for HF patients with reduced ejection fraction and New York Heart Association Class III or II (with a recent history of III). Baroreflex activation therapy (BAT) is delivered by an implantable device that stimulates the baroreceptors through an electrode attached to the outside of the carotid artery, which rebalances the autonomic nervous system to regain cardiovascular (CV) homeostasis. The BeAT-HF trial evaluated the safety and effectiveness of BAT.
METHODS
A cost impact model was developed from a U.S. health care payer or integrated delivery network perspective over a 3-year period for BAT + GDT versus GDT alone. Expected costs were calculated by utilizing 6-month data from the BeAT-HF trial and existing literature. HF hospitalization rates were extrapolated based on improvement in NT-proBNP.
RESULTS
At baseline the expected cost of BAT + GDT were $29,526 per patient more than GDT alone due to BAT device and implantation costs. After 3 years, the predicted cost per patient was $9521 less expensive for BAT + GDT versus GDT alone due to lower rates of significant HF hospitalizations, CV non-HF hospitalizations, and resource intensive late-stage procedures (LVADs and heart transplants) among the BAT + GDT group.
CONCLUSIONS
BAT + GDT treatment becomes less costly than GDT alone beginning between years 1 and 2 and becomes less costly cumulatively between years 2 and 3, potentially providing significant savings over time. As additional BeAT-HF trial data become available, the model can be updated to show longer term effects.
Topics: Baroreflex; Chronic Disease; Cost Savings; Cost-Benefit Analysis; Electric Stimulation Therapy; Health Care Costs; Heart Failure; Humans; Models, Economic; Outcome and Process Assessment, Health Care; Pressoreceptors; Time Factors; Treatment Outcome; United States
PubMed: 33771104
DOI: 10.1186/s12872-021-01958-y -
Hypertension Research : Official... Feb 2024Electrode-based electrophysiological interfaces with peripheral nerves have come a long way since the 1960s, with several neurostimulation applications witnessing... (Review)
Review
Electrode-based electrophysiological interfaces with peripheral nerves have come a long way since the 1960s, with several neurostimulation applications witnessing widespread clinical implementation since then. In resistant hypertension, previous clinical trials have shown that "carotid" baroreflex stimulation using device-based baroreflex activation therapy (BAT) can effectively lower blood pressure (BP). However, device-based "aortic" baroreflex stimulation remains untouched for clinical translation. The rat is a remarkable animal model that facilitates exploration of mechanisms pertaining to the baroreceptor reflex and preclinical development of novel therapeutic strategies for BP modulation and hypertension treatment. Specifically, the aortic depressor nerve (ADN) in rats carries a relatively pure population of barosensitive afferent neurons, which enable selective investigation of the aortic baroreflex function. In a rat model of essential hypertension, the spontaneously hypertensive rat (SHR), we have recently investigated the aortic baroreceptor afferents as an alternate target for BP modulation, and showed that "low intensity" stimulation is able to evoke clinically meaningful reductions in BP. Deriving high quality short-term and long-term data on aortic baroreflex modulation in rats is currently hampered by a number of unresolved experimental challenges, including anatomical variations across rats which complicates identification of the ADN, the use of unrefined neurostimulation tools or paradigms, and issues arising from anesthetized and conscious surgical preparations. With the goal of refining existing experimental protocols designed for preclinical investigation of the baroreflex, this review seeks to outline current challenges hindering further progress in aortic baroreflex modulation studies in rats and present some practical considerations and recently emerging ideas to overcome them. Aortic baroreflex modulation.
Topics: Rats; Animals; Baroreflex; Electric Stimulation; Hypertension; Pressoreceptors; Rats, Inbred SHR; Blood Pressure; Heart Rate
PubMed: 37919429
DOI: 10.1038/s41440-023-01486-6 -
Journal of Anatomy Nov 2019The glossopharyngeal nerve, via the carotid sinus nerve (CSN), presents baroreceptors from the internal carotid artery (ICA) and chemoreceptors from the carotid body....
The glossopharyngeal nerve, via the carotid sinus nerve (CSN), presents baroreceptors from the internal carotid artery (ICA) and chemoreceptors from the carotid body. Although neurons in the nodose ganglion were labelled after injecting tracer into the carotid body, the vagal pathway to these baro- and chemoreceptors has not been identified. Neither has the glossopharyngeal intracranial afferent/sensory pathway that connects to the brainstem been defined. We investigated both of these issues in male Sprague-Dawley rats (n = 40) by injecting neural tracer wheat germ agglutinin-horseradish peroxidase into: (i) the peripheral glossopharyngeal or vagal nerve trunk with or without the intracranial glossopharyngeal rootlet being rhizotomized; or (ii) the nucleus of the solitary tract right after dorsal and ventral intracranial glossopharyngeal rootlets were dissected. By examining whole-mount tissues and brainstem sections, we verified that only the most rostral rootlet connects to the glossopharyngeal nerve and usually four caudal rootlets connect to the vagus nerve. Furthermore, vagal branches may: (i) join the CSN originating from the pharyngeal nerve base, caudal nodose ganglion, and rostral or caudal superior laryngeal nerve; or (ii) connect directly to nerve endings in the middle segment of the ICA or to chemoreceptors in the carotid body. The aortic depressor nerve always presents and bifurcates from either the rostral or the caudal part of the superior laryngeal nerve. The vagus nerve seemingly provides redundant carotid baro- and chemoreceptors to work with the glossopharyngeal nerve. These innervations confer more extensive roles on the vagus nerve in regulating body energy that is supplied by the cardiovascular, pulmonary and digestive systems.
Topics: Animals; Carotid Artery, Internal; Carotid Body; Chemoreceptor Cells; Male; Neuronal Tract-Tracers; Pressoreceptors; Rats; Rats, Sprague-Dawley; Vagus Nerve
PubMed: 31347697
DOI: 10.1111/joa.13054 -
Acta Histochemica Feb 2020Sensory nerve endings respond to various stimuli and subsequently transmit afferent informations to central nervous system, but their responsibility has been suggested...
Sensory nerve endings respond to various stimuli and subsequently transmit afferent informations to central nervous system, but their responsibility has been suggested to be modulated by glutamate. In the present study, we examined the immunohistochemical localization of vesicular glutamate transporter 1 (vGLUT1) and vGLUT2 in baroreceptor nerve endings immunoreactive for P2X2 and P2X3 purinoceptors in the rat carotid sinus by immunohistochemistry of whole-mount preparations with confocal scanning laser microscopy. P2X3-immunoreactive flat leaf-like axon terminals were immunoreactive to vGLUT2, but not to vGLUT1. Among members of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex, immunoreactivities for synaptosomal-associated protein, 25 kDa, Syntaxin1, and vesicle-associated membrane protein 2 (VAMP2) were localized in P2X2- and P2X3-immunoreactive axon terminals. Punctate immunoreactive products for VAMP2 and vGLUT2 were co-localized in axon terminals. These results suggest that vGLUT2 is localized in P2X3-immunoreactive baroreceptor terminals in the carotid sinus, and these terminals may release glutamate by exocytosis in order to modulate baroreceptor function in the carotid sinus.
Topics: Animals; Carotid Sinus; Exocytosis; Immunohistochemistry; Male; Nerve Endings; Pressoreceptors; Presynaptic Terminals; Rats, Wistar; Vesicular Glutamate Transport Protein 2
PubMed: 31784233
DOI: 10.1016/j.acthis.2019.151469 -
American Journal of Physiology.... Mar 2021Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications. Similar to OSA, chronic intermittent...
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications. Similar to OSA, chronic intermittent hypoxia (CIH) (a model for OSA) leads to oxidative stress and impairs baroreflex control of the heart rate (HR) in rodents. The baroreflex arc includes the aortic depressor nerve (ADN), vagal efferent, and central neurons. In this study, we used mice as a model to examine the effects of CIH on baroreflex sensitivity, aortic baroreceptor afferents, and central and vagal efferent components of the baroreflex circuitry. Furthermore, we tested whether human Cu/Zn Superoxide Dismutase (SOD1) overexpression in transgenic mice offers protection against CIH-induced deficit of the baroreflex arc. Wild-type C57BL/6J and SOD1 mice were exposed to room air (RA) or CIH and were then anesthetized, ventilated, and catheterized for measurement of mean arterial pressure (MAP) and HR. Compared with wild-type RA control, CIH impaired baroreflex sensitivity but increased maximum baroreceptor gain and bradycardic response to vagal efferent stimulation. Additionally, CIH reduced the bradycardic response to ADN stimulation, indicating a diminished central regulation of bradycardia. Interestingly, SOD1 overexpression prevented CIH-induced attenuation of HR responses to ADN stimulation and preserved HR responses to vagal efferent stimulation in transgenic mice. We suggest that CIH decreased central mediation of the baroreflex and SOD1 overexpression may prevent the CIH-induced central deficit.
Topics: Animals; Arterial Pressure; Baroreflex; Bradycardia; Brain; Cardiovascular System; Chronic Disease; Disease Models, Animal; Electric Stimulation; Heart Rate; Humans; Hypoxia; Male; Mice, Inbred C57BL; Mice, Transgenic; Pressoreceptors; Superoxide Dismutase-1; Up-Regulation; Vagus Nerve; Mice
PubMed: 33296277
DOI: 10.1152/ajpregu.00147.2020 -
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 -
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