Carotid Baroreceptor Stimulation Ameliorates Pulmonary Arterial Remodeling in Rats With Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Sympathetic hyperactivity plays an important role in the initiation and maintenance of pulmonary hypertension. Carotid baroreceptor stimulation (CBS) is an effective autonomic neuromodulation therapy. We aim to investigate the effects of CBS on hypoxia-induced pulmonary hypertension and its underlying mechanisms. METHODS AND RESULTS: Rats were randomly assigned into 4 groups, including a Control-sham group (n=7), a Control-CBS group (n=7), a Hypoxia-sham group (n=10) and a Hypoxia-CBS group (n=10). Echocardiography, ECG, and hemodynamics examination were performed. Samples of blood, lung tissue, pulmonary arteries, and right ventricle were collected for the further analysis. In the in vivo study, CBS reduced wall thickness and muscularization degree in pulmonary arterioles, thereby improving pulmonary hemodynamics. Right ventricle hypertrophy, fibrosis and dysfunction were all improved. CBS rebalanced autonomic tone and reduced the density of sympathetic nerves around pulmonary artery trunks and bifurcations. RNA-seq analysis identified BDNF and periostin (POSTN) as key genes involved in hypoxia-induced pulmonary hypertension, and CBS downregulated the mRNA expression of BDNF and POSTN in rat pulmonary arteries. In the in vitro study, norepinephrine was found to promote pulmonary artery smooth muscle cell proliferation while upregulating BDNF and POSTN expression. The proliferative effect was alleviated by silence BDNF or POSTN. CONCLUSIONS: Our results showed that CBS could rebalance autonomic tone, inhibit pulmonary arterial remodeling, and improve pulmonary hemodynamics and right ventricle function, thus delaying hypoxia-induced pulmonary hypertension progression. There may be a reciprocal interaction between POSTN and BDNF that is responsible for the underlying mechanism.

Carotid baroreceptor stimulation prevents oxidative stress by inhibiting MAO-A and prevents cardiac remodeling in obese rats.

OBJECTIVE: Sympathetic nervous system overactivation and abnormal lipid metabolism are featured in obesity and may lead to cardiac remodeling. The effects of carotid baroreceptor stimulation (CBS) on cardiac remodeling in obese rats and the underlying mechanisms were explored. METHODS: An obesity model was induced by 16-week high-fat diet feeding. A CBS device was implanted at the 8th week. Body weight and blood pressure measurements, electrocardiography, echocardiography, and glucose and insulin tolerance tests were conducted before sampling. Plasma analysis and histological and biological analyses of left ventricle were also performed. Neonatal rat cardiomyocytes cocultured with 3T3-L1 in transwell chambers were used to investigate the mechanisms. RESULTS: CBS alleviated several manifestations of obesity, including increased body weight, high blood pressure, hyperlipidemia, and enhanced sympathetic activity. In obese hearts, norepinephrine levels decreased, and the monoamine oxidase A (MAO-A) and reactive oxygen species level increased; these changes, as well as cardiac fibrosis, lipid metabolic disorders, and heart dysfunction, were inhibited by CBS. Neonatal rat cardiomyocytes incubated with norepinephrine showed MAO-A upregulation, increased reactive oxygen species levels, lipid metabolic disorders, and inflammatory response, which were inhibited by clorgyline, a selective MAO-A inhibitor. CONCLUSIONS: CBS effectively suppresses sympathetic nervous system activity and oxidative stress mediated by MAO-A and prevents cardiac remodeling in obese rats.

Changes in fetal baroreceptor sensitivity during intrauterine inflammation in preterm fetal sheep.

OBJECTIVE: Baroreflex is a regulatory mechanism that slows the fetal heart rate. This study aimed to investigate the effects of lipopolysaccharide (LPS)-induced endotoxemia on fetal baroreceptor sensitivity in preterm fetal sheep. METHODS: The changes in fetal baroreceptor sensitivity were measured in seven chronically instrumented preterm fetal sheep. Fetal baroreceptor sensitivity was measured in three phases: (A) control phase, defined as the 24 h before the first injection of LPS; (B) acute phase, defined as the 24 h between the first and second injections of LPS; and (C) fetal acidosis phase, defined as the time from the second LPS injection until intrauterine fetal death. Histological examinations of the fetal membrane and umbilical cord were also conducted. RESULTS: Each fetus developed metabolic acidosis after the second injection of LPS. The fetuses died 24.7 (SD = 6.1) hours after the second injection of LPS. Both the umbilical cord and fetal membranes showed histological evidence of severe inflammation. In total, 163 fetal baroreceptor measurements were performed in this experiment (A, n = 77 times; B, n = 60 times; C, n = 26 times). Fetal baroreceptor sensitivity showed significant differences in all three phases (A: 2.7 [SD = 0.2]; B: 2.5 [SD = 0.2]; and C: 1.5 [SD = 0.2]). Post hoc tests showed that baroreceptor sensitivity in the acidosis phase had decreased significantly compared to that in the control and acute phases (p<.001 and p=.002, respectively). CONCLUSIONS: Fetal baroreceptor sensitivity decreased during fetal acidosis induced by LPSs.

Central α7 and α4ß2 nicotinic acetylcholine receptors offset arterial baroreceptor dysfunction in endotoxic rats.

Cardiac autonomic neuropathy is a prominent feature of endotoxemia. Given the defensive role of the cholinergic pathway in inflammation, we assessed the roles of central homomeric α7 and heteromeric α4ß2 nAChRs in arterial baroreceptor dysfunction caused by endotoxemia in rats. Endotoxemia was induced by i.v. administration of lipopolysaccharides (LPS, 10 mg/kg), and baroreflex activity was measured by the vasoactive method, which assesses reflex chronotropic responses to increments (phenylephrine, PE) or decrements (sodium nitroprusside, SNP) in blood pressure. Shifts caused by LPS in PE/SNP baroreflex curves and associated decreases in baroreflex sensitivity (BRS) were dose-dependently reversed by nicotine (25-100 µg/kg, i.v.). The nicotine effect disappeared after intracisternal administration of methyllycaconitine (MLA) or dihydro-ß-erythroidine (DHßE), selective blockers of α7 and α4ß2 receptors, respectively. The advantageous effect of nicotine on BRSPE was replicated in rats treated with PHA-543613 (α7-nAChR agonist) or 5-iodo-A-85380 (5IA, α4ß2-nAChRs agonist) in dose-dependent fashions. Conversely, the depressed BRSSNP of endotoxic rats was improved after combined, but not individual, treatments with PHA and 5IA. Central α7 and α4ß2 nAChR activation underlies the nicotine counteraction of arterial baroreflex dysfunction induced by endotoxemia. Moreover, the contribution of these receptors depends on the nature of the reflex chronotropic response (bradycardia vs. tachycardia).

Ah-type Baroreceptor Neurons Expressing Estrogen Dependent mGluR7 Mediate Descending Inhibition of Cardiac Nociception.

Silent myocardial infarction (MI) is critical for clinical practice with increasing risk for women and the cause remains a medical mystery. Upon the discovery of female-specific Ah-type baroreceptor neurons (BRNs), we hypothesize that glutamate mediates depressor response through afferent-specific expression of particular glutamate receptors (mGluRs) leading descending inhibition of cardiac nociception. In vivo, tail-flick reflex and electromyography were assessed to evaluate glutamate-mediated blood pressure regulation, peripheral and cardiac nociception. The results showed that glutamate decreased mean arterial pressure (MAP) and increased peripheral nociception. Interestingly, glutamate-mediated capsaicin-induced cardiac nociception was strongly reduced in female rats compared with males. Furthermore, Nodose (NG) microinjection of mGluR7 agonist significantly increased MAP in males and slightly decreased that in females. Even though mGluR8 direct activation intensified baroreceptor activation, the sensitivity was similar between sexes. In vitro, the expression profiles of mGluRs were investigated using Western blot and identified BRNs using single-cell qRT-PCR under ischemic conditions. Glutamate in serum, NG and nucleus tractus solitary (NTS) was raised significantly in the model rats of both sexes vs. sham-controls. Female-specific expression of mGluR7 in the baroreflex afferent pathway, especially higher expression in Ah-type BRNs, contributes significantly to cardiac analgesia, which may explain that the pathogenesis of silent MI occurs mainly in female patients. Therefore, higher expression of mGluR7 in female-specific subpopulation of Ah-type BRNs plays a critical role in cardiac analgesia and peripheral nociception.

Estrogen-dependent depressor response of melatonin via baroreflex afferent function and intensification of PKC-mediated Nav1.9 activation.

Recent studies suggest that melatonin (Mel) plays an important role in the regulation of blood pressure (BP) via the aortic baroreflex pathway. In this study, we investigated the interaction between the baroreflex afferent pathway and Mel-mediated BP regulation in rats under physiological and hypertensive conditions. Mel (0.1, 0.3, and 1.0 mg/mL) was microinjected into the nodose ganglia (NG) of rats. We showed that Mel-induced reduction of mean arterial pressure in female rats was significantly greater than that in male and in ovariectomized rats under physiological condition. Consistently, the expression of Mel receptors (MTNRs) in the NG of female rats was significantly higher than that of males. In L-NAME-induced hypertensive and spontaneously hypertensive rat models, MTNRs were upregulated in males but downregulated in female models. Interestingly, Mel-induced BP reduction was found in male hypertensive models. In whole-cell recording from identified baroreceptor neurons (BRNs) in female rats, we found that Mel (0.1 µM) significantly increased the excitability of a female-specific subpopulation of Ah-type BRNs by increasing the Nav1.9 current density via a PKC-mediated pathway. Similar results were observed in baroreceptive neurons of the nucleus tractus solitarius, showing the facilitation of spontaneous and evoked excitatory post-synaptic currents in Ah-type neurons. Collectively, this study reveals the estrogen-dependent effect of Mel/MTNRs under physiological and hypertensive conditions is mainly mediated by Ah-type BRNs, which may provide new theoretical basis and strategies for the gender-specific anti-hypertensive treatment in clinical practice.

Estrogen-dependent KCa1.1 modulation is essential for retaining neuroexcitation of female-specific subpopulation of myelinated Ah-type baroreceptor neurons in rats.

Female-specific subpopulation of myelinated Ah-type baroreceptor neurons (BRNs) in nodose ganglia is the neuroanatomical base of sexual-dimorphic autonomic control of blood pressure regulation, and KCa1.1 is a key player in modulating the neuroexcitation in nodose ganglia. In this study we investigated the exact mechanisms underlying KCa1.1-mediated neuroexcitation of myelinated Ah-type BRNs in the presence or absence of estrogen. BRNs were isolated from adult ovary intact (OVI) or ovariectomized (OVX) female rats, and identified electrophysiologically and fluorescently. Action potential (AP) and potassium currents were recorded using whole-cell recording. Consistently, myelinated Ah-type BRNs displayed a characteristic discharge pattern and significantly reduced excitability after OVX with narrowed AP duration and faster repolarization largely due to an upregulated iberiotoxin (IbTX)-sensitive component; the changes in AP waveform and repetitive discharge of Ah-types from OVX female rats were reversed by G1 (a selective agonist for estrogen membrane receptor GPR30, 100 nM) and/or IbTX (100 nM). In addition, the effect of G1 on repetitive discharge could be completely blocked by G15 (a selective antagonist for estrogen membrane receptor GPR30, 3 µM). These data suggest that estrogen deficiency by removing ovaries upregulates KCa1.1 channel protein in Ah-type BRNs, and subsequently increases AP repolarization and blunts neuroexcitation through estrogen membrane receptor signaling. Intriguingly, this upregulated KCa1.1 predicted electrophysiologically was confirmed by increased mean fluorescent intensity that was abolished by estrogen treatment. These electrophysiological findings combined with immunostaining and pharmacological manipulations reveal the crucial role of KCa1.1 in modulation of neuroexcitation especially in female-specific subpopulation of myelinated Ah-type BRNs and extend our current understanding of sexual dimorphism of neurocontrol of BP regulation.

Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis.

[Figure: see text].

Ventilatory response to hypercapnia is increased after 4 h of head down bed rest.

Head-down bed rest (HDBR) has previously been shown to alter cerebrovascular and autonomic control. Previous work found that sustained HDBR (≥ 20 days) attenuates the hypercapnic ventilatory response (HCVR); however, little is known about shorter-term effects of HDBR nor the influence of HDBR on the hypoxic ventilatory response (HVR). We investigated the effect of 4-h HDBR on HCVR and HVR and hypothesized attenuated ventilatory responses due to greater carotid and brain blood flow. Cardiorespiratory responses of young men (n = 11) and women (n = 3) to 5% CO2 or 10% O2 before and after 4-h HDBR were examined. HDBR resulted in lower HR, lower cardiac output index, lower common carotid artery flow, higher SpO2, and higher pulse wave velocity. After HDBR, tidal volume and ventilation responses to 5% CO2 were enhanced (all P < 0.05), yet no other changes in cardiorespiratory variables were evident. There was no influence of HDBR on the cardiorespiratory responses to hypoxia (all P > 0.05). Short-duration HDBR does not alter the HVR, yet enhances the HCVR, which we hypothesize is a consequence of cephalic CO2 accumulation from cerebral congestion.

Piezo2-peripheral baroreceptor channel expressed in select neurons of the mouse brain: a putative mechanism for synchronizing neural networks by transducing intracranial pressure pulses.

Here we use immunohistochemistry to examine the expression of Piezo2 in neurons of the mouse dorsal root ganglia and brain. Whereas Piezo2 is expressed in the large majority (≥ 90%) of dorsal root ganglia neurons, Piezo2 expression is restricted to select neuron types in specific brain regions, including neocortical and hippocampal pyramidal neurons, cerebellar Purkinje cells and mitral cells of the olfactory bulb. Given the well-established role of Piezo2 as a low-threshold pressure sensor (i.e., ≤5 mmHg) in peripheral mechanosensation, including the regulation of breathing and blood pressure, its expression in central neurons has interesting implications. In particular, we hypothesize that Piezo2 provides neurons with an intrinsic resonance that promotes their entrainment by the normal intracranial pressure pulses (~5 mmHg) associated with breathing and cardiac cycles. The pressure-induced change in neural activity need only be very subtle to increase, for example, the robustness of respiration-entrained oscillations reported previously in widely distributed neuronal networks in both rodent and human brains. This idea of a "global brain rhythm" first arose from the effect of nasal airflow in activating mechanosensitive olfactory sensory neurons, which then synaptically entrain mitral cells within the olfactory bulb and through their projections, neural networks in other brain regions, including the hippocampus and neocortex. Our proposed, non-synaptic, intrinsic mechanism, where Piezo2 tracks the highly predictable and "metronome-like" intracranial pressure pulses-to date generally considered epiphenomena-would have the advantage that a physical force rapidly transmitted throughout the brain also contributes to this synchronization.

Potential role of intermittent functioning of baroreflexes in the etiology of hypertension in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is a genetic model of primary hypertension with an etiology that includes sympathetic overdrive. To elucidate the neurogenic mechanisms underlying the pathophysiology of this model, we analyzed the dynamic baroreflex response to spontaneous fluctuations in arterial pressure in conscious SHRs, as well as in the Wistar-Kyoto (WKY), the Dahl salt-sensitive, the Dahl salt-resistant, and the Sprague-Dawley rat. Observations revealed the existence of long intermittent periods (lasting up to several minutes) of engagement and disengagement of baroreflex control of heart rate. Analysis of these intermittent periods revealed a predictive relationship between increased mean arterial pressure and progressive baroreflex disengagement that was present in the SHR and WKY strains but absent in others. This relationship yielded the hypothesis that a lower proportion of engagement versus disengagement of the baroreflex in SHR compared with WKY contributes to the hypertension (or increased blood pressure) in SHR compared with WKY. Results of experiments using sinoaortic baroreceptor denervation were consistent with the hypothesis that dysfunction of the baroreflex contributes to the etiology of hypertension in the SHR. Thus, this study provides experimental evidence for the roles of the baroreflex in long-term arterial pressure regulation and in the etiology of primary hypertension in this animal model.

Irradiation of carotid baroreceptor with low-intensity pulsed ultrasound exerts different metabolic protection in perirenal, epididymal white adipose tissue and interscapular brown adipose tissue of obese rats.

This study was designed to clarify whether the irradiation of carotid baroreceptor (CB) with low-intensity pulsed ultrasound (LIPUS) protects against obesity by rebalancing the autonomic nervous system (ANS). Obesity was induced using a high-fat diet (HFD) for 8 weeks in Sprague-Dawley rats. Irradiation with LIPUS was daily (20 minutes a day) applied to the right CB. In our study, LIPUS significantly ameliorated metabolic disorders in obese rats. LIPUS partly restored norepinephrine (NE) and acetylcholine (ACH) levels in the perirenal white adipose tissue (PWAT), epididymal white adipose tissue (EWAT), interscapular brown adipose tissue (IBAT), and plasma of obese rats. LIPUS partially rectified the dysregulated AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor (PPAR) α/É£ pathway in the PWAT, EWAT, and IBAT of obese rats. PPARγ and PPARγ target genes respond more sensitively to HFD and LIPUS in PWAT and EWAT than in IBAT. NE, ACH, uncoupling protein-1, phosphorylated AMPK, PPARα, and PPARα target genes respond more sensitively to HFD and LIPUS in IBAT than in PWAT and EWAT. Conclusion: LIPUS irradiation of CB exerts different metabolic protection in PWAT, EWAT, and IBAT by rebalancing the ANS and rectifying the AMPK/PPARα/É£ pathway in obese rats.

"Comparison of cardiovascular autonomic activity (heart rate variability and baroreceptor sensitivity) in young healthy females during fasting and hyperglycaemia".

BACKGROUND AND AIM: The present study compared cardiovascular autonomic activity and reactivity during fasting (FS) and hyperglycemia (HS) states in young healthy females. METHODS: This case crossover study was conducted on 30 females recruited by convenient sampling. Blood glucose levels were measured in FS and after oral glucose load i.e., HS. Finger arterial blood pressure (BP) and ECG were recorded constantly to monitor baroreceptor sensitivity (BRS) and heart rate variability (HRV). Autonomic reactivity was tested with deep breathing (DB), Valsalva manoeuvre (VM), and head-up-tilt (HUT) test under FS and HS. HRV parameters not normally distributed were natural log (ln) transformed. RESULTS: Significantly reduced Valsalva ratio and higher heart rate and BP were observed in HS that continued during HUT (P < 0.05). The lnSDNN (standard deviation of normal-to-normal intervals) and lnRMSSD (root mean square of successive differences) were significantly lower (p < 0.05) in HS during HUT. After HUT, lnRMSSD remained lower (P = 0.031), whereas lnLF/HF (low frequency/high frequency power) ratio (P = 0.042) and LFnu (normalized units) (P = 0.024) were higher in HS. BRS was significantly lower in supine position in HS compared to FS and further reduced in HUT position in both FS and HS (P < 0.05). CONCLUSION: Compared to FS, the HS exhibited heightened sympathetic activity with attenuation of parasympathetic activity and this phenomenon was further accentuated by HUT. BRS was more sensitive indicator of autonomic effects of hyperglycemia in resting state. In addition to standard tests, autonomic reactivity in vulnerable young subjects could be useful to detect autonomic imbalance at an early stage.

Tentonin 3/TMEM150C senses blood pressure changes in the aortic arch.

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.

Vesicular glutamate transporter 2-immunoreactive afferent nerve terminals in rat carotid sinus baroreceptors.

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.

Transient Receptor Potential Vanilloid 4 Regulation of Adenosine Triphosphate Release by the Adenosine Triphosphate Transporter Vesicular Nucleotide Transporter, a Novel Therapeutic Target for Gastrointestinal Baroreception and Chronic Inflammation.

BACKGROUND: Transient receptor potential vanilloid 4 (TRPV4) is activated by stretch (mechanical), warm temperature, some epoxyeicosatrienoic acids, and lipopolysaccharide. TRPV4 is expressed throughout the gastrointestinal epithelia and its activation induces adenosine triphosphate (ATP) exocytosis that is involved in visceral hypersensitivity. As an ATP transporter, vesicular nucleotide transporter (VNUT) mediates ATP storage in secretory vesicles and ATP release via exocytosis upon stimulation. SUMMARY: TRPV4 is sensitized under inflammatory conditions by a variety of factors, including proteases and serotonin, whereas methylation-dependent silencing of TRPV4 expression is associated with various pathophysiological conditions. Gastrointestinal epithelia also release ATP in response to hypo-osmolality or acid through molecular mechanisms that remain unclear. These synergistically released ATP could be involved in visceral hypersensitivity. Low concentrations of the first generation bisphosphate, clodronate, were recently reported to inhibit VNUT activity and thus clodronate may be a safe and potent therapeutic option to treat visceral pain. Key Messages: This review focuses on: (1) ATP and TRPV4 activities in gastrointestinal epithelia; (2) factors that could modulate TRPV4 activity in gastrointestinal epithelia; and (3) the inhibition of VNUT as a potential novel therapeutic strategy for functional gastrointestinal disorders.

Increased fibroblast growth factor-21 in chronic kidney disease is a trade-off between survival benefit and blood pressure dysregulation.

Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liver-derived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. However, roles that FGF21 plays in pathophysiology of CKD remains elusive. Here we show in mice that FGF21 is required to survive CKD but responsible for blood pressure dysregulation. When introduced with CKD, Fgf21-/- mice died earlier than wild-type mice. Paradoxically, these Fgf21-/- CKD mice escaped several complications observed in wild-type mice, including augmentation of blood pressure elevating response and activation of the sympathetic nervous system during physical activity and increase in serum noradrenalin and corticosterone levels. Supplementation of FGF21 by administration of an FGF21-expressing adeno-associated virus vector recapitulated these complications in wild-type mice and restored the survival period in Fgf21-/- CKD mice. In CKD patients, high serum FGF21 levels are independently associated with decreased baroreceptor sensitivity. Thus, increased FGF21 in CKD can be viewed as a survival response at the sacrifice of blood pressure homeostasis.

Arterial Baroreceptors Sense Blood Pressure through Decorated Aortic Claws.

Mechanosensory neurons across physiological systems sense force using diverse terminal morphologies. Arterial baroreceptors are sensory neurons that monitor blood pressure for real-time stabilization of cardiovascular output. Various aortic sensory terminals have been described, but those that sense blood pressure are unclear because of a lack of selective genetic tools. Here, we find that all baroreceptor neurons are marked in Piezo2-ires-Cre mice and then use genetic approaches to visualize the architecture of mechanosensory endings. Cre-guided ablation of vagal and glossopharyngeal PIEZO2 neurons eliminates the baroreceptor reflex and aortic depressor nerve effects on blood pressure and heart rate. Genetic mapping reveals that PIEZO2 neurons form a distinctive mechanosensory structure: macroscopic claws that surround the aortic arch and exude fine end-net endings. Other arterial sensory neurons that form flower-spray terminals are dispensable for baroreception. Together, these findings provide structural insights into how blood pressure is sensed in the aortic vessel wall.

Baroreflex activation therapy systems: current status and future prospects.

Introduction: Resistant hypertension is characterized by an hyperadrenergic tone and by a neurohumoral activation. In this condition drug therapies are unable to obtain a good control of blood pressure and therefore need a contribution from non-pharmachological approach. To this aim it has been hypothesized that to lower blood pressure this could be obtained through stimulation of carotid baroreceptors and modulation of the adrenergic tone.Areas covered: several studies and trials have evaluated the safety and efficacy of two devices-based therapies and this review will discuss the research obtained mainly in resistant hypertensive subjects.Expert opinion: the studies performed have clearly shown the safety and efficacy of these approaches. The stimulation of carotid baroreceptors induces a significant reduction in blood pressure values associated with a reduction in adrenergic tone. The two systems have same limitations. While baroreflex activation therapy has been upgraded to a more simple system, an upgrade of endovascular baroreflex amplification will be able to reduce the side effects. Due to the fact that neurohumoral activation and hyperadrenergic tone are present in several pathophysiological conditions it is possible to assume a wider use of these systems in the future.

Vagal baro- and chemoreceptors in middle internal carotid artery and carotid body in rat.

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.