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Concept: Baroreflex


Objective. Hypertension is the largest threat to patient health and a burden to health care systems. Despite various options, 30% of patients do not respond sufficiently to medical treatment. Mechanoreceptors in the aortic arch relay blood pressure (BP) levels through vagal nerve (VN) fibers to the brainstem and trigger the baroreflex, lowering the BP. Selective electrical stimulation of these nerve fibers reduced BP in rats. However, there is no technique described to localize and stimulate these fibers inside the VN without inadvertent stimulation of non-baroreceptive fibers causing side effects like bradycardia and bradypnea. Approach. We present a novel method for selective VN stimulation to reduce BP without the aforementioned side effects. Baroreceptor compound activity of rat VN (n = 5) was localized using a multichannel cuff electrode, true tripolar recording and a coherent averaging algorithm triggered by BP or electrocardiogram. Main results. Tripolar stimulation over electrodes near the barofibers reduced the BP without triggering significant bradycardia and bradypnea. The BP drop was adjusted to 60% of the initial value by varying the stimulation pulse width and duration, and lasted up to five times longer than the stimulation. Significance. The presented method is robust to impedance changes, independent of the electrode’s relative position, does not compromise the nerve and can run on implantable, ultra-low power signal processors.

Concepts: Medicine, Electrochemistry, Vagus nerve, Carotid sinus, Vagus nerve stimulation, Electrochemical cell, Hypotension, Baroreflex


The mechanisms by which dietary salt promotes hypertension are unknown. Previous work established that plasma [Na(+)] and osmolality rise in proportion with salt intake and thus promote release of vasopressin (VP) from the neurohypophysis. Although high levels of circulating VP can increase blood pressure, this effect is normally prevented by a potent GABAergic inhibition of VP neurons by aortic baroreceptors. Here we show that chronic high salt intake impairs baroreceptor inhibition of rat VP neurons through a brain-derived neurotrophic factor (BDNF)-dependent activation of TrkB receptors and downregulation of KCC2 expression, which prevents inhibitory GABAergic signaling. We show that high salt intake increases the spontaneous firing rate of VP neurons in vivo and that circulating VP contributes significantly to the elevation of arterial pressure under these conditions. These results provide the first demonstration that dietary salt can affect blood pressure through neurotrophin-induced plasticity in a central homeostatic circuit.

Concepts: Blood, Blood pressure, Artery, Vein, Potassium, Glossopharyngeal nerve, Baroreceptor, Baroreflex


A multitude of nonpharmacological interventions to terminate hiccup belong to the public-domain hiccup “mythology” or have been described in the medical literature as case reports. While usually effective in terminating bouts of acute hiccup, they are mostly ineffective in cases of hiccupping that have been present for an extended period. The common denominator of most of these therapeutic maneuvers (some also used to terminate paroxysmal supraventricular tachycardia) is their ability to directly or indirectly increase efferent vagal activity. Among the best known “vagal maneuvers” are the oculo-cardiac reflex (Dagnini-Aschner), the carotid sinus massage, the Valsalva maneuver, stimulation of the ear/auditory canal, ice ingestion, and induction of emesis. This short report provides an overview on hiccups and attempts to identify the lesser known personalities who pioneered its treatment by vagal maneuvers. The recent introduction of electrical vagus nerve stimulation for therapy-resistant hiccup is the ultimate compliment to these pioneers.

Concepts: Vagus nerve, Cranial nerves, Supraventricular tachycardia, Carotid sinus, Vagus nerve stimulation, Carotid sheath, Baroreflex, Paroxysmal tachycardia


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 post-exercise 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{plus minus}4.7%, mean{plus minus}SE, P<0.05), while MAP was unchanged. When LBPP was applied during PEI, MSNA BF decreased significantly at PEI-L (-40.0{plus minus}9.2%, P<0.05) and PEI-M (-27.0{plus minus}6.3%, P<0.05), but not at PEI-H (+1.9{plus minus}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.

Concepts: Blood pressure, Muscle, Muscle contraction, Acetylcholine, Autonomic nervous system, Sympathetic nervous system, Baroreceptor, Baroreflex


As the left vagus nerve (LVN) mediates a baroreflex blood pressure (BP) decrease, LVN stimulation (LVNS) could be a therapy for hypertension. Moreover, LVNS could elegantly be adjusted to the patient’s actual BP and physical activity by using the neural information about BP and respiration extractable from LVN. However, unselective LVNS will trigger undesirable side-effects and therefore we here investigated the feasibility of using an intraneural electrode for extracting BP and respiration markers from the LVN and for selective LVNS.

Concepts: Pharmacology, Blood pressure, Vagus nerve, Cranial nerves, Carotid sinus, Vagus nerve stimulation, Orthostatic hypotension, Baroreflex


The progression of heart failure with reduced ejection fraction is promoted by sympathovagal imbalance. Baroreflex activation therapy (BAT) by the electrical stimulation of baroreceptors at the carotid sinus significantly improved exercise capacity and NT-proBNP levels in a randomized trial; however, no significant difference in left ventricular ejection fraction (LV-EF) between groups was found. Here, we report the case of a 30-year-old man with a long history of dilated cardiomyopathy and severely reduced LV-EF despite optimal medical therapy, who was treated with BAT since October 2014 and showed a remarkable improvement in both symptoms and LV-EF under this treatment.

Concepts: Medicine, Myocardial infarction, Cardiology, Cardiomyopathy, Heart failure, Ejection fraction, Carotid sinus, Baroreflex


Although electrical activation of the carotid sinus baroreflex (baroreflex activation therapy) is being explored as a device therapy for resistant hypertension, possible effects on baroreflex dynamic characteristics of interaction between electrical stimulation and pressure inputs are not fully elucidated. To examine whether the electrical stimulation of the baroreceptor afferent nerve impedes normal short-term arterial pressure (AP) regulation mediated by the stimulated nerve, we electrically stimulated the right aortic depressor nerve (ADN) while estimating the baroreflex dynamic characteristics by imposing pressure inputs to the isolated baroreceptor region of the right ADN in nine anesthetized rats. A Gaussian white noise signal with a mean of 120 mmHg and standard deviation of 20 mmHg was used for the pressure perturbation. A tonic ADN stimulation (2 or 5 Hz, 10 V, 0.1-ms pulse width) decreased mean sympathetic nerve activity (367.0 ± 70.9 vs. 247.3 ± 47.2 arbitrary units, P < 0.01) and mean AP (98.4 ± 7.8 vs. 89.2 ± 4.5 mmHg, P < 0.01) during dynamic pressure perturbation. The ADN stimulation did not affect the slope of dynamic gain in the neural arc transfer function from pressure perturbation to sympathetic nerve activity (16.9 ± 1.0 vs. 14.7 ± 1.6 dB/decade, not significant). These results indicate that electrical stimulation of the baroreceptor afferent nerve does not significantly impede the dynamic characteristics of the arterial baroreflex concomitantly mediated by the stimulated nerve. Short-term AP regulation by the arterial baroreflex may be preserved during the baroreflex activation therapy.

Concepts: Blood pressure, Common carotid artery, Carotid sinus, Autonomic nervous system, Standard deviation, White noise, Baroreceptor, Baroreflex


The arterial baroreflex is crucial for short-term blood pressure control - abnormal baroreflex function predisposes to syncope and falling. Hypersensitive responses to carotid baroreflex stimulation using carotid sinus massage (CSM) are common in older adults and may be associated with syncope. The pathophysiology of this hypersensitivity is unknown, but chronic denervation of the sternocleidomastoid muscles is common in elderly patients with carotid sinus hypersensitivity (CSH), and is proposed to interfere with normal integration of afferent firing from the carotid baroreceptors with proprioceptive feedback from the sternocleidomastoids, producing large responses to CSM. We hypothesized that simulation of sternocleidomastoid “denervation” using pharmacological blockade would increase cardiovascular responses to CSM. Thirteen participants received supine and tilted CSM prior to intramuscular injections (6-8 mL distributed over four sites) of 2% lidocaine hydrochloride, and 0.9% saline (placebo) in contralateral sternocleidomastoid muscles. Muscle activation was recorded with electromyography (EMG) during maximal unilateral sternocleidomastoid contraction both pre- and postinjection. Supine and tilted CSM were repeated following injections and responses compared to preinjection. Following lidocaine injection, the muscle activation fell to 23 ± 0.04% of the preinjection value (P < 0.001), confirming neural block of the sternocleidomastoid muscles. Cardiac (RRI, RR interval), forearm vascular resistance (FVR), and systolic arterial pressure (SAP) responses to CSM did not increase after lidocaine injection in either supine or tilted positions (supine: ΔRRI -72 ± 31 ms, ΔSAP +2 ± 1 mmHg, ΔFVR +4 ± 4%; tilted: ΔRRI -20 ± 13 ms, ΔSAP +2 ± 2 mmHg, ΔFVR +2 ± 4%; all P > 0.05). Neural block of the sternocleidomastoid muscles does not increase cardiovascular responses to CSM. The pathophysiology of CSH remains unknown.

Concepts: Blood, Heart, Blood pressure, Muscular system, Carotid sinus, Accessory nerve, Sternocleidomastoid muscle, Baroreflex


Reduced baroreflex sensitivity (BRS) has been reported in patients with acute cardiovascular events. We tested the hypothesis that BRS is substantially reduced in patients with spontaneous intracerebral hemorrhage (ICH) and that BRS can predict treatment outcomes.

Concepts: Cardiovascular disease, Cerebral hemorrhage, Baroreceptor, Baroreflex


Decompensation, a critical phase in the response to haemorrhage, is characterized by profound sympathoinhibition and the overriding of baroreflex mediated compensation. As sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) maintain vasomotor tone and are essential for sympathetic baroreceptor reflex function, the RVLM is the likely mediator. However, how decompensation occurs is a mystery. Our previous work demonstrated that the inhibitory neuropeptide somatostatin (SST), evokes potent sympathoinhibition (1). Here we test the hypothesis that, in response to hypovolemia, SST in the RVLM evokes sympathoinhibition, driving decompensation and suppressing baroreflex compensation. We evaluated neuronal activation at sites that contain SST mRNA and project to the RVLM and, in SST2A expressing neurons in the RVLM. We determined the effects on cardiovascular and sympathetic responses to haemorrhage, of bilateral blockade of SST2 receptors in both the RVLM and A1 regions. Haemorrhage in conscious rats evoked c-Fos immunoreactivity in the amygdala, periaqueductal gray, and parabrachial nuclei, regions previously associated with haemorrhage, shown to contain SST and project to the RVLM. Although c-Fos labelling was found throughout the ventrolateral medulla, only a small subset of RVLM SST2A receptor expressing neurons were activated, consistent with the idea that these neurons are inhibited during haemorrhage. However, SST2 receptor antagonists bilaterally injected in the RVLM or the A1 region did not affect the decompensation response to haemorrhage. Thus somatostatin in the RVLM does not mediate decompensation. The physiological role associated with somatostatin induced sympathoinhibition in the RVLM together with the central mechanisms responsible for decompensation remain elusive.

Concepts: Nervous system, Receptor, Receptor antagonist, Sympathetic nervous system, Magic, Baroreceptor, Rostral ventrolateral medulla, Baroreflex