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The autonomic regulation of the pulmonary vasculature has been under‐appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension. What is the topic of this review?This review examines our understanding of the autonomic control of pulmonary circulation, with an emphasis on its clinical relevance and potential therapeutic targeting in pulmonary hypertension.What advances does it highlight?The sympathetic and parasympathetic nervous systems both regulate pulmonary vascular tone and stiffness, in integration with systemic autonomic homeostasis. Pulmonary vascular afferents responsive to pulmonary arterial pressure produce distinct pulmonary baroreflex responses. Dysfunction in autonomic control both to and from the pulmonary vasculature might contribute to pulmonary hypertension, and new approaches targeting this have demonstrated early success. [ABSTRACT FROM AUTHOR]

The first act of life was the capture of water within a cell membrane, 1 and maintaining fluid homeostasis is critical for the survival of most organisms. In this review, we discuss the neural mechanisms that drive animals to seek out and consume water and salt. We discuss the cellular and molecular mechanisms for sensing imbalances in blood osmolality, volume, and sodium content; how this information is integrated in the brain to produce thirst and salt appetite; and how these motivational drives are rapidly quenched by the ingestion of water and salt. We also highlight some of the gaps in our current understanding of the fluid homeostasis system, including the molecular identity of the key sensors that detect many fluid imbalances, as well as the mechanisms that control drinking in the absence of physiologic deficit, such as during meals. Thirst and salt appetite are critical for maintaining fluid balance. In this review, Grove and Knight discuss how fluid imbalances are sensed at a molecular level and how these signals converge on brain circuits to drive water and salt consumption. [ABSTRACT FROM AUTHOR]

Key points 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. 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. [ABSTRACT FROM AUTHOR]

The flower‐spray nerve endings are afferent nerve terminals in the carotid sinus that arise from carotid sinus nerve of glossopharyngeal nerve. However, the three‐dimensional ultrastructural characteristics of flower‐spray nerve endings and spatial relationships between the terminal parts and other cellular elements have not been fully understood. To elucidate their detailed relationship, backscattered electron imaging of serial sections was performed with a scanning electron microscope to produce a three‐dimensional reconstruction of the flower‐spray endings. The terminal parts of flower‐spray endings were distributed horizontally approximately 5 µm outside the external elastic membrane in the tunica adventitia of the internal carotid artery. The three‐dimensional reconstruction showed that the terminal parts of flower‐spray endings were flat with irregular contours and were partially covered by the thin cytoplasmic processes of Schwann cells. The complex consisting of the nerve terminals and associated Schwann cells was surrounded by a multilayered basement membrane. The terminal parts of the endings were also surrounded by fibroblasts with elastic fibers and collagen fibrils. Secretory vesicles without an electron‐dense core were observed in the terminal parts of the endings. The accumulation of vesicles just below the axonal membrane was observed in terminal parts not covered by Schwann cell cytoplasmic processes on both the luminal and basal sides. Swollen mitochondria, concentric membranous structures, and glycogen granule‐like electron‐dense materials were often noted in some of the terminal parts of the endings and the parent axon. Collectively, the present results suggest that flower‐spray endings are baroreceptors because their morphology was similar to other mechanoreceptors. Furthermore, flower‐spray endings may be affected by glutamate secreted in an autocrine manner. [ABSTRACT FROM AUTHOR]

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2. To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension. [ABSTRACT FROM AUTHOR]

Hyponatremia is frequently found in patients with congestive heart failure. A reduction in effective circulatory blood volume in a volume-expanded patient with decreased cardiac output is linked to a baroreceptor-mediated non-osmotic release of arginine vasopressin (AVP). The increased production of AVP and salt and water retention in the proximal and distal tubules of the kidney by humoral, hemodynamic, and neural mechanisms increase circulatory blood volume and contribute to hyponatremia. Recent studies have indicated that hyponatremia predicts the short-term and long-term prognosis of heart failure by increasing cardiac death and rehospitalization. In addition, the early development of hyponatremia in acute myocardial infarction also predicts the long-term prognosis of worsening heart failure. AVP V2 receptor antagonism may relieve water retention, but it is unknown whether the V2 receptor inhibitor, tolvaptan, improves the long-term prognosis of congestive heart failure. The newly identified natriuretic factor in renal salt wasting has the potential of improving clinical outcomes when combined with a distal diuretic. [ABSTRACT FROM AUTHOR]

• Perceived increase in vascular stretch decreases salt intake after water deprivation. • NTS AT1R+ neurons and afferents may integrate sensory and endocrine input. • NTS AT1R+neurons and afferents regulate salt intake in water-deprived mice. Angiotensin-II (Ang-II) production is driven by deviations in blood volume and osmolality, and serves the role of regulating blood pressure and fluid intake to maintain cardiovascular and hydromineral homeostasis. These actions are mediated by Ang-II acting on its type 1a receptor (AT1aR) within the central nervous system and periphery. Of relevance, AT1aR are expressed on sensory afferents responsible for conveying cardiovascular information to the nucleus of the solitary tract (NTS). We have previously determined that optical excitation of neurons and vagal afferents within the NTS that express AT1aR (referred to as NTSAT1aR) mimics the perception of increased vascular stretch and induces compensatory responses to restore blood pressure. Here, we test whether NTSAT1aR are also involved in the modulation of water and sodium intake. We directed the light-sensitive excitatory channelrhodopsin-2 (ChR2) or inhibitory halorhodopsin (Halo) to Agtr1a -containing neurons and measured water and sodium chloride (NaCl) intake in the presence and absence of optical stimulation within the NTS during various challenges to fluid homeostasis. Optical perturbation of NTSAT1aR modulates NaCl intake, such that excitation attenuates, whereas inhibition increases intake. This effect is only observed in the water-deprived condition, suggesting that NTSAT1aR are involved in the regulation of sodium intake during an imbalance in both the intracellular and extracellular fluid compartments. Furthermore, optical excitation of NTSAT1aR increases c-Fos expression within oxytocinergic neurons of the paraventricular nucleus of the hypothalamus (PVN), indicating that the regulation of sodium intake by NTSAT1aR may be mediated by oxytocin. Collectively, these results reveal that NTSAT1aR are sufficient and necessary to modulate sodium intake relative to perceived changes in vascular stretch. [ABSTRACT FROM AUTHOR]

A growing body of research suggests that perception and cognition are affected by fluctuating bodily states. For example, the rate of information sampling is coupled with cardiac phases. However, the benefits of such spontaneous coupling between bodily oscillations and decision-making remains unclear. Here, we studied the role of the cardiac cycle in information sampling by testing whether sequential information sampling phase-locked to systolic or diastolic parts of the cardiac cycle impacts the rate of information gathering and processing. To this aim, we employed a modified Information Sampling Task, a standard measure of the rate of information gathering before reaching a decision, in which the onset of new information delivery in each trial was coupled either to cardiac systole or diastole. Information presented within cardiac systole did not significantly modulate the information processing in a manner that would produce clear behavioral changes. However, we found evidence suggesting that higher interoceptive awareness increased accuracy, especially in the costly version of the task, when new information was sequentially presented at systole. Overall, our results add to a growing body of research on body-brain interactions and suggest that our internal bodily rhythms (i.e., heartbeats) and our awareness of them can interact with the way we process the noisy world around us. [Display omitted] • We developed a cardiac Information Sampling Task. • Information gathering in systole or diastole did not affect information gathering. • Higher interoceptive awareness increased accuracy in the costly version of the task. • This was particularly strong when new information was delivered at cardiac systole. [ABSTRACT FROM AUTHOR]

The most commonly used technique to study the barostatic regulation of blood pressure in ectothermic vertebrates consists of determining the heart rate response to pharmacological manipulations of blood pressure, the so‐called "Oxford method." Although well established, the Oxford method has some important limitations, such as induction of hypervolemia in small animals and undesired effects of vasoactive drugs on central and peripheral baroreflex components. As an alternative, the sequence method, which consists in the computerized evaluation of naturally‐occurring baroreflex adjustments of heart rate without the need for pharmacological administrations, was developed to study baroreflexes. In the present study, we compare this sequence method with the Oxford technique in two teleost species with different life styles, and we assess the optimal software configuration for the employment of the sequence method in fish. Calculation of baroreflex gain through the sequence method was adequate and reliable when the software was configured to search for baroreflex sequences with a minimum length of three cardiac cycles with a delay of one cardiac cycle between fluctuations in mean ventral aortic blood pressure and reflex changes in pulse interval. When properly configured, the sequence and the Oxford methods yielded similar determinations of the baroreflex gain in fish. Research Highlights: The nonpharmacological sequence method was validated to study the baroreflex function of fish.When properly configured, the sequence method yielded determinations of baroreflex gain similar to that of the Oxford method. [ABSTRACT FROM AUTHOR]

This review describes and summarizes the role of neuronal nitric oxide synthase (nNOS) on the central nervous system, particularly on brain regions such as the ventrolateral medulla (VLM) and the periaqueductal gray matter (PAG), and on blood vessels and the heart that are involved in the regulation and control of the cardiovascular system (CVS). Furthermore, we shall also review the functional aspects of nNOS during several physiological, pathophysiological, and clinical conditions such as exercise, pain, cerebral vascular accidents or stroke and hypertension. For example, during stroke, a cascade of molecular, neurochemical, and cellular changes occur that affect the nervous system as elicited by generation of free radicals and nitric oxide (NO) from vulnerable neurons, peroxide formation, superoxides, apoptosis, and the differential activation of three isoforms of nitric oxide synthases (NOSs), and can exert profound effects on the CVS. Neuronal NOS is one of the three isoforms of NOSs, the others being endothelial (eNOS) and inducible (iNOS) enzymes. Neuronal NOS is a critical homeostatic component of the CVS and plays an important role in regulation of different systems and disease process including nociception. The functional and physiological roles of NO and nNOS are described at the beginning of this review. We also elaborate the structure, gene, domain, and regulation of the nNOS protein. Both inhibitory and excitatory role of nNOS on the sympathetic autonomic nervous system (SANS) and parasympathetic autonomic nervous system (PANS) as mediated via different neurotransmitters/signal transduction processes will be explored, particularly its effects on the CVS. Because the VLM plays a crucial function in cardiovascular homeostatic mechanisms, the neuroanatomy and cardiovascular regulation of the VLM will be discussed in conjunction with the actions of nNOS. Thereafter, we shall discuss the up-to-date developments that are related to the interaction between nNOS and cardiovascular diseases such as hypertension and stroke. Finally, we shall focus on the role of nNOS, particularly within the PAG in cardiovascular regulation and neurotransmission during different types of pain stimulus. Overall, this review focuses on our current understanding of the nNOS protein, and provides further insights on how nNOS modulates, regulates, and controls cardiovascular function during both physiological activity such as exercise, and pathophysiological conditions such as stroke and hypertension. • NOSs catalyze the following reaction: 2 L-arginine + 3 NADPH + 1 H+ + 4 O 2 → 2 citrulline + 2 NO + 4 H 2 O + 3 NADP+. • The glutamate receptor regulating NO production is altered in hypertension and cerebrovascular accidents. • The glutamate receptor regulating NO production is altered in hypertension and cerebrovascular accidents. • The alteration in the nNOS activity within the RVLM and CVLM provides differential roles in neurotransmission release. • The unilateral ischemic stroke differentially affects ipsilateral nNOS protein abundance within the RVLM and the CVLM. [ABSTRACT FROM AUTHOR]

The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In this review, we described the evidence that the inflammatory process regulates visceral afferent sensitivity and tonicity, affecting the control of the cardiovascular and respiratory system. Some inflammatory mediators like nitric oxide, angiotensin II, endothelin-1, and arginine vasopressin may inhibit baroreceptor afferents and contribute to the baroreflex impairment observed in cardiovascular diseases. Cytokines may act directly on peripheral afferent terminals that transmit information to the central nervous system (CNS). TLR-4 receptors, which recognize lipopolysaccharide, were identified in the nodose and petrosal ganglion and have been implicated in disrupting the blood-brain barrier, which can potentiate the inflammatory process. For example, cytokines may cross the blood-brain barrier to access the CNS. Additionally, pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and some of their receptors have been identified in the nodose ganglion and carotid body. These pro-inflammatory cytokines also sensitize the dorsal root ganglion or are released in the nucleus of the solitary tract. In cardiovascular disease, pro-inflammatory mediators increase in the brain, heart, vessels, and plasma and may act locally or systemically to activate/sensitize afferent nervous terminals. Recent evidence demonstrated that the carotid body chemoreceptor cells might sense systemic pro-inflammatory molecules, supporting the novel proposal that the carotid body is part of the afferent pathway in the central anti-inflammatory reflexes. The exact mechanisms of how pro-inflammatory mediators affects visceral afferent signals and contribute to the pathophysiology of cardiovascular diseases awaits future research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Baroreceptors play a pivotal role in the regulation of blood pressure through moment to moment sensing of arterial blood pressure and providing information to the central nervous system to make autonomic adjustments to maintain appropriate tissue perfusion. A recent publication by Zeng and colleagues (Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, Liberles SD, Science 362: 464 – 467, 2018) suggests the mechanosensitive ion channels Piezo1 and Piezo2 represent the cellular mechanism by which baroreceptor nerve endings sense changes in arterial blood pressure. However, before Piezo1 and Piezo2 are accepted as the sensor of baroreceptors, the question must be asked of what criteria are necessary to establish this and how well the report of Zeng and colleagues (Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, Liberles SD, Science 362: 464 – 467, 2018) satisfies these criteria. We briefly review baroreceptor function, outline criteria that a putative neuronal sensor of blood pressure must satisfy, and discuss whether the recent findings of Zeng and colleagues suitably meet these criteria. Despite the provocative hypothesis, there are significant concerns regarding the evidence supporting a role of Piezo1/Piezo2 in arterial baroreceptor function. [ABSTRACT FROM AUTHOR]

Systemic anaphylaxis is a life-threatening and allergic reaction that affects various organs. We previously reported that, in the stomach, gastric vasoconstriction occurring at the late phase (15–55 min after injection of ovalbumin antigen) was observed in anesthetized rats sensitized with ovalbumin. In addition, anaphylaxis enhances gastric motility and delays emptying. However, the role of extrinsic autonomic nervous system on antigen-induced gastric alterations was not known. Thus, using the same rat anaphylaxis model, we aimed to determine the changes in the efferent and afferent autonomic nerve activities in the stomach during anaphylactic hypotension. The findings showed that injection of ovalbumin antigen caused substantial systemic hypotension in all sensitized rats. The efferent gastric sympathetic nerve activity (efGSNA), but not the efferent vagal nerve activity, increased only at the early phase (1–10 min after injection of ovalbumin antigen) and showed baroreceptor reflex, as evidenced by a stimulatory response to sodium nitroprusside-induced hypotension. In general, excitation of ef-GSNA could induce pylorus sphincter contraction and gastric vasoconstriction. In the present study, we found that sympathectomy attenuated the anaphylaxis-induced decrease in gastric flux but not the increase in gastric vascular resistance. Thus, the increase in ef-GSNA may cause anaphylactic pylorus sphincter contraction but not anaphylactic gastric vasoconstriction. On the other hand, the afferent gastric vagal nerve activity, but not the afferent sympathetic nerve activity, increased during the early phase of anaphylactic hypotension. However, vagotomy produced no effects on the anaphylactic gastric dysfunction. In conclusion, the gastric sympathetic nerves partly modulate stomach function during systemic anaphylaxis. [ABSTRACT FROM AUTHOR]

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers. [ABSTRACT FROM AUTHOR]

Highlights • The joint effect of attentional and bodily resources on cognitive performance is examined. • Attention to a target boosts the short-term memory of coincide background information. • Cardiac phase modulates short term memory, with enhanced performance during systole. • These two effects are approximately additive, indicating they may act through distinct underlying pathways. Abstract Studies on mind-body interactions have largely focused on how mental states modulate bodily physiological responses. Increasing evidence suggests that bodily states also modulate mental states. Here we investigated how both may be integrated in the brain at the resolution of a heartbeat, examining how phasic fluctuations of peripheral blood pressure and central attentional resources combine to influence cognition. We examined the effects of cardiac phase on the performance of two simultaneous tasks: a go/no-go letter detection task where targets were concurrently presented on background faces and a short-term memory face discrimination task. Short-term memory for the background face was better when the initial face was encoded during the systole rather than diastole phase and when it was paired with a target rather than a distractor. There was no significant interaction between cardiac phase and letter detection. These data suggest that peripheral blood pressure and central attention independently regulate cognitive performance. [ABSTRACT FROM AUTHOR]

Cardiac cycle phase is known to modulate processing of simple sensory information. This effect of the heartbeat on brain function is likely exerted via baroreceptors, the neurons sensitive for changes in blood pressure. From baroreceptors, the signal is conveyed all the way to the forebrain and the medial prefrontal cortex. In the two experiments reported, we examined whether learning, as a more complex form of cognition, can be modulated by the cardiac cycle phase. Human participants (experiment 1) and rabbits (experiment 2) were trained in trace eyeblink conditioning while neural activity was recorded. The conditioned stimulus was presented contingently with either the systolic or diastolic phase of the cycle. The tone used as the conditioned stimulus evoked amplified responses in both humans (electroencephalogram from “vertex,” Cz) and rabbits (hippocampal CA1 local field potential) when its onset was timed at systole. In humans, the cardiac cycle phase did not affect learning, but rabbits trained at diastole learned significantly better than those trained at a random phase of the cardiac cycle. In summary, our results suggest that neural processing of external stimuli and also learning can be affected by targeting stimuli on the basis of cardiac cycle phase. These findings might be useful in applications aimed at maximizing or minimizing the effects of external stimulation. [ABSTRACT FROM AUTHOR]

Whole body heat stress (WBH) results in numerous cardiovascular alterations that ultimately reduce orthostatic tolerance. While impaired carotid baroreflex (CBR) function during WBH has been reported as a potential reason for this decrement, study design considerations may limit interpretation of previous findings. We sought to test the hypothesis that CBR function is unaltered during WBH. CBR function was assessed in 10 healthy male subjects (age: 26 ± 3; height: 185 ± 7 cm; weight: 82 ± 10 kg; BMI: 24 ± 3 kg/m2; means ± SD) using 5-s trials of neck pressure (+45, +30, and +15 Torr) and neck suction (−20, −40, −60, and −80 Torr) during normothermia (NT) and passive WBH (Δ core temp ∼1°C). Analyses of stimulus response curves (four-parameter logistic model) for CBR control of heart rate (CBR-HR) and mean arterial pressure (CBR-MAP), as well as separate two-way ANOVA of the hypotensive and hypertensive stimuli (factor 1: thermal condition, factor 2: chamber pressure), were performed. For CBR-HR, maximal gain was increased during WBH (−0.73 ± 0.11) compared with NT (−0.39 ± 0.04, mean ± SE, P = 0.03). In addition, the CBR-HR responding range was increased during WBH (33 ± 5) compared with NT (19 ± 2 bpm, P = 0.03). Separate analysis of hypertensive stimulation revealed enhanced HR responses during WBH at −40, −60, and −80 Torr (condition × chamber pressure interaction, P = 0.049) compared with NT. For CBR-MAP, both logistic analysis and separate two-way ANOVA revealed no differences during WBH. Therefore, in response to passive WBH, CBR control of heart rate (enhanced) and arterial pressure (no change) is well preserved. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the degree of sympathetic postganglionic neuronal loss required to impair cardiovascular-related sympathetic activity. To produce neuronal loss separate groups of rats were treated daily with guanethidine for either 5 days or 11 days, followed by a recovery period. Sympathetic activity was measured by renal sympathetic nerve activity (RSNA). Stereology of thoracic (T13) ganglia was performed to determine neuronal loss. Despite loss of more than two thirds of neurons in T13 ganglia in both treated groups no effect on resting blood pressure (BP) or heart rate (HR) was detected. Basal RSNA in rats treated for 5 days (0.61 ± 0.10 μV ∗ s) and 11 days (0.37 ± 0.08 μV ∗ s) was significantly less than vehicle-treated rats (0.99 ± 0.13 μV ∗ s, p < 0.05). Increases in RSNA by baroreceptor unloading were significantly lower in 5-day (1.09 ± 0.19 μV ∗ s) and 11-day treated rats (0.59 ± 0.11 μV ∗ s) compared with vehicle-treated rats (1.82 ± 0.19 μV ∗ s, p < 0.05). Increases in RSNA to chemoreceptor stimulation were significantly lower in 5-day treated rats (1.54 ± 0.25 μV ∗ s) compared with vehicle-treated rats (2.69 ± 0.23 μV ∗ s, p < 0.05). Increases in RSNA in 11-day treated rats were significantly lower (0.75 ± 0.15 μV ∗ s, p < 0.05) compared with both vehicle-treated and 5-day treated rats. A positive correlation of neurons to sympathetic responsiveness but not basal activity was detected. These data suggest that diminished capacity for reflex sympathetic responsiveness rather than basal activity alone must be assessed for complete detection of neurophysiological cardiovascular impairment. [ABSTRACT FROM AUTHOR]

Hypertension (HTN) and heart failure (HF) have a significant global impact on health, and lead to increased morbidity and mortality. Despite recent advances in pharmacologic and device therapy for these conditions, there is a need for additional treatment modalities. Patients with sub-optimally treated HTN have increased risk for stroke, renal failure and heart failure. The outcome of HF patients remains poor despite modern pharmacological therapy and with established device therapies such as CRT and ICDs. Therefore, the potential role of neuromodulation via renal denervation, baro-reflex modulation and vagal stimulation for the treatment of resistant HTN and HF is being explored. In this manuscript, we review current evidence for neuromodulation in relation to established drug and device therapies and how these therapies may be synergistic in achieving therapy goals in patients with treatment resistant HTN and heart failure. We describe lessons learned from recent neuromodulation trials and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 11th annual CardioVascular Clinical Trialist Forum in Washington, DC on December 5–7, 2014. [ABSTRACT FROM AUTHOR]

Synaptic and extrasynaptic transmission mediated by ionotropic GABA and glycine receptors plays a critical role in shaping the action potential firing (spiking) activity of hypothalamic magnocellular neurosecretory cells and therefore determines the rate at which vasopressin and oxytocin are released from the neurohypophysis. The inhibitory effect of these transmitters relies on the maintenance of a low concentration of intracellular chloride ions such that, when activated by GABA or glycine, a hyperpolarisation of the neuronal membrane potential results. In this review, we highlight the various ways by which the two types of inhibitory receptors contribute to homeostasis by fine-tuning the spiking rate of vasopressin-releasing magnocellular neurosecretory cells in a manner dependent on the hydration state of the animal. In addition, we review the currently available evidence on how the strength of these inhibitory pathways can be regulated during chronic hypernatraemia via a form of activity-dependent depolarisation of the chloride reversal potential, leading to an abolition of these inhibitory pathways potentially causing sodium-dependent elevations in blood pressure. [ABSTRACT FROM AUTHOR]

Baroreflex regulation of blood pressure is important for maintaining appropriate tissue perfusion. Although temperature affects heart rate ( fH) reflex regulation in some reptiles and toads, no data are available on the influence of temperature-independent metabolic states on baroreflex. The South American tegu lizard Salvator merianae exhibits a clear seasonal cycle of activity decreasing fH along with winter metabolic downregulation, independent of body temperature. Through pharmacological interventions (phenylephrine and sodium nitroprusside), the baroreflex control of fH was studied at ~25°C in spring-summer- and winter-acclimated tegus. In winter lizards, resting and minimum fH were lower than in spring-summer animals (respectively, 13.3±0.82 versus 10.3±0.81 and 11.2±0.65 versus 7.97±0.88 beats min-1), while no acclimation differences occurred in resting blood pressure (5.14±0.38 versus 5.06±0.56 kPa), baroreflex gain (94.3±10.7 versus 138.7±30.3% kPa-1) or rate-pressure product (an index ofmyocardial activity).Vagal tone exceeded the sympathetic tone of fH, especially in the winter group. Therefore, despite the lower fH, winter acclimation does not diminish the fH baroreflex responses or rate-pressure product, possibly because of increased stroke volume that may arise because of heart hypertrophy. Independent of acclimation, fH responded more to hypotension than to hypertension. This should imply that tegus, which have no pressure separation within the single heart ventricle, must have other protection mechanisms against pulmonary hypertension or oedema, presumably through lymphatic drainage and/or vagal vasoconstriction of pulmonary artery. Such a predominant fH reflex response to hypotension, previously observed in anurans, crocodilians and mammals, may be a common feature of tetrapods. [ABSTRACT FROM AUTHOR]

AIM: Myocardial infarction in humans is one of the leading causes of sudden death. Experimental myocardial infarction has been produced by the occlusion of the left main coronary artery or other branches in animals. The carotid artery is cannulated to measure blood pressure in this model. Our hypothesis in this study is that the reflex sympathetic stimulation occurring in carotid artery cannulation may decrease arrhythmia. This study is aimed to investigate the effect of femoral artery cannulation, considered, to have low-baroreceptor stimulation and the effects of unilateralvagal denervation on ischemia/reperfusion arrhythmias. METHODS: In this study 58, 6-7 months-old male Sprague-Dawley rats were used; Four groups were produced. In the first group right carotid artery was cannulated and the right femoral artery was in the second. The left main coronary artery is ligated with the silk thread and reperfusion by loosening ligature to produce myocardial ischemia. In the others, vagal denervation is produced by cutting the N-Vagus. In sham operations, the nerve is just separated from the carotid artery. Blood pressure, heart rate, arrhythmia types, and durations were determined during ischemia/reperfusion. Statistical analyses were done by using oneway ANOVA with LCD posthoc test, one-tailed t-test, and Chisquared test. RESULTS: During ischemia/reperfusion, blood pressure and heart rate were lower in the femoral artery group than in the carotid artery group (p<0,05). The arrhythmia score was higher in the femoral group than in the carotid group (p<0,01). Unilateral-vagal denervation increased arrhythmias in the carotid group (p<0.01), but was ineffective in the femoral artery group. CONCLUSION: The reflex sympathetic stimulation induced following carotid artery cannulation decreases the arrhythmia observed during ischemia and reperfusion. In the model of experimental myocardial infarction, femoral artery cannulation is more favorable to decrease the effect of baroreceptor stimulation on the ischemia-reperfusion-induced arrhythmias. [ABSTRACT FROM AUTHOR]

Mental processes depend upon a dynamic integration of brain and body. Emotions encompass internal physiological changes which, through interoception (sensing bodily states), underpin emotional feelings, for example, cardiovascular arousal can intensify feelings of fear and anxiety. The brain is informed about how quickly and strongly the heart is beating by signals from arterial baroreceptors. These fire in bursts after each heartbeat, and are quiet between heartbeats. The processing of fear stimuli is selectively enhanced by these phasic signals, and these inhibit the processing of other types of stimuli including physical pain. Behavioural and neuroimaging studies detail this differential impact of heart signals on the processing of salient stimuli, and add to knowledge linking rhythmic activity in brain and body to perceptual consciousness. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) is abundantly expressed by both developing and adult rat visceral sensory neurons from the nodose ganglion (NG) in vivo and in vitro . We have previously shown that BDNF is released from neonatal NG neurons by activity and regulates dendritic development in their postsynaptic targets in the brainstem. The current study was carried out to examine the cellular and molecular mechanisms of activity-dependent BDNF expression in neonatal rat NG neurons, using our established in vitro model of neuronal activation by electrical field stimulation with patterns that mimic neuronal activity in vivo . We show that BDNF mRNA (transcript 4) increases over threefold in response to a 4-h tonic or bursting pattern delivered at the frequency of 6 Hz, which corresponds to the normal heart rate of a newborn rat. No significant increase in BDNF expression was observed following stimulation at 1 Hz. The latter effect suggests a frequency-dependent mechanism of regulated BDNF expression. In addition to BDNF transcript 4, which is known to be regulated by activity, transcript 1 also showed significant upregulation. The increases in BDNF mRNA were followed by BDNF protein upregulation of a similar magnitude after 24 h of stimulation at 6 Hz. Electrical stimulation-evoked BDNF expression was inhibited by pretreating neurons with the blocker of voltage-gated sodium channels tetrodotoxin and by removing extracellular calcium. Moreover, our data show that repetitive stimulation-evoked BDNF expression requires calcium influx through N-, but not L-type, channels. Together, our study reveals novel mechanisms through which electrical activity stimulates de novo synthesis of BDNF in sensory neurons, and points to the role of N-type calcium channels in regulating BDNF expression in sensory neurons in response to repetitive stimulation. [ABSTRACT FROM AUTHOR]

The aim of the study was to identify the contribution of myelinated (A-fiber) and unmyelinated (Cfiber) baroreceptor central pathways to the baroreflex control of sympathetic nerve activity (SNA) and arterial pressure (AP) in anesthetized Wistar-Kyoto (WKY; n 8) and spontaneously hypertensive rats (SHR; n 8). The left aortic depressor nerve (ADN) was electrically stimulated with two types of binary white noise signals designed to preferentially activate A-fibers (A-BRx protocol) or C-fibers (C-BRx protocol). In WKY, the central arc transfer function from ADN stimulation to SNA estimated by A-BRx showed strong derivative characteristics with the slope of dynamic gain between 0.1 and 1 Hz (Gslope) of 14.63 ± 0.89 dB/decade. In contrast, the central arc transfer function estimated by C-BRx exhibited nonderivative characteristics with Gslope of 0.64 ± 1.13 dB/decade. This indicates that A-fibers are important for rapid baroreflex regulation, whereas C-fibers are likely important for more sustained regulation of SNA and AP. In SHR, the central arc transfer function estimated by A-BRx showed higher Gslope (18.46 ± 0.75 dB/decade, P < 0.01) and that estimated by C-BRx showed higher Gslope (8.62 ± 0.64 dB/decade, P < 0.001) with significantly lower dynamic gain at 0.01 Hz (6.29 ± 0.48 vs. 2.80 ± 0.36%/Hz, P < 0.001) compared with WKY. In conclusion, the dynamic characteristics of the A-fiber central pathway are enhanced in the high-modulation frequency range (0.1-1 Hz) and those of the C-fiber central pathway are attenuated in the lowmodulation frequency range (0.01- 0.1 Hz) in SHR. [ABSTRACT FROM AUTHOR]

To address mechanoreceptive roles of trigeminal ganglion (TG) nerve endings in the inner walls of rat anterior eye chambers, we investigated the mechanotransduction process and mechanosensitive (MS) channel on somata of TG neurons innervating this area in vitro. Rat TG neurons innervating inner walls of anterior chambers were labeled by anterior chamber injection of 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine, 4-chlorobenzenesulfonate (FAST DiI). The neuronal cell bodies were voltage clamped using a whole cell patch-clamp technique, while it was deformed by ejection of bath solution to verify mechanotransduction. Immunofluorescence staining was performed on sections of TG ganglia to determine the specific MS channel proteins. Mechanical stimuli induced MS currents in 55 out of 96 FAST DiI-labeled TG neurons. The MS currents exhibited mechanical intensity-dependent and clamp voltage-dependent characteristics. Mechanical stimulation further enhanced the membrane potential and increased the frequency of action potentials. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), acid-sensing ion channel (ASIC) 2 and ASIC3 channel proteins were expressed in FAST DiI-labeled TG neurons. The inhibitory effect of HC-030031, a specific inhibitor of TRPA1, on MS currents demonstrated that TRPA1 was an essential MS channel protein. Taken together, our results show that mechanical stimuli induce MS currents via MS channels such as TRPA1 to trigger mechanotransduction in TG neurons innervating inner walls of anterior chambers. Our results indicate the existence of mechanoreceptive TG nerve endings in inner walls of anterior chambers. Whether the mechanoreceptive TG nerve endings play a role in intraocular pressure sensation warrants further investigation. [ABSTRACT FROM AUTHOR]

In this review we address primarily the role of ASICs in determining sensory signals from arterial baroreceptors, peripheral chemoreceptors, and cardiopulmonary and somatic afferents. Alterations in these sensory signals during acute cardiovascular stresses result in changes in sympathetic and parasympathetic activities that restore cardiovascular homeostasis. In pathological states, however, chronic dysfunctions of these afferents result in serious sympatho-vagal imbalances with significant increases in mortality and morbidity. We identified a role for ASIC2 in the mechano-sensitivity of aortic baroreceptors and of ASIC3 in the pH sensitivity of carotid bodies. In spontaneously hypertensive rats, we reported decreased expression of ASIC2 in nodose ganglia neurons and overexpression of ASIC3 in carotid bodies. This reciprocal expression of ASIC2 and ASIC3 results in reciprocal changes in sensory sensitivity of baro- and chemoreceptors and a consequential synergistic exaggeration sympathetic nerve activity. A similar reciprocal sensory dysautonomia prevails in heart failure and increases the risk of mortality. There is also evidence that ASIC heteromers in skeletal muscle afferents contribute significantly to the exercise pressor reflex. In cardiac muscle afferents of the dorsal root ganglia, they contribute to nociception and to the detrimental sympathetic activation during ischemia. Finally, we report that an inhibitory influence of ASIC2-mediated baroreceptor activity suppresses the sympatho-excitatory reflexes of the chemoreceptors and skeletal muscle afferents, as well as the ASIC1a-mediated excitation of central neurons during fear, threat, or panic. The translational potential of activation of ASIC2 in cardiovascular disease states may be a beneficial sympatho-inhibition and parasympathetic activation. This article is part of the Special Issue entitled ‘Acid-Sensing Ion Channels in the Nervous System’. [ABSTRACT FROM AUTHOR]

Input signals originating from baroreceptors and vestibular receptors are integrated in the rostral ventrolateral medulla (RVLM) to maintain blood pressure during postural movement. The contribution of baroreceptors and vestibular receptors in the maintenance of blood pressure following hypotension were quantitatively analyzed by measuring phosphorylated extracellular regulated protein kinase (pERK) expression and glutamate release in the RVLM. The expression of pERK and glutamate release in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) following hypotension induced by a sodium nitroprusside (SNP) infusion. The expression of pERK was significantly increased in the RVLM in the control group following SNP infusion, and expression peaked 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than seen in the control group. The SAD group showed a relatively higher reduction in pERK expression when compared with the BL group. The level of glutamate release was significantly increased in the RVLM in control, BL, SAD groups following SNP infusion, and this peaked 10 min after SNP infusion. The SAD group showed a relatively higher reduction in glutamate release when compared with the BL group. These results suggest that the baroreceptors are more powerful in pERK expression and glutamate release in the RVLM following hypotension than the vestibular receptors, but the vestibular receptors still have an important role in the RVLM. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The baroreceptor(BR) is very important in the control of the peripheral circulation and blood pressure (BP) which are regulated in diverse circumstances. We studied the baroreceptor regulation during the change from supine to upright position as this is the most important function of the baroreceptor reflex. OBJECTIVE: Recording and measure the baroreflex sensitivity (BRS) in recumbent and standing positions. METHODS: We used the Finometer®, a non-invasive beat-to-beat method, to record and to measure BP, heart rate, total peripheral resistance, R-R interval and the BRS. We obtained the BRS by dividing the R-R interval (ms) to systolic blood pressure (mmHg) of the previous beat. We evaluated 15 healthy subjects who fulfilled the inclusion criteria. All subjects were studied at rest in recumbent position during 20 min and 5 min in standing position. Graphics and time series of all hemodynamic parameters were obtained in both recumbent and upright positions. RESULTS: We investigated 11 men and 4 women aged between 21 and 39 years old (28.73 ± 5.2). BRS had values from 9.18 to 9.42 ms/mmHg (9.3 ± 0.8) in recumbent position, while in standing up position the values were from 7.57 to 7.75 ms/mmHg (7.66 ± 0.62) (p = 0.01). CONCLUSIONS: BRS had lower values in upright than in recumbent position. [ABSTRACT FROM AUTHOR]

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-mm Hg 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. [ABSTRACT FROM AUTHOR]

Control of blood pressure is maintained by the interaction between the arterial baroreflex and vestibulosympathetic reflex during postural changes. In this study, the contributions of vestibular receptors and baroreceptors to the maintenance of blood pressure following acute hypotension were compared in terms of phosphorylated extracellular regulated protein kinase (pERK) expression in the nucleus tractus solitaries (NTS). Expression of pERK in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) 5, 10, 20, and 40 min following acute hypotension induced by sodium nitroprusside (SNP) infusion. Expression of pERK increased significantly in the NTS in the control group following SNP infusion, and the expression peaked at 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than in control group. The BL group showed a relatively higher reduction in pERK expression than the SAD group, and the pERK expression in the NTS was localized to the caudal portion of the nuclei in the BL and SAD groups. These results suggest that the vestibular receptors may play a key role in maintaining blood pressure following acute hypotension; thus, the vestibular system may contribute to compensate for orthostatic hypotension. [ABSTRACT FROM AUTHOR]

Aims: This study aims to identify the contribution of myelinated (A-fiber) and unmyelinated (C-fiber) baroreceptor central pathways to the baroreflex control of sympathetic nerve activity and arterial pressure. Main methods: Two binary white noise stimulation protocols were used to electrically stimulate the aortic depressor nerve and activate reflex responses from either A-fiber (3V, 20–100Hz) or C-fiber (20V, 0–10Hz) baroreceptor in anesthetized Sprague-Dawley rats (n =10). Transfer function analysis was performed between stimulation and sympathetic nerve activity (central arc), sympathetic nerve activity and arterial pressure (peripheral arc), and stimulation and arterial pressure (Stim-AP arc). Key findings: The central arc transfer function from nerve stimulation to splanchnic sympathetic nerve activity displayed derivative characteristics for both stimulation protocols. However, the modeled steady-state gain (0.28±0.04 vs. 4.01±0.2%·Hz−1, P <0.001) and coherence at 0.01Hz (0.44±0.05 vs. 0.81±0.03, P <0.05) were significantly lower for A-fiber stimulation compared with C-fiber stimulation. The slope of the dynamic gain was higher for A-fiber stimulation (14.82±1.02 vs. 7.21±0.79dB·decade−1, P <0.001). The steady-state gain of the Stim-AP arc was also significantly lower for A-fiber stimulation compared with C-fiber stimulation (0.23±0.05 vs. 3.05±0.31mmHg·Hz−1, P <0.001). Significance: These data indicate that the A-fiber central pathway contributes to high frequency arterial pressure regulation and the C-fiber central pathway provides more sustained changes in sympathetic nerve activity and arterial pressure. A sustained reduction in arterial pressure from electrical stimulation of arterial baroreceptor afferents is likely mediated through the C-fiber central pathway. [ABSTRACT FROM AUTHOR]

Cognitions and emotions can be influenced by bodily physiology. Here, we investigated whether the processing of brief fear stimuli is selectively gated by their timing in relation to individual heartbeats. Emotional and neutral faces were presented to human volunteers at cardiac systole, when ejection of blood from the heart causes arterial baroreceptors to signal centrally the strength and timing of each heartbeat, and at diastole, the period between heartbeats when baroreceptors are quiescent. Participants performed behavioral and neuroimaging tasks to determine whether these interoceptive signals influence the detection of emotional stimuli at the threshold of conscious awareness and alter judgments of emotionality of fearful and neutral faces. Our results show that fearful faces were detected more easily and were rated as more intense at systole than at diastole. Correspondingly, amygdala responses were greater to fearful faces presented at systole relative to diastole. These novel findings highlight a major channel by which short-term interoceptive fluctuations enhance perceptual and evaluative processes specifically related to the processing of fear and threat and counter the view that baroreceptor afferent signaling is always inhibitory to sensory perception. [ABSTRACT FROM AUTHOR]

Highlights: [•] Nitric oxide increases presynaptic glutamate release to baroreceptor NTS neurons. [•] Nitric oxide increases N-type Ca2+ currents in baroreceptor NTS neurons in nodose ganglion. [•] Cav2.2 subunit is present on the baroreceptor afferent nerve terminals. [ABSTRACT FROM AUTHOR]

Highlights: [•] c-Fos protein following acute hypotension was measured in NTS of conscious rats. [•] Activation in NTS following acute hypotension is largely due to baroreceptor inputs. [•] And moderately due to the signals originating from vestibular receptors. [•] And at least partly dependent on the other inputs except vestibular and baroreceptors. [•] c-Fos protein expression was localized to caudal portion of NTS in BL and SAD groups. [Copyright &y& Elsevier]

We investigated a unique microzone of the cerebellum located in folium-p (fp) of rabbit flocculus. In fp, Purkinje cells were potently excited by stimulation of the hypothalamus or mesencephalic periaqueductal gray, which induced defense reactions. Using multiple neuroscience techniques, we determined that this excitation was mediated via beaded axons of orexinergic hypothalamic neurons passing collaterals through the mesencephalic periaqueductal gray. Axonal tracing studies using DiI and biotinylated dextran amine evidenced the projection of fp Purkinje cells to the ventrolateral corner of the ipsilateral parabrachial nucleus (PBN). Because, in defense reactions, arterial blood flow has been known to redistribute from visceral organs to active muscles, we hypothesized that, via PBN, fp adaptively controls arterial blood flow redistribution under orexin-mediated neuromodulation that could occur in defense behavior. This hypothesis was supported by our finding that climbing fiber signals to fp Purkinje cells were elicited by stimulation of the aortic nerve, a high arterial blood pressure, or a high potassium concentration in muscles, all implying errors in the control of arterial blood flow. We further examined the arterial blood flow redistribution elicited by electric foot shock stimuli in awake, behaving rabbits. We found that systemic administration of an orexin antagonist attenuated the redistribution and that lesioning of fp caused an imbalance in the redistribution between active muscles and visceral organs. Lesioning of fp also diminished foot shock-induced increases in the mean arterial blood pressure. These results collectively support the hypothesis that the fp microcomplex adaptively controls defense reactions under orexin-mediated neuromodulation. [ABSTRACT FROM AUTHOR]

The male refractory period (MRP) continues to be a topic of discussion and debate within the field of sexual medicine. To date explanations rely on central descending (efferent) influences involving specific neurotransmitter systems. Herein we explore the issue of the male refractory period, identifying problems with current explanations, specifying the parameters of an adequate model, and suggesting possible mechanisms mediating this phenomenon., We review the literature regarding existing explanations for the MRP and look to other systems of physiological regulation that might provide a model for the conceptualization of the MRP., Our approach differs from traditional explanations in that it emphasizes the possible roles of various peripheral, rather than central, feedback (afferent) systems that affect peripheral autonomic functioning and response., Yet our approach is consistent with other peripheral regulatory feedback systems controlling autonomic response related to such processes as heart rate, respiration, and gut motility., Although direct empirical research supporting our approach is lacking, sufficient evidence exists to support the idea that such processes are not only possible but likely with respect to the male refractory period. We suggest several lines of research that might provide empirical support for this approach. [ABSTRACT FROM AUTHOR]

Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM. [ABSTRACT FROM AUTHOR]

Cardiac baroreflex gain is usually quantified as the reflex alteration in heart rate during changes in blood pressure without considering the effect of the rate of change in blood pressure on the estimated gain. This study sought to ( i) characterize baroreflex gain as a function of blood pressure oscillation frequencies using a repeat sit-to-stand method and ( ii) compare baroreflex gain values obtained using the sit-to-stand method against the modified Oxford method. Fifteen healthy individuals underwent the repeated sit-to-stand method in which blood pressure oscillations were driven at 0.03, 0.05, 0.07, and 0.1 Hz. Sixteen healthy participants underwent the sit-to-stand and modified Oxford methods to examine their agreement. Sit-to-stand baroreflex gain was highest at 0.05 Hz (8.8 ± 3.2 ms·mm Hg−1) and lowest at 0.1 Hz (5.8 ± 3.0 ms·mm Hg−1). Baroreflex gains at 0.03 Hz (7.7 ± 3.0 ms·mm Hg−1) and 0.07 Hz (7.5 ± 3.3 ms·mm Hg−1) were not different from the baroreflex gain at 0.05 Hz. There was moderate correlation between phenylephrine gain and sit-to-stand gain ( r values ranged from 0.52 to 0.75; all frequencies, p < 0.05), but no correlation between sodium nitroprusside gain and sit-to-stand gain ( r values ranged from -0.07 to 0.22; all p < 0.05). Bland-Altman analysis of phenylephrine gain and sit-to-stand gain showed poor agreement and a positive proportional bias. These results show that baroreflex gains derived from these 2 methods cannot be used interchangeably. Furthermore, cardiac baroreflex gain is frequency dependent between 0.03 Hz and 0.1 Hz, which challenges the conventional practice of summarizing baroreflex gain as a single number. [ABSTRACT FROM AUTHOR]

Mental functions are influenced by states of physiological arousal. Afferent neural activity from arterial baroreceptors at systole conveys the strength and timing of individual heartbeats to the brain. We presented words under limited attentional resources time-locked to different phases of the cardiac cycle, to test a hypothesis that natural baroreceptor stimulation influences detection and subsequent memory of words. We show memory for words presented around systole was decreased relative to words at diastole. The deleterious memory effect of systole was greater for words detected with low confidence and amplified in individuals with low interoceptive sensitivity, as indexed using a heartbeat counting task. Our observations highlight an important cardiovascular channel through which autonomic arousal impacts a cognitive function, an effect mitigated by metacognition (perceptual confidence) and interoceptive sensitivity. [ABSTRACT FROM AUTHOR]

Abstract: Voltage gated ion channels (VGC) make possible the frequency coding of arterial pressure and the neurotransmission of this information along myelinated and unmyelinated fiber pathways. Although many of the same VGC isoforms are expressed in both fiber types, it is the relative expression of each that defines the unique discharge properties of myelinated A-type and unmyelinated C-type baroreceptors. For example, the fast inward Na+ current is a major determinant of the action potential threshold and the regenerative transmembrane current needed to sustain repetitive discharge. In A-type baroreceptors the TTX-sensitive Nav1.7 VGC contributes to the whole cell Na+ current. Nav1.7 is expressed at a lower density in C-type neurons and in conjunction with TTX-insensitive Nav1.8 and Nav1.9 VGC. As a result, action potentials of A-type neurons have firing thresholds that are 15–20mV more negative and upstroke velocities that are 5–10 times faster than unmyelinated C-type neurons. A more depolarized threshold in conjunction with a broader complement of non-inactivating KV VGC subtypes produces C-type action potentials that are 3–4 times longer in duration than A-type neurons and at markedly lower levels of cell excitability. Unmyelinated baroreceptors also express KCa1.1 which provides approximately 25% of the total outward K+ current. KCa1.1 plays a critically important role in shaping the action potential profile of C-type neurons and strongly impacts neuronal excitability. A-type neurons do not functionally express the KCa1.1 channel despite having a whole cell CaV current quite similar to that of C-type neurons. As a result, A-type neurons do not have the frequency-dependent braking forces of KCa1.1. Lack of a KCa current and only a limited complement of non-inactivating KV VGC in addition to a hyperpolarization activated HCN1 current that is nearly 10 times larger than in C-type neurons leads to elevated levels of discharge in A-type neurons, a hallmark of myelinated baroreceptors. Interestingly, HCN2 and HCN4 expression levels are comparable in both fiber types. Collectively, such apportion of VGC constrains the neural coding of myelinated A-type baroreceptors to low threshold, high frequency, high fidelity discharge but with a limited capacity for neuromodulation of afferent bandwidth. Unmyelinated C-type baroreceptors require greater depolarizing forces for spike initiation and have a low frequency discharge profile that is often poorly correlated with the physiological stimulus. But the complement of VGC in C-type neurons provides far greater capacity for neuromodulation of cell excitability than can be obtained from A-type baroreceptors. [Copyright &y& Elsevier]

Abstract: The predominant calcium current in nodose sensory neurons, including the subpopulation of baroreceptor neurons, is the N-type channel, Cav2.2. It is also the primary calcium channel responsible for transmitter release at their presynaptic terminals in the nucleus of the solitary tract in the brainstem. The P/Q channel, Cav2.1, the other major calcium channel responsible for transmitter release at mammalian synapses, represents only 15–20% of total calcium current in the general population of sensory neurons and makes a minor contribution to transmitter release at the presynaptic terminal. In the present study we identified a subpopulation of the largest nodose neurons (capacitance>50pF) in which, surprisingly, Cav2.1 represents over 50% of the total calcium current, differing from the remainder of the population. Consistent with these electrophysiological data, anti-Cav2.1 antibody labeling was more membrane delimited in a subgroup of the large neurons in slices of nodose ganglia. Data reported in other synapses in the central nervous system assign different roles in synaptic information transfer to the P/Q-type versus N-type calcium channels. The study raises the possibility that the P/Q channel which has been associated with high fidelity transmission at other central synapses serves a similar function in this group of large myelinated sensory afferents, including arterial baroreceptors where a high frequency regular discharge pattern signals the pressure pulse. This contrasts to the irregular lower frequency discharge of the unmyelinated fibers that make up the majority of the sensory population and that utilize the N-type channel in synaptic transmission. [Copyright &y& Elsevier]

Control of the renin system by physiological mechanisms such as the baroreceptor or the macula densa (MD) is characterized by asymmetry in that the capacity for renin secretion and expression to increase is much larger than the magnitude of the inhibitory response. The large stimulatory reserve of the renin-angiotensin system may be one of the causes for the remarkable salt-conserving power of the mammalian kidney. Physiological stimulation of renin secretion and expression relies on the activation of regulatory pathways that converge on the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. Mice with selective Gs-alpha (Gsα) deficiency in juxtaglomerular granular cells show a marked reduction of basal renin secretion, and an almost complete unresponsiveness of renin release to furosemide, hydralazine, or isoproterenol. Cyclooxygenase-2 generating prostaglandin E (PGE) and prostacyclin (PGI) in MD and thick ascending limb cells is one of the main effector systems utilizing Gsα-coupled receptors to stimulate the renin-angiotensin system. In addition, β-adrenergic receptors are critical for the expression of high basal levels of renin and for its release response to lowering blood pressure or MD sodium chloride concentration. Nitric oxide generated by nitric oxide synthases in the MD and in endothelial cells enhances cAMP-dependent signaling by stabilizing cAMP through cyclic guanosine monophosphate-dependent inhibition of phosphodiesterase 3. The stimulation of renin secretion by drugs that inhibit angiotensin II formation or action results from the convergent activation of cAMP probably through indirect augmentation of the activity of PGE and PGI receptors, β-adrenergic receptors, and nitric oxide. [ABSTRACT FROM AUTHOR]

Abstract: There is limited but increasing evidence that space environment, namely weightless condition, may affect astronauts'' cerebral neurotransmitters and cognitive performance. The present experiment hypothesized that learning and brain plasticity are affected by simulated microgravity condition. To this aim, 22 male subjects matching astronauts'' characteristics were divided in two groups, Head-Down Bed Rest (HDBR) and Sitting Control. After 3-h bed rest (or sitting condition) subjects started a picture viewing task during which 30 acoustic startle probes (100dBA loudness), divided into three consecutive blocks, were delivered through headphones while startle reflex amplitude was measured from the EMG of the orbicularis oculi muscle. Habituation analysis of the startle reflex showed a normal reflex inhibition across blocks in sitting controls and no habituation in HDBR subjects. Results point to a microgravity-induced lack of startle reflex plasticity in subjects matching astronauts, a learning deficit which may affect the success of long-term space missions. [Copyright &y& Elsevier]

Abstract: Introduction: The high pressure baroreceptor reflex rapidly buffers changes in systemic arterial pressure in response to postural changes, altered gravitational conditions, diseases, and pharmacological agents. Drug-induced exaggeration of changes in heart rate and in systemic arterial pressure is a leading cause of adverse events and of patients terminating use of drugs, particularly in the aging population. This paper presents a facile method for monitoring the high pressure baroreceptor reflex in rats, and presents an alternative to quantifying the magnitude of this reflex using 2 dependent variables, heart rate and systemic arterial pressure, rather than merely change in heart rate. Methods: Twenty-four rats were allocated to 3 groups: group I anesthetized with 100mg/kg thiopental, group II anesthetized with 2% isoflurane given by inhalation, group III anesthetized with thiopental but pretreated for 2weeks with 2μg/kg aldosterone given SQ bid. After induction to anesthesia, hair was clipped from the ventral aspect of the neck, and petrolatum was applied to the skin to permit an air-tight seal with a glass funnel attached to a source of variable and controllable negative pressure. Systemic arterial pressure, ECG, heart rate, and a force of suction applied to the neck were all recorded continuously. Results: After baseline recordings, a force of −20mmHg was applied for 20s over the carotid artery. In rats receiving thiopental, the average changes in heart rate and systemic arterial pressure following the application of −20mmHg neck suction were 30±11bpm and 45±14mmHg, respectively. The ratios of change in heart and change in systemic arterial pressure to application of negative force over the carotid sinus are 1.5±0.6bpm/mmHg and 0.7±04mmHg/mmHg, respectively. Mean values for heart rate and for mean systemic arterial pressure during baseline and after application of neck suction for 20s showed little to no decrease (i.e., blunting) in rats anesthetized with isoflurane or pretreated with aldosterone. Discussion: Thus this methodology was able to detect, in rats, blunting of baroreceptor function for at least 2 perturbations of this important homeostatic control system. [Copyright &y& Elsevier]

Abstract: The present study investigated whether the effects of central cholinergic stimulation on thermoregulation during exercise are modulated by arterial baroreceptors. Wistar rats were submitted to sinoaortic denervation (SAD) or sham denervation (SHAM) and then fitted with a chronic guide cannula into the lateral cerebral ventricle. After 2weeks, a catheter was implanted into the ascending aorta, and a temperature sensor was implanted into the peritoneal cavity. Two days later, the rats were submitted to exercise on a treadmill at 18m/min until fatigued. Thermoregulatory and cardiovascular responses were measured after injection of 2μL of 10mM physostigmine (Phy) or 0.15M NaCl solution (Sal) into the cerebral ventricle. In SHAM rats, Phy injection induced a greater exercise-induced increase in blood pressure and lower increase in heart rate than Sal treatment. In the SAD group, the attenuation of heart rate in response to Phy was blocked despite an exaggerated increase in blood pressure. SHAM rats treated with Phy had a higher increase in tail skin temperature compared to Sal injection (31.9±0.4°C Phy-SHAM vs. 30.1±0.6°C Sal-SHAM, 5min after injection; p <0.05), resulting in a lower exercise-induced increase in core temperature. In contrast, SAD blocked the Phy injection effects in thermoregulatory responses during exercise (tail temperature: 30.1±1.2°C Phy-SAD vs. 29.5±1.2°C Sal-SAD, 5min, p =0.65). Therefore, we conclude that the enhancement of cutaneous heat loss induced by central cholinergic stimulation during exercise is mediated primarily by arterial baroreceptors. [ABSTRACT FROM AUTHOR]

Abstract: Focused attention typically enhances neural nociceptive responses, reflected electroencephalographically as increased amplitude of pain-evoked event-related potentials (ERPs). Additionally, pain-evoked ERPs are attenuated by hypertension and baroreceptor activity, through as yet unclear mechanisms. There is indirect evidence that these two effects may interact, suggesting that baroreceptor-related modulation of nociception is more than a low-level gating phenomenon. To address this hypothesis, we explored in a group of healthy participants the combined effects of cue-induced expectancy and baroreceptor activity on the amplitude of pain-evoked ERPs. Brief nociceptive skin stimuli were delivered during a simple visual task; half were preceded by a visual forewarning cue, and half were unpredictable. Nociceptive stimuli were timed to coincide either with systole (maximum activation of cardiac baroreceptors) or with diastole (minimum baroreceptor activation). We observed a strong interaction between expectancy and cardiac timing for the amplitude of the P2 ERP component; no effects were observed for the N2 component. Cued stimuli were associated with larger P2 amplitude, but this effect was abolished for stimuli presented during baroreceptor activation. No cardiac timing effect was observed for un-cued stimuli. Taken together, these findings suggest a close integration of cognitive–affective aspects of expectancy and baroreceptor influences on pain, and as such may cast further light on mechanisms underlying mental and physiological contributions to clinical pain. [Copyright &y& Elsevier]

Abstract: The neural systems that control breathing and the circulation are located in adjacent longitudinal columns in the ventrolateral medulla. They have much in common, in terms of their structure, function, and evolution. In the most part, both systems are affected by the same sensory modalities and receive input from many of the same higher centres. Indeed, such is the parallel organisation of the two systems that stimuli that alter the behaviour of the one almost invariably influence the other. It is well-known that rhythmic respiratory inputs exert powerful effects on parasympathetic and sympathetic outputs. However, the question of whether cardiovascular inputs exert any influence on respiratory rhythmogenesis is more contentious. Here, we review the effects of baroreceptor activation, classically considered a ‘cardiovascular’ stimulus, on respiratory drive. We show that, although subtle, baroreceptor inputs evoke reproducible prolongation of expiration in a range of preparations. The consequences of this reflex are discussed with regard to cardiorespiratory coordination. [ABSTRACT FROM AUTHOR]

In the XIX century Claude Bernard discovered the action of the nervous system on the peripheral circulation. In the first half of the XX century Ewald Hering discovered the baro-receptor and the reflex control of the heart rate and blood pressure. Cowley and Guyton demonstrated that sino-aortic denervation induces persistent changes in the blood pressure in the dog. The autonomic nervous system is mainly responsible for the regulation of the circulation and blood pressure in the short term on a beat to beat basis. It controls the vasomotor tone, the heart rate and the cardiac output. With the advent of non invasive methods that measure the blood pressure on a beat to beat basis (Finapres) and with the methods of measurement of the variability of the blood pressure in the frequency domain (spectral analysis) we can currently measure many variables including heart rate, blood pressure, stroke volume, peripheral resistances and the baroreceptor sensitivity and make some inferences about their control mechanisms. These variables can be measured at rest in the supine position, standing up, during rhythmic breathing and during the Valsalva maneuver. In this article we present a review of the neural control of the blood pressure and heart rate. [ABSTRACT FROM AUTHOR]