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New Findings: Cardio‐ventilatory coupling refers to the onset of inspiration occurring at a preferential latency following the last heartbeat (HB) in expiration. According to the cardiac‐trigger hypothesis, the pulse pressure initiates an inspiration via baroreceptor activation. However, the central neural substrate mediating this coupling remains undefined. Using a combination of animal data, human data and mathematical modelling, this study tests the hypothesis that the HB, by way of pulsatile baroreflex activation, controls the initiation of inspiration that occurs through a rapid neural activation loop from the carotid baroreceptors to Bötzinger complex expiratory neurons. Cardio‐ventilatory coupling refers to a heartbeat (HB) occurring at a preferred latency prior to the next breath. We hypothesized that the pressure pulse generated by a HB activates baroreceptors that modulate brainstem expiratory neuronal activity and delay the initiation of inspiration. In supine male subjects, we recorded ventilation, electrocardiogram and blood pressure during 20‐min epochs of baseline, slow–deep breathing and recovery. In in situ rodent preparations, we recorded brainstem activity in response to pulses of perfusion pressure. We applied a well‐established respiratory network model to interpret these data. In humans, the latency between a HB and onset of inspiration was consistent across different breathing patterns. In in situ preparations, a transient pressure pulse during expiration activated a subpopulation of expiratory neurons normally active during post‐inspiration, thus delaying the next inspiration. In the model, baroreceptor input to post‐inspiratory neurons accounted for the effect. These studies are consistent with baroreflex activation modulating respiration through a pauci‐synaptic circuit from baroreceptors to onset of inspiration. [ABSTRACT FROM AUTHOR]

Abstract: The carotid bodies (CBs) are multi‐modal sensory organs located bilaterally at the bifurcation of the carotid artery and innervated by the carotid sinus nerve (Hering's nerve), a branch of the IX cranial nerve. While the CBs (or embryologically analogous structures) are well known as the dominant oxygen‐sensing organ in vertebrates, in mammals there is evidence that the CBs may also sense glucose and temperature, and respond to circulating hormones and other factors. Additionally, the CBs likely participate in regulating baseline levels of sympathetic tone. In this brief review, we focus on the evolution of our efforts to understand ‘what else’ beyond oxygen sensing the CBs do in humans. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? Hyperoxia blunts hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in carotid body-resected patients; and (ii) carotid body-resected patients would exhibit an impaired counterregulatory response to hypoglycaemia., What is the main finding and its importance? Our data indicate that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, a relatively normal counterregulatory response to hypoglycaemia in carotid body-resected patients highlights: (i) the potential for long-term adaptations after carotid body resection; and (ii) the importance of redundant mechanisms in mediating hypoglycaemia counterregulation., Hyperoxia reduces hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in patients with bilateral carotid body resection; and (ii) carotid body-resected patients would exhibit an impaired counterregulatory response to hypoglycaemia. Five patients (three male and two female) with bilateral carotid body resection for glomus tumours underwent two 180 min hyperinsulinaemic, hypoglycaemic (∼3.3 mmol l−1) clamps separated by a minimum of 1 week and randomized to either normoxia (21% fractional inspired O2) or hyperoxia (100% fractional inspired O2). Ten healthy adults (seven male and three female) served as control subjects. Hypoglycaemia counterregulation in carotid body-resected patients was not significantly altered by hyperoxia (area under the curve expressed as a percentage of the normoxic response: glucose infusion rate, 111 ± 10%; cortisol, 94 ± 6%; glucagon, 107 ± 7%; growth hormone, 92 ± 10%; adrenaline, 89 ± 26%; noradrenaline, 79 ± 15%; main effect of condition, P > 0.05). This is in contrast to previously published results from healthy adults. However, the counterregulatory responses to hypoglycaemia during normoxia were not impaired in carotid body-resected patients when compared with control subjects (main effect of group, P > 0.05). Our data provide further corroborative evidence that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, relatively normal counterregulatory responses to hypoglycaemia in carotid body-resected patients highlight the importance of redundant mechanisms in mediating hypoglycaemia counterregulation. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor-mediated responses in humans. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia)., What is the main finding and its importance? We show that hypoglycaemia-mediated changes in heart rate variability and baroreflex sensitivity cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range during hypoglycaemia. These results provide a potential mechanism for impaired glycaemic control and increased risk of cardiac arrhythmias in patients with carotid chemoreceptor overactivity (i.e. sleep apnoea)., Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor-mediated responses. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia) by testing the following hypotheses: (i) activation of the carotid body chemoreceptors with hypoglycaemia would reduce spontaneous cardiac baroreflex sensitivity (sCBRS) in healthy humans; and (ii) desensitization of the carotid chemoreceptors with hyperoxia would restore sCBRS to baseline levels during hypoglycaemia. Ten young healthy adults completed two 180 min hyperinsulinaemic [2 mU (kg fat-free mass)−1 min−1], hypoglycaemic (∼3.2 μmol ml−1) clamps, separated by at least 1 week and randomized to normoxia (arterial partial pressure of O2, 122 ± 10 mmHg) or hyperoxia (arterial partial pressure of O2, 424 ± 123 mmHg; to blunt activation of the carotid body glomus cells). Changes in heart rate, blood pressure, plasma catecholamines, heart rate variability (HRV) and sCBRS were assessed. During hypoglycaemia, HRV and sCBRS were reduced ( P < 0.05) and the baroreflex working range was shifted to higher heart rates. When hyperoxia was superimposed on hypoglycaemia, there was a greater reduction in blood pressure and a blunted rise in heart rate when compared with normoxic conditions ( P < 0.05); however, there was no detectable effect of hyperoxia on sCBRS or HRV during hypoglycaemia ( P > 0.05). In summary, hypoglycaemia-mediated changes in HRV and sCBRS cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors appear to play a role in resetting the baroreflex working range during hypoglycaemia. [ABSTRACT FROM AUTHOR]

Chemoreceptors in the carotid bodies sense arterial oxygen tension and regulate respiration. Isolated carotid body glomus cells also sense glucose, and animal studies have shown the carotid bodies play a role in the counterregulatory response to hypoglycaemia. Thus, we hypothesized that glucose infusion rate would be augmented and neuro-hormonal counterregulation blunted during hypoglycaemia when the carotid bodies were desensitized by hyperoxia. Seven healthy adults (four male, three female) underwent two 180 min hyperinsulinaemic (2 mU (kg fat-free mass (FFM)) min), hypoglycaemic (3.33 mmol l) clamps 1 week apart, randomized to either normoxia (arterial () 111 ± 6.3 mmHg) or hyperoxia ( 345 ± 80.6 mmHg) ( P < 0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline (5.52 ± 0.15 vs. 5.55 ± 0.13 μmol ml) and during the clamp (3.4 ± 0.05 vs. 3.3 ± 0.05 μmol ml). The glucose infusion rate was 44.2 ± 3.5% higher ( P < 0.01) during hyperoxia than normoxia at steady state during the clamp (28.2 ± 0.15 vs. 42.7 ± 0.65 μmol (kg FFM) min; P < 0.01). Area under the curve values (expressed as percentage normoxia response) for counterregulatory hormones during hypoglycaemia were significantly suppressed by hyperoxia (noradrenaline 50.7 ± 5.2%, adrenaline 62.6 ± 3.3%, cortisol 63.2 ± 2.1%, growth hormone 53.1 ± 2.7%, glucagon 48.6 ± 2.1%, all P < 0.05 vs. normoxia). These data support the idea that the carotid bodies respond to glucose and play a role in the counterregulatory response to hypoglycaemia in humans. Chemoreceptors in the carotid bodies sense arterial oxygen tension and regulate respiration. Isolated carotid body glomus cells also sense low glucose. Animal studies have shown that the carotid bodies play a role in the counterregulatory response to hypoglycaemia. Using hyperoxia to desensitize the carotid bodies, we tested the role of the carotid bodies in hypoglycaemic counterregulation in humans. The glucose infusion rate during hypoglycaemic clamp was significantly augmented with hyperoxia versus normoxia. Counterregulatory hormones (noradrenaline, adrenaline, cortisol, growth hormone and glucagon) were significantly suppressed during hypoglycaemia with hyperoxia. These data support the idea that the carotid bodies respond to low glucose and support a novel role in mediating the counterregulatory response to hypoglycaemia in humans. Altered carotid body sensing/control of blood glucose might also have implications for clinical conditions associated with altered regulation of blood glucose including sleep apnoea, Type II diabetes and also hypoglycaemia unawareness in Type I diabetes. [ABSTRACT FROM AUTHOR]

The cardiac neuronal norepinephrine transporter (NET) is responsible for uptake of NE from the neuroeffector junction. There is ample evidence of reduced function of NET in hypertension, heart failure, and orthostatic intolerance. Studies on the localization of cardiac NET are limited, and suggest that NET is found in sympathetic fibers and intrinsic cardiac adrenergic cells. We hypothesized that NET would also be present in sensory terminals that innervate the heart. Histology and RT-PCR were used. Fixed atria and mesenteric vessels from normal, adult rats were stained for tyrosine hyrdoxylase (TH) and NET to confirm localization of NET to cardiac sympathetic nerve fibers (n=1). NET and TH were colocalized in the majority of fibers. However, there are NET-positive fibers that were TH-negative and presumably nonsympathetic. In these nerve fibers NET colocalized with calcitonin gene related peptide (CGRP), a marker of sensory neurons (n=2). The pattern of NET staining was the same in mesenteric blood vessels (n=1), suggesting that NET and CGRP colocalization is not unique to the heart. Dorsal root ganglion cell bodies, which receive sensory afferents from heart and mesentery, are positive for NET protein and express NET mRNA (n=4). In conclusion, sensory neurons are a source of NET in the heart that should be considered when assessing dysfunction of cardiac NET in disease. This is the first report of NET mRNA and protein in cardiac sensory nerves. [ABSTRACT FROM AUTHOR]

6-hydroxydopamine (6-OHDA) is used to "chemically denervate" tissues innervated by nerves containing catecholamine transporters. Treatment reduces the norepinephrine (NE) content of the heart but little is known about other markers of sympathetic nerves. The purpose of this study was to examine the effects of 6-OHDA on cardiac sympathetic neurons innervating the right atrium. 6-OHDA (250 mg/kg, sub.q, 3 doses over 7 days) was administered to adult rats and on day 7 hearts were removed. There was a significant decrease in NE levels determined by capillary electrophoresis with electrochemical detection (p<0.001, n=3) confirming that the treatment was effective. However, immunocytochemical staining showed tyrosine hydroxylase was still visible in neurons after denervation (n=3). Western blotting revealed no differences in protein expression for either the neuronal marker Protein Gene Product 9.5 (p>0.05, n=4) or for three molecular weight variants of NE transporter (NET) (80, 54, and 46 kD) in the right atria (p>0.05. n=3-4). In addition, qPCR showed no change in the levels of mRNA for NET compared to untreated controls (p>0.05, n=6). Similar results were seen in all other heart chambers. Therefore, 6-OHDA does not destroy cardiac sympathetic nerve fibers; its action appears limited to the depletion of NE. [ABSTRACT FROM AUTHOR]

Cardiac sympathetic innervation originates in the stellate ganglia. Norepinephrine (NE) reuptake via NE transporter (NET), and release of NE from sympathetic nerve terminals are regulated by the endothelin-I (ET1) receptors, ETA and ETB, respectively. Regulation of NET by ET1 in the stellate ganglia is unknown. ETB receptor deficient rats (ETB -/-) lack functional ETB receptors in all tissues except those expressing dopamine beta hyrdoxylase (DBH). Since functional ETB expression is coupled to DBH promoter (DBH-ETB) in this model, it is possible that sympathetic neurons overexpress ETB. The purpose of this study was to examine ETB and NET in the stellate ganglia of ETB -/- rats using histology and PCR. Histology revealed that there was a significant elevation of ETB receptor protein in both the nuclear (n=4, p<0.0001) and cytoplasmic compartments (n=4, p<0.0001) in bilateral stellate ganglia from ETB -/- rats. In all stellate ganglion neurons from ETB -/- rats, NET protein was significantly increased (n=3, p<0.05), while NET mRNA was unchanged (n=3-6, p>0.05), suggesting that ET1 modulation of NET is post-transcriptional. In summary, the ETB -/- rat overexpresses ETB and NET protein in the stellate ganglia revealing an important feature of this animal model that is otherwise devoid of functional ETB receptors. This supports the notion that altered ET1 signaling can regulate NET in ganglia. [ABSTRACT FROM AUTHOR]

Reduced norepinephrine (NE) reuptake and NE transporter (NET) in the heart are associated with hypertension. Sympathetic neurons in the stellate ganglia innervate the heart and direct nearly all cardiac sympathetic activity. The purpose of this study was to compare the regulation of NET in bilateral stellate ganglia of normotensive and hypertensive rats (DOCA-salt). Total RNA was isolated from ganglia and RT-qPCR was performed to analyze NET mRNA levels. NET mRNA levels were 4.48 fold higher in hypertensive left stellate than in normotensive left stellate (p=.13, n=6-7). NET mRNA in the right stellate was unchanged with hypertension (p>.05, n=7-10). Additional ganglia were fixed and sectioned for immunohistochemistry with a NET antibody against a cytoplasmic loop of the protein. All neurons in both ganglia were immunoreative for NET. Staining for NET in left stellate neurons from hypertensive animals was significantly more intense than normotensive (p<0.05, n=4). NET staining intensity in right stellate neurons was not different in hypertension (p>0.05, n=4). Increased NET mRNA and protein levels in the left stellate ganglia may serve as a compensatory mechanism when NET function is reduced in the heart during hypertension. This study indicates separate regulatory control of NET between right and left stellate, and also between nerve cell bodies and terminals. [ABSTRACT FROM AUTHOR]