Chemoreflex mediated arrhythmia during apnea at 5,050 m in low- but not high-altitude natives.

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P < 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir -39 ± 18 beats/min; P < 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P < 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir -10 ± 14 beats/min; P < 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P < 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW & NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings.

Potential roles of ATP and local neurons in the monitoring of blood O2 content by rat aortic bodies.

Aortic bodies are arterial chemoreceptors presumed to monitor blood O2 content by unknown mechanisms, in contrast to their well-studied carotid body counterparts, which monitor PO2 and /pH. We recently showed that rat aortic body chemoreceptors (type I cells), located at the left vagus-recurrent laryngeal nerve bifurcation, responded to PO2 and PCO2 /pH in a manner similar to carotid body type I cells. These aortic bodies are uniquely associated with a group of local neurons, which are also sensitive to these stimuli. Here, we hypothesized that these local neurons may contribute to monitoring blood O2 content. During perforated patch recordings, ATP, known to be released from (carotid body) type I cells and red blood cells during hypoxia, induced inward currents and excited ≈ 45% of local neurons (EC50 ≈ 1 µm), mainly via heteromeric P2X2/3 purinoceptors. While ATP also induced a rise in intracellular [Ca(2+)] in a subpopulation of these neurons, almost all of them responded to nicotinic cholinergic agonists. During paired recordings, several juxtaposed neurons showed strong bidirectional electrical coupling, suggesting a local co-ordination of electrical activity. Perfusion with Evans Blue dye resulted in labelling of aortic body paraganglia, suggesting they have ready access to circulatory factors, e.g. ATP released from red blood cells during hypoxia. When combined with confocal immunofluorescence, the dye-labelled regions coincided with areas containing tyrosine hydroxylase-positive type I cell clusters and P2X2-positive nerve endings. We propose a working model whereby local neurons, red blood cells, ATP signalling and low blood flow contribute to the unique ability of the aortic body to monitor blood O2 content.

Favorable effects of carotid endarterectomy on baroreflex sensitivity and cardiovascular neural modulation: a 4-month follow-up.

Carotid surgery variably modifies carotid afferent innervation, thus affecting arterial baroreceptor sensitivity. Low arterial baroreflex sensitivity is a well-known independent risk factor for cardiovascular diseases. The aim of this study was to assess the 4-mo effects of carotid endarterectomy (CEA) on arterial baroreceptor sensitivity and cardiovascular autonomic profile in patients with unilateral carotid stenosis. We enrolled 20 patients (72 ± 8 yr) with unilateral >70% carotid stenosis. ECG, beat-by-beat blood pressure, and respiration were continuously recorded before and 126 ± 9 days after CEA, at rest and during a 75° head-up tilt. Both pharmacological (modified Oxford technique, BRS) and spontaneous (index α, spectral analysis) arterial baroreflex sensitivity were assessed. Cardiovascular autonomic profile was evaluated by plasma catecholamines and spectral indexes of cardiac sympathovagal modulation [low-frequency R-R interval (LFRR), low frequency-to high frequency ratio (LF/HF), high-frequency R-R interval (HFRR)] and sympathetic vasomotor control [low-frequency systolic arterial pressure (LFSAP)] obtained from heart rate and SAP variability. After CEA, both the index α and BRS were higher (P < 0.02) at rest. SAP variance decreased both at rest and during tilt (P < 0.02). Before surgery, tilt did not modify the autonomic profile compared with baseline. After CEA, tilt increased LF/HF and LFSAP and reduced HFRR compared with rest (P < 0.02). Four months after CEA was performed, arterial baroreflex sensitivity was enhanced. Accordingly, the patients' autonomic profile had shifted toward reduced cardiac and vascular sympathetic activation and enhanced cardiac vagal activity. The capability to increase cardiovascular sympathetic activation in response to orthostasis was restored. Baroreceptor sensitivity improvement might play an additional role in the more favorable outcome observed in patients after carotid surgery.

Spontaneous fluctuation indices of the cardiovagal baroreflex accurately measure the baroreflex sensitivity at the operating point during upright tilt.

Spontaneous fluctuation indices of cardiovagal baroreflex have been suggested to be inaccurate measures of baroreflex function during orthostatic stress compared with alternate open-loop methods (e.g. neck pressure/suction, modified Oxford method). We therefore tested the hypothesis that spontaneous fluctuation measurements accurately reflect local baroreflex gain (slope) at the operating point measured by the modified Oxford method, and that apparent differences between these two techniques during orthostasis can be explained by a resetting of the baroreflex function curve. We computed the sigmoidal baroreflex function curves supine and during 70° tilt in 12 young, healthy individuals. With the use of the modified Oxford method, slopes (gains) of supine and upright curves were computed at their maxima (Gmax) and operating points. These were compared with measurements of spontaneous indices in both positions. Supine spontaneous analyses of operating point slope were similar to calculated Gmax of the modified Oxford curve. In contrast, upright operating point was distant from the centering point of the reset curve and fell on the nonlinear portion of the curve. Whereas spontaneous fluctuation measurements were commensurate with the calculated slope of the upright modified Oxford curve at the operating point, they were significantly lower than Gmax. In conclusion, spontaneous measurements of cardiovagal baroreflex function accurately estimate the slope near operating points in both supine and upright position.

[Assessment of chemoreflex involved in reflex cardio-respiratory control]. / Metody oceny wrailiwosci chemoreceptorów uczestniczacych w odruchowej regulacji ukladu krazenia i oddychania.

Impaired chemosensitivity is an important element of the pathogenesis and the course of various cardiovascular diseases. Our paper presents the assessment of the sensitivity of the central (located on the ventrolateral medullary surface, sensitive to hypercapnea and acidosis) and peripheral (located in the carotid and aortic bodies, sensitive to hypoxia) chemoreceptors, pointing out a physiological and clinical aspects of their application.

The effect of pro-inflammatory cytokines on the discharge rate of vagal nerve paraganglia in the rat.

Vagal paraganglia resemble the carotid body and are chemosensitive to reduction in the partial pressure of oxygen (P O2) (O'Leary et al., 2004). We hypothesised that they may also mediate communication between the immune system and the central nervous system and more specifically respond to the pro-inflammatory cytokines: interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). We recorded axonal firing rate of isolated superfused rat glomus cells - located at the bifurcation of the superior laryngeal nerve - to IL-1 beta or TNF-alpha at concentrations of 0.5 ng/ml, 5 ng/ml and 50 ng/ml. Twenty-three successful single fibre recordings were obtained from 10 animals. IL-1 beta and TNF-alpha had no statistically significant effect on the frequency of action potentials observed (p=0.39 and 0.42, respectively, repeated measures ANOVA). The activity of both cytokines was tested by observing translocation of P65-NF kappaB from cytoplasm to nucleus in cultured HELA cells. In conclusion, an immune role for SLN paraganglia has not been established.

Screening for ventriculo-aortic functional disturbances in patients with apparently successful repaired coarctation of aorta.

Patients with apparently successful repair for coarctation of aorta have reduced life expectancy irrespective of the occurrence of recoarctation, biscupid aortic valvular complications or systemic hypertension. The increasingly recognized ventriculo-aortic functional disturbances (subendocardial ischemia and central aortic stiffness) that persist after operation may contribute to the known significant cardiovascular mortality and morbidity. Echocardiography and cardiac magnetic resonance imaging allow earlier identification of these high-risk features in patients may thus guide towards optimum therapy.

Interactions of carotid sinus or aortic input with emetic signals from gastric afferents and vestibular system.

This study investigated how baro- and chemoreceptor afferents interact with emetic signals from gastric afferents and the vestibular system, and how these interactions modulate emetic and prodromal responses. We performed splanchnic denervation and abdominal vagotomy in anesthetized shrews (Suncus murinus), and then induced emetic responses by gastric distension. Next, we investigated the effects of these gastric afferent sections on cardiovascular and emetic responses induced by electrical stimulation of the aortic depressor nerve (ADN) and the carotid sinus nerve (CSN) with or without gastric distension. Splanchnic denervation abolished the prodromal response before retching and aortic baroreflex inhibition caused by gastric distension, but had no effects on the emetic response. In contrast, abdominal vagotomy abolished the emetic response induced by gastric distension with or without CSN stimulation, but without affecting gastric distension-induced or CSN stimulation-induced vascular and respiratory responses. In conscious animals, CSN denervation significantly suppressed veratrine- and motion-induced emetic responses, whereas ADN denervation had no significant effects. These results suggest that aortic baroreflex inhibition via the activation of splanchnic afferents contributes to the prodromal response before retching and circulatory homeostasis. In contrast, carotid sinus inputs, which are usually non-emetic signals, interact with vagal and vestibular inputs, and modulate the development of retching and vomiting.

Similar cardiac vagal withdrawal at the onset of arm and leg dynamic exercise.

Electrocardiogram RR intervals duration reduce rapidly in the first seconds of dynamic exercise mainly due to a cardiac vagal withdrawal. However, it remains unclear if this response varies between exercises performed with different body segments (i.e. arm vs. leg). Our aim was to compare the vagal withdrawal at the onset of arm and leg dynamic exercise. Cardiac vagal withdrawal was assessed by the 4-s exercise test (4sET), a pharmacologically validated and highly reliable procedure. Initially, 60 healthy subjects performed the 4sET using arms (ARM 4sET) and legs (LEG 4sET), in a random order. Later, 20 of them repeated the testing, controlling for cycling rate and time of exercise onset within a RR interval, potential intervenient variables. Similar results were found for ARM and LEG 4sET considering the RR interval duration obtained immediately before the onset of exercise (RRB) (mean +/- SEM; 852 +/- 23 vs. 857 +/- 23 ms; P = 0.55), the shortest RR interval duration during exercise (RRC) (570 +/- 10 vs. 563 +/- 10 ms; P = 0.22) and the cardiac vagal index (CVI), which is the ratio between RRB and RRC (1.49 +/- 0.03 vs. 1.52 +/- 0.03; P = 0.10). Furthermore, high intraclass correlation coefficients were found (RRB r (i) = 0.94, P < 0.001; RRC r (i) = 0.85, P < 0.001; CVI r (i) = 0.81, P < 0.001). We conclude that similar cardiac vagal withdrawal was induced by 4-s fast unloaded cycling exercise performed with arms or legs.

Brain-derived neurotrophic factor-immunoreactive neurons in the rat vagal and glossopharyngeal sensory ganglia; co-expression with other neurochemical substances.

Immunohistochemistry for brain-derived neurotrophic factor (BDNF) was performed on the rat vagal and glossopharyngeal sensory ganglia. In the jugular, petrosal and nodose ganglia, 56.1+/-5.5%, 52.4+/-9.4% and 80.0+/-3.0% of sensory neurons, respectively, were immunoreactive for BDNF. These neurons were small- to medium-sized and observed throughout the ganglia. In the solitary tract nucleus, the neuropil showed BDNF immunoreactivity. A double immunofluorescence method demonstrated that BDNF-immunoreactive neurons were also immunoreactive for calcitonin gene-related peptide (CGRP), P2X3 receptor, the capsaicin receptor (VR1) or vanilloid receptor 1-like receptor (VRL-1) in the jugular (CGRP, 43.5%; P2X3 receptor, 51.1%; VR1, 71.7%; VRL-1, 0.5%), petrosal (CGRP, 33.2%; P2X3 receptor, 58.4%; VR1, 54.2%; VRL-1, 23.3%) and nodose ganglia (CGRP, 1.8%; P2X3 receptor, 49.1%; VR1, 70.7%; VRL-1, 11.5%). The co-expression with tyrosine hydroxylase was also detected in the petrosal (2.9%) and nodose ganglia (2.2%). However, BDNF-immunoreactive neurons were devoid of parvalbumin in these ganglia. The present findings suggest that BDNF-containing vagal and glossopharyngeal sensory neurons have nociceptive and chemoreceptive functions.

Does respiratory sinus arrhythmia occur in fishes?

The hypothesis that respiratory modulation of heart rate variability (HRV) or respiratory sinus arrhythmia (RSA) is restricted to mammals was tested on four Antarctic and four sub-Antarctic species of fish, that shared close genotypic or ecotypic similarities but, due to their different environmental temperatures, faced vastly different selection pressures related to oxygen supply. The intrinsic heart rate (fH) for all the fish species studied was approximately 25% greater than respiration rate (fV), but vagal activity successively delayed heart beats, producing a resting fH that was synchronized with fV in a progressive manner. Power spectral statistics showed that these episodes of relative bradycardia occurred in a cyclical manner every 2-4 heart beats in temperate species but at >4 heart beats in Antarctic species, indicating a more relaxed selection pressure for cardio-respiratory coupling. This evidence that vagally mediated control of fH operates around the ventilatory cycle in fish demonstrates that influences similar to those controlling RSA in mammals operate in non-mammalian vertebrates.

Electrical stimulation of the rabbit pulmonary artery increases respiratory output.

This study was conducted to test the hypothesis that the pulmonary artery is involved in neural respiratory control and to identify the involved topographical region, if any. Six adult rabbits were anesthetized, artificially ventilated, and the chest was opened. The outer surface of the extra-pulmonary portion of the pulmonary artery was electrically stimulated by monitoring phrenic nerve activity. Phrenic nerve activity increased in three of the six rabbits when the proximal dorsal surface of the pulmonary trunk was stimulated. This positive response was abolished after bilateral vagotomy. In histological examinations we found densely grouped cells, i.e. pulmonary glomic tissue, with a fine nerve bundle in the tissue adjacent to the dorsal surface of the pulmonary trunk where electrical stimulation elicited respiratory augmentation. We suggest that there is a neural substrate which is involved in respiratory control inside the wall of or in the region adjacent to the proximal dorsal surface of the pulmonary trunk. Further studies to anatomically identify the neural substrate and clarify its physiological role in respiratory control are necessary.

The role of 5-hydroxytryptamine3 receptors in the vagal afferent activation-induced inhibition of the first cervical dorsal horn spinal neurons projected from tooth pulp in the rat.

To test the hypothesis that vagal afferent (VA) stimulation modulates the first cervical dorsal horn (C(1)) neuron activity, which is projected by tooth pulp (TP) afferent inputs through the activation of a local GABAergic mechanism via 5-hydroxytryptamine(3) (5-HT(3)) receptors, we used the technique of microiontophoretic application of drugs. In pentobarbital-anesthetized rats, we recorded C(1) spinal neuron activity responding to TP stimulation. The TP stimulation-evoked C(1) spinal neuron excitation was inhibited by VA stimulation, and this inhibition was significantly attenuated by iontophoretic application of the 5-HT(3) receptor antagonist ICS 205-930 (3-tropanyl-indole-3-carboxylate hydrochloride [endo-8-methyl-8-azabicyclo [3.2.1] oct-3-ol indol-3-yl-carboxylate hydrochloride]) (40 nA) or the GABA(A) receptor antagonist bicuculline (40 nA). In another series of experiments, we determined that 60 nA iontophoretic application of glutamate produced a maximal increase in the C(1) spinal neuron activity at a minimal current. In 53 of 65 neurons (81.5%), VA conditioning stimulation (1.0 mA x 0.1 ms, 50 Hz for 30 s) caused a significant inhibition (35.1%) of the glutamate (60 nA) application-evoked C(1) spinal neuron excitation. Iontophoretic application of ICS 205-930 (40 nA) or bicuculline (40 nA) significantly attenuated the VA stimulation-induced inhibition of glutamate iontophoretic application (60 nA)-evoked C(1) spinal neuron excitation. These results suggest that VA stimulation-induced suppression of C(1) spinal neuron activity, responding to TP stimulation, involve 5-HT(3) receptor activation, possibly originating in the descending serotonergic inhibitory system, and postsynaptic modulation of inhibitory GABAergic neurons.

Attenuated outward potassium currents in carotid body glomus cells of heart failure rabbit: involvement of nitric oxide.

It has been shown that peripheral chemoreceptor sensitivity is enhanced in both clinical and experimental heart failure (HF) and that impairment of nitric oxide (NO) production contributes to this enhancement. In order to understand the cellular mechanisms associated with the alterations of chemoreceptor function and the actions of NO in the carotid body (CB), we compared the outward K+ currents (IK) of glomus cells in sham rabbits with that in HF rabbits and monitored the effects of NO on these currents. Ik was measured in glomus cells using conventional and perforated whole-cell configurations. IK was attenuated in glomus cells of HF rabbits, and their resting membrane potentials (-34.7 +/- 1.0 mV) were depolarized as compared with those in sham rabbits (-47.2 +/- 1.9 mV). The selective Ca(2+)-dependent K+ channel (KCa) blocker iberiotoxin (IbTx, 100 nm) reduced IK in glomus cells from sham rabbits, but had no effect on IK from HF rabbits. In perforated whole-cell mode, the NO donor SNAP (100 microm) increased IK in glomus cells from HF rabbits to a greater extent than that in sham rabbits (P < 0.01), and IbTx inhibited the effects of SNAP. However, in conventional whole-cell mode, SNAP had no effect. N omega-nitro-L-arginine (L-NNA, NO synthase inhibitor) decreased Ik in sham rabbits but not in HF rabbits. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) inhibited the effect of SNAP on Ik. These results demonstrate that IK is reduced in CB glomus cells from HF rabbits. This effect is due mainly to the suppression of KCa channel activity caused by decreased availability of NO. In addition, intracellular cGMP is necessary for the KCa channel modulation by NO.

Differential increases in P2X receptor levels in rat vagal efferent neurones following a vagal nerve section.

Extracellular ATP can influence cells via activation of P2X purinoceptors, the distribution of which can be altered in the central and peripheral nervous systems following injury or tissue damage. Here we have investigated the effect of a unilateral section of the cervical vagus nerve on the distribution of P2X(1), P2X(2), P2X(3), P2X(4) and P2X(7) receptor subunit immunoreactivity (R-IR) in the dorsal vagal motor nucleus (DVN) and the nucleus ambiguus (NA) in the medulla oblongata. As early as 2 days, and followed up to 14 days, there was a dramatic ipsilateral increase in P2X(1), P2X(2) and P2X(4)R-IR in the cell soma of vagal efferent neurones in the DVN following the nerve section, but not the NA. There were no changes in P2X(3) and P2X(7)R-IR in either nuclei. To test for possible functional consequences of increased P2X receptor levels, whole-cell patch-clamp recordings were made from DVN cells in brainstem slices 4 days following unilateral vagotomy. Application of ATP revealed large cell-to-cell variance in the current amplitude in neurones from both sectioned and control DVN. However, when ATP responses were compared to those elicited by the nicotinic acetylcholine receptor agonist carbachol, the mean ratio of the peak ATP-evoked current to the peak carbachol-evoked current was significantly larger in DVN neurones ipsilateral to the section. Thus the increase in P2XR levels in DVN cells ipsilateral to a nerve section are likely to reflect an increase in expression of functional P2XRs on the cell surface.

A role for TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve terminals.

Using single-unit extracellular recording techniques, we have examined the role of the vanilloid receptor-1 (VR1 aka TRPV1) in bradykinin-induced activation of vagal afferent C-fiber receptive fields in guinea pig isolated airways. Of 17 airway C-fibers tested, 14 responded to bradykinin and capsaicin, 2 fibers responded to neither capsaicin nor bradykinin, and 1 fiber responded to capsaicin but not bradykinin. Thus, every bradykinin-responsive C-fiber was also responsive to capsaicin. Bradykinin (200 microl of 0.3 microM solution) evoked a burst of approximately 130 action potentials in C-fibers. In the presence of the TRPV1 antagonist capsazepine (10 microM), bradykinin evoked 83 +/- 9% (n = 6; P < 0.01) fewer action potentials. Similarly, the TRPV1 blocker, ruthenium red (10 microM), inhibited the number of bradykinin-evoked action potentials by 75 +/- 10% (n = 4; P < 0.05). In the presence of 5,8,11,14-eicosatetraynoic acid (10 microM), an inhibitor of lipoxygenase and cyclooxygenase enzymes, the number of bradykinin-induced action potentials was reduced by 76 +/- 10% (n = 6; P < 0.05). Similarly, a combination of the 12-lipoxygenase inhibitor, baicalein (10 microM) and the 5-lipoxygenase inhibitor ZD2138 [6-[3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone] (10 microM) caused significant inhibition of bradykinin-induced responses. Our data suggest a role for lipoxygenase products in bradykinin B(2) receptor-induced activation of TRPV1 in the peripheral terminals of afferent C-fibers within guinea pig trachea.