Carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension.

KEY POINTS: Dysfunction of post-exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases. The afferent mechanisms that regulate the post-exercise cardiac autonomic control remain unclear. We found that afferent signals from carotid chemoreceptors restrain the post-exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH). Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults. The results demonstrate that the carotid chemoreceptors contribute to the regulation of post-exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post-exercise cardiac autonomic dysfunction in patients with PAH. ABSTRACT: Dysfunction of post-exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post-exercise cardiac autonomic control. Twenty non-hypoxaemic patients with PAH and 13 age- and sex-matched HA pedalled until 90% of peak work rate observed in a symptom-limited ramp-incremental exercise test. Recovery consisted of unloaded pedalling for 5 min followed by seated rest for 6 min. During recovery, subjects randomly inhaled either 100% O2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O2 (normoxia) as control. Post-exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300 s of recovery, using linear and non-linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post-exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120 s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH.

Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant pathophysiological disturbance in OSA-intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field.

Catecholaminergic neurons in the comissural region of the nucleus of the solitary tract modulate hyperosmolality-induced responses.

Noradrenergic A2 neurons of the nucleus of the solitary tract (NTS) have been suggested to contribute to body fluid homeostasis and cardiovascular regulation. In the present study, we investigated the effects of lesions of A2 neurons of the commissural NTS (cNTS) on the c-Fos expression in neurons of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, arterial pressure, water intake, and urinary excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats (280-320 g) received an injection of anti-dopamine-ß-hydroxylase-saporin (12.6 ng/60 nl; cNTS/A2-lesion, n = 28) or immunoglobulin G (IgG)-saporin (12.6 ng/60 nl; sham, n = 24) into the cNTS. The cNTS/A2 lesions increased the number of neurons expressing c-Fos in the magnocellular PVN in rats treated with hypertonic NaCl (90 ± 13, vs. sham: 47 ± 20; n = 4), without changing the number of neurons expressing c-Fos in the parvocellular PVN or in the SON. Contrary to sham rats, intragastric 2 M NaCl also increased arterial pressure in cNTS/A2-lesioned rats (16 ± 3, vs. sham: 2 ± 2 mmHg 60 min after the intragastric load; n = 9), an effect blocked by the pretreatment with the vasopressin antagonist Manning compound (0 ± 3 mmHg; n = 10). In addition, cNTS/A2 lesions enhanced hyperosmolality-induced water intake (10.5 ± 1.4, vs. sham: 7.7 ± 0.8 ml/60 min; n = 8-10), without changing renal responses to hyperosmolality. The results suggest that inhibitory mechanisms dependent on cNTS/A2 neurons reduce water intake and vasopressin-dependent pressor response to an acute increase in plasma osmolality.

Involvement of sinoaortic afferents in renal sympathoinhibition and vasodilation induced by acute hypernatremia.

Despite the abundance of evidence that supports the important role of aortic and carotid afferents to short-term regulation of blood pressure and detection of variation in the arterial PO2 , PCO2 and pH, relatively little is known regarding the role of these afferents during changes in the volume and composition of extracellular compartments. The present study sought to determine the involvement of these afferents in the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Sinoaortic-denervated and sham male Wistar rats were anaesthetised with intravenous (i.v.) urethane (1.2 g/kg body weight (bw)) prior to the measurement of the mean arterial pressure (MAP), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA). In the sham group, the HS infusion (3 mol/L NaCl, 1.8 mL/kg bw, i.v.) induced transient hypertension (12 ± 4 mmHg from baseline, peak at 10 min; P < 0.05), an increase in RVC (127 ± 9% and 150 ± 13% from baseline, at 20 and 60 min respectively; P < 0.05) and a decrease in RSNA (-34 ± 10% and -29 ± 5% from baseline, at 10 and 60 min respectively; P < 0.05). In sinoaortic-denervated rats, HS infusion promoted a sustained pressor response (30 ± 5 and 17 ± 6 mmHg of baseline values, at 10 and 30 min respectively; P < 0.05) and abolished the increase in RVC (85 ± 8% from baseline, at 10 min) and decrease in RSNA (-4 ± 3% from baseline, at 10 min). These results suggest that aortic and carotid afferents are involved in cardiovascular and renal sympathoinhibition responses induced by acute hypernatremia.

Discharge of RVLM vasomotor neurons is not increased in anesthetized angiotensin II-salt hypertensive rats.

Neurons of the rostral ventrolateral medulla (RVLM) are critical for generating and regulating sympathetic nerve activity (SNA). Systemic administration of ANG II combined with a high-salt diet induces hypertension that is postulated to involve elevated SNA. However, a functional role for RVLM vasomotor neurons in ANG II-salt hypertension has not been established. Here we tested the hypothesis that RVLM vasomotor neurons have exaggerated resting discharge in rats with ANG II-salt hypertension. Rats in the hypertensive (HT) group consumed a high-salt (2% NaCl) diet and received an infusion of ANG II (150 ng·kg(-1)·min(-1) sc) for 14 days. Rats in the normotensive (NT) group consumed a normal salt (0.4% NaCl) diet and were infused with normal saline. Telemetric recordings in conscious rats revealed that mean arterial pressure (MAP) was significantly increased in HT compared with NT rats (P < 0.001). Under anesthesia (urethane/chloralose), MAP remained elevated in HT compared with NT rats (P < 0.01). Extracellular single unit recordings in HT (n = 28) and NT (n = 22) rats revealed that barosensitive RVLM neurons in both groups (HT, 23 cells; NT, 34 cells) had similar cardiac rhythmicity and resting discharge. However, a greater (P < 0.01) increase of MAP was needed to silence discharge of neurons in HT (17 cells, 44 ± 5 mmHg) than in NT (28 cells, 29 ± 3 mmHg) rats. Maximum firing rates during arterial baroreceptor unloading were similar across groups. We conclude that heightened resting discharge of sympathoexcitatory RVLM neurons is not required for maintenance of neurogenic ANG II-salt hypertension.

Noxious somatic stimuli diminish respiratory-sympathetic coupling by selective resetting of the respiratory rhythm in anaesthetized rats.

Noxious somatic stimulation evokes respiratory and autonomic responses. The mechanisms underlying the responses and the manner in which they are co-ordinated are still unclear. The effects of activation of somatic nociceptive fibres on lumbar sympathetic nerve activity at slow (2-10 Hz) and fast frequency bands (100-1000 Hz) and the effects on respiratory-sympathetic coupling are unknown. In anaesthetized, artificially ventilated Sprague-Dawley rats under neuromuscular blockade, ensemble averaging of sympathetic activity following high-intensity single-pulse stimulation of the sciatic nerve revealed two peaks (~140 and ~250 ms) that were present at similar latencies whether or not slow or fast band filtering was used. Additionally, in the slow band of both lumbar and splanchnic sympathetic nerve activity, a third peak with a very slow latency (~650 ms) was apparent. In the respiratory system, activation of the sciatic nerve decreased the expiratory period when the stimulus occurred during the first half of expiration, but increased the expiratory period if the stimulus was delivered in the second half of the expiratory phase. The phase shifting of the respiratory cycle also impaired the respiratory-sympathetic coupling in both splanchnic and lumbar sympathetic nerve activity in the subsequent respiratory cycle. The findings suggest that noxious somatosympathetic responses reduce the co-ordination between respiration and perfusion by resetting the respiratory pattern generator.

Interaction of medullary P2 and glutamate receptors mediates the vasodilation in the hindlimb of rat.

In the nucleus tractus solitarii (NTS) of rats, blockade of extracellular ATP breakdown to adenosine reduces arterial blood pressure (AP) increases that follow stimulation of the hypothalamic defense area (HDA). The effects of ATP on NTS P2 receptors, during stimulation of the HDA, are still unclear. The aim of this study was to determine whether activation of P2 receptors in the NTS mediates cardiovascular responses to HDA stimulation. Further investigation was taken to establish if changes in hindlimb vascular conductance (HVC) elicited by electrical stimulation of the HDA, or activation of P2 receptors in the NTS, are relayed in the rostral ventrolateral medulla (RVLM); and if those responses depend on glutamate release by ATP acting on presynaptic terminals. In anesthetized and paralyzed rats, electrical stimulation of the HDA increased AP and HVC. Blockade of P2 or glutamate receptors in the NTS, with bilateral microinjections of suramin (10 mM) or kynurenate (50 mM) reduced only the evoked increase in HVC by 75 % or more. Similar results were obtained with the blockade combining both antagonists. Blockade of P2 and glutamate receptors in the RVLM also reduced the increases in HVC to stimulation of the HDA by up to 75 %. Bilateral microinjections of kynurenate in the RVLM abolished changes in AP and HVC to injections of the P2 receptor agonist α,ß-methylene ATP (20 mM) into the NTS. The findings suggest that HDA-NTS-RVLM pathways in control of HVC are mediated by activation of P2 and glutamate receptors in the brainstem in alerting-defense reactions.

A new method to produce obstructive sleep apnoea in conscious unrestrained rats.

We developed a new method to produce obstructive apnoea in conscious rats. An inflatable balloon contained in a rigid Teflon tube was implanted in the trachea to allow the induction of apnoea without inducing pain. We also developed a balloon-tipped catheter that was advanced along the trachea into the mediastinum for the measurement of intrathoracic pressure. Rats recovered well from implantation of these balloons. The tracheal implant, while deflated, did not significantly impair normal breathing (thoracic pressure swing during rest was 4.5 ± 0.4 mmHg before implantation and 5.8 ± 0.5 mmHg 4 weeks after implantation; P > 0.2; n = 7). Apnoeas of up to 16 s could be made during rapid eye movement sleep without awakening the rat. During 15 s of balloon inflation, arterial O(2) saturation fell from 98 ± 0 to 80 ± 2% and partial pressure of CO(2) increased from 35 ± 1 to 44 ± 1 mmHg (n = 9; P < 0.001). Intrathoracic pressure changes during the respiratory cycle increased from 6.3 ± 0.2 to 38.5 ± 6.0 mmHg (P < 0.001; n = 4), indicating increased breathing effort. Heart rate fell from 373 ± 23 to 141 ± 18 beats min(-1) (P < 0.001; n = 4), and the heart beat became irregular, with few beats during expiratory effort. These responses remained intact after 60 apnoea episodes. Responses developed slightly more slowly when apnoea started at the end than at the beginning of the respiratory cycle. As these balloons last for a long time, cause few complications, allow induction of apnoea during sleep, allow induction of apnoeas that start at a fixed point in the respiratory cycle and elicit cardiorespiratory responses similar to those observed in humans, these balloons may aid investigation of both acute apnoea and chronic intermittent sleep apnoea.

Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats.

It is thought that cardiovascular changes may contribute to sudden death in patients with epilepsy. To examine cardiovascular alterations that occur during epileptogenesis, we measured the heart rate of rats submitted to the electrical amygdala kindling model. Heart rate was recorded before, during, and after the induced seizures. Resting heart rate was increased in stages 1, 3, and 5 as compared with the unstimulated control condition. In the initial one third of the seizures, we observed bradycardia, which increased in intensity with increasing stage and was blocked by injecting methyl atropine. During stage 5 seizures, a rebound tachycardia was observed that also increased in intensity with increasing number of seizures. This study demonstrated the influence of seizure frequency on cardiac autonomic modulation, providing a basis for discussion of potential mechanisms that cause patients with epilepsy to die suddenly.

Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: role of the peripheral chemoreflex.

The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in nonhypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity [i.e., peak oxygen consumption (V̇o2peak)]; and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptor inhibition) or 21% O2 (control session) while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEI for all sequences (cBEIALL) at rest [means ± SD: PAH = 0.5 ± 0.2 vs. HA = 0.7 ± 0.1 arbitrary units (a.u.), P = 0.02] and lower cBRSALL (PAH = 6.8 ± 7.0 vs. HA = 9.7 ± 5.0 ms·mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs. HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇o2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in nonhypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇o2peak, suggesting that it could be functionally relevant.NEW & NOTEWORTHY Does the peripheral chemoreflex play a role in cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension (PAH)? Here we provide new evidence of cardiac baroreflex dysfunction under spontaneous and, most notably, provoked blood pressure fluctuations in patients with nonhypoxemic PAH. Importantly, impaired cardiac baroreflex effectiveness during provoked blood pressure fluctuations was independently associated with poorer functional capacity. Finally, our results indicated that the peripheral chemoreflex did not mediate cardiac baroreflex dysfunction among those patients.

Chronic apnea during REM sleep increases arterial pressure and sympathetic modulation in rats.

STUDY OBJECTIVES: Obstructive sleep apnea can induce hypertension. Apneas in REM may be particularly problematic: they are independently associated with hypertension. We examined the role of sleep stage and awakening on acute cardiovascular responses to apnea. In addition, we measured cardiovascular and sympathetic changes induced by chronic sleep apnea in REM sleep. METHODS: We used rats with tracheal balloons and electroencephalogram and electromyogram electrodes to induce obstructive apnea during wakefulness and sleep. We measured the electrocardiogram and arterial pressure by telemetry and breathing effort with a thoracic balloon. RESULTS: Apneas induced during wakefulness caused a pressor response, intense bradycardia, and breathing effort. On termination of apnea, arterial pressure, heart rate, and breathing effort returned to basal levels within 10 s. Responses to apnea were strongly blunted when apneas were made in sleep. Post-apnea changes were also blunted when rats did not awake from apnea. Chronic sleep apnea (15 days of apnea during REM sleep, 8 h/day, 13.8 ± 2 apneas/h, average duration 12 ± 0.7 s) reduced sleep time, increased awake arterial pressure from 111 ± 6 to 118 ± 5 mmHg (p < 0.05) and increased a marker for sympathetic activity. Chronic apnea failed to change spontaneous baroreceptor sensitivity. CONCLUSION: Our results suggest that sleep blunts the diving-like response induced by apnea and that acute post-apnea changes depend on awakening. In addition, our data confirm that 2 weeks of apnea during REM causes sleep disruption and increases blood pressure and sympathetic activity.

Increased sympathetic responses induced by chronic obstructive sleep apnea are caused by sleep fragmentation.

Obstructive sleep apnea (OSA) is often associated with sympathetic overactivity and hypertension. These associations are mainly attributed to hypoxia acting on arterial chemoreceptors. However, the contribution of arousal from sleep is unclear. We measured the effect of OSA and sleep fragmentation on cardiovascular and sympathetic function and gene expression in the brain in rats. Male Wistar rats were fitted with a tracheal balloon and EEG and electromyogram electrodes and assigned to control (n = 6), OSA (n = 9), or arousal (n = 8) treatments. The OSA group was subjected to obstructive apnea, each time the rat entered sleep, for 8 h/day for 15 days. The arousal group was similarly exposed to vibration, which was produced with a miniature vibration motor mounted on the rat's head. Vibration intensity slowly increased until the rat awoke. One day after the last apnea or arousal, rats were anesthetized and arterial blood pressure and splanchnic sympathetic nerve activity (SSNA) were recorded. Baseline mean and diastolic pressure were increased after OSA. Resting SSNA was similar in the three groups, but both OSA and sleep fragmentation increased sympathetic activation in response to airway obstruction and chemoreflex activation by cyanide. OSA increased superoxide dismutases 1 and 2 in the brainstem, whereas sleep fragmentation did not. Our results suggest that sympathetic overactivity to chemoreceptor stimulation was a consequence of arousal from sleep. Our study suggests that sleep disruption may have an important role in the development of apnea-related sympathetic activation.NEW & NOTEWORTHY Obstructive sleep apnea causes a hyperactive chemoreflex, with increased sympathetic activation. However, it is not clear whether this pathophysiologic mechanism is due to repeated hypoxia or to sleep disruption. The present study suggests that sleep fragmentation contributes importantly to increased sympathetic activation after chemoreceptor stimulation. This suggests that sleep fragmentation has an important role in the sympathetic activation seen in sleep apnea patients.

Renal vasodilation induced by hypernatraemia: role of alpha-adrenoceptors in the median preoptic nucleus.

1. The renal vasodilation induced by infusion of hypertonic saline (HS) in anaesthetized rats has been shown to depend on the integrity of the median preoptic nucleus (MnPO), as well as noradrenergic afferents to this nucleus. In the present study, we sought to determine the role of alpha(1) and alpha(2)-adrenoceptors in the MnPO in cardiovascular responses induced by intravenous HS infusion (3 mol/L NaCl; 1.8 mL/kg, i.v., over 1 min). 2. Male Wistar rats (320-360 g) were anaesthetized with urethane (1.2 g/kg, i.v.) and instrumented for recording of mean arterial pressure (MAP), renal blood flow (RBF) and vascular conductance (RVC). In one experimental group, rats were injected with yohimbine, prazosin or saline (control) 20 min before HS infusion. In another experimental group, rats were injected with yohimbine or prazosin 20 min after HS infusion. 3. In control rats (n = 7), HS infusion 20 min after saline nanoinjection produced a transient hypertension. Ten minutes after HS infusion, RBF and RVC increased to 159 +/- 14% and 145 +/- 11% of baseline, respectively. Nanoinjection of the alpha(1)-adrenoceptor antagonist prazosin (0.25 mmol/L; n = 6) into the MnPO 20 min before HS infusion increased the HS-induced pressor response. However, HS-induced increases in RBF and RVC were significantly reduced (130 +/- 11% and 105 +/- 6% of baseline, respectively, 10 min after HS). Nanoinjection of the alpha(2)-adrenoceptor antagonist yohimbine (0.23 mmol/L; n = 5) into the MnPO 20 min before HS infusion increased the duration of the pressor response and reduced the increases in RBF and RVC induced by HS (117 +/- 10% and 97 +/- 11% of baseline, respectively, 10 min after HS). 4. We also observed that nanoinjections of the prazosin into the MnPO 60 min after HS infusion resulted in a gradual return of RBF and RVC to baseline values. However nanoinjection of yohimbine 60 min after HS failed to reduce renal vasodilatation induced by hypernatremia. 5. The results of the present study demonstrate that the integrity of adrenergic neurotransmission in the MnPO is essential for the renal vasodilation that follows acute increases in blood sodium concentration.

Role of the medulla oblongata in normal and high arterial blood pressure regulation: the contribution of Escola Paulista de Medicina - UNIFESP.

Several forms of experimental evidence gathered in the last 37 years have unequivocally established that the medulla oblongata harbors the main neural circuits responsible for generating the vasomotor tone and regulating arterial blood pressure. Our current understanding of this circuitry derives mainly from the studies of Pedro Guertzenstein, a former student who became Professor of Physiology at UNIFESP later, and his colleagues. In this review, we have summarized the main findings as well as our collaboration to a further understanding of the ventrolateral medulla and the control of arterial blood pressure under normal and pathological conditions.

Hibernating mammals in sudden cardiac death in epilepsy: what do they tell us?

Epilepsy is the most common neurological disorder; approximately 1% of the population worldwide have epilepsy. Moreover, sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency and AED number. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. Very recently, our research group was the first to annunciate that winter temperatures may lead a cardiac abnormalities and hence sudden death, become a new potential risk factor to SUDEP. Quite interesting, several mammalian species have evolved to develop a physiological phenomenon called hibernation as a strategy for survival under adverse cold conditions. From cardiovascular point of view, it has been established that hibernating mammals inherited a stable cardiovascular function as a result of adaptation to extreme external and internal environments during hibernation. For instance, hibernating mammals show resistance to hypothermia at a cellular level, the membrane potentials and excitability are more stable in the cardiac cells of these animals (action potentials (60 mV) have been recorded in hibernators myocardium at -5 degrees C), the aortic smooth muscle cells from hibernators are able to maintain ionic gradients upon prolonged exposure to low temperatures, and cardiac myocytes from hibernating mammals maintain constant levels of intracellular free calcium and forceful contractility at 10 degrees C or lower. Taken together, in this paper we postulate that hibernators have some cardiovascular particularities that confer heart protection that could positively influence the cardiovascular system of patients with epilepsy.

Airway obstruction produces widespread sympathoexcitation: role of hypoxia, carotid chemoreceptors, and NTS neurotransmission.

Obstructive sleep apnea (OSA) is the most common respiratory disturbance of sleep and is closely associated to cardiovascular diseases. In humans, apnea increases respiratory effort and elevates muscle sympathetic nerve activity (SNA), but the primary stimulus for the SNA activation has not been identified. We recently developed a model of apnea in rodents using acute airway obstruction. In this study, we employed this model to test whether the elevation in SNA was mediated by hypoxia, carotid chemoreceptors, or neurotransmission in the nucleus tractus solitarius (NTS). In anesthetized, male Sprague-Dawley rats, airway obstruction (20s) increased phrenic nerve activity (PNA), arterial blood pressure (ABP), and lumbar, renal, and splanchnic SNA. The changes in SNA were similar across all three sympathetic nerves. Inactivation of chemoreceptors by hyperoxia (100% O2 ) or surgical denervation of carotid chemoreceptors attenuated, but did not eliminate, the changes in SNA and ABP produced by airway obstruction. To interrupt afferent information from carotid chemoreceptor and extracarotid afferents to the hindbrain, airway obstruction was performed before and after NTS microinjection of the GABAA agonist muscimol or a cocktail of NMDA and non-NMDA antagonists. Inhibition of NTS neurons or blockade of glutamatergic receptors attenuated the increase in lumbar SNA, splanchnic SNA, renal SNA, and PNA. Collectively, these findings suggest that PNA and SNA responses induced by airway obstruction depend, in part, on chemoreceptors afferents and glutamatergic neurotransmission in the NTS.

Do the carotid body chemoreceptors mediate cardiovascular and sympathetic adjustments induced by sodium overload in rats?

Acute plasma hypernatremia induces several cardiovascular and sympathetic responses. It is conceivable that these responses contribute to rapid sodium excretion and restoration of normal conditions. Afferent pathways mediating these responses are not entirely understood. The present study analyses the effects of acute carotid chemoreceptor inactivation on cardiovascular and sympathetic responses induced by infusion of hypertonic saline (HS). All experiments were performed on anesthetized male Wistar rats instrumented for recording of arterial blood pressure (ABP), renal blood flow (RBF) and renal sympathetic nerve activity (RSNA). Animals were subjected to sham surgery or carotid chemoreceptor inactivation by bilateral ligation of the carotid body artery (CBA). In sham rats (n=8), intravenous infusion of HS (3 M NaCl, 1.8 ml/kg b.wt.) elicited a transient increase (9±2mmHg) in ABP, and long lasting (30 min) increases in RBF (138±5%) and renal vascular conductance (RVC) (128±5%) with concurrent decrease in RSNA (-19±4%). In rats submitted to CBA ligation (n=8), the pressor response to HS was higher (24±2mmHg; p<0.05). However, RBF and RVC responses to HS infusion were significantly reduced (113±5% and 93±4%, respectively) while RSNA was increased (13±2%). When HS (3M NaCl, 200µl) was administrated into internal carotid artery (ICA), distinct sympathetic and cardiovascular responses were observed. In sham-group, HS infusion (3M NaCl, 200µl) into ICA promoted an increase in ABP (26±8mmHg) and RSNA (29±13%). In CBA rats, ABP (-3±5.6mmHg) remained unaltered despite sympathoinhibition (-37.6±5.4%). These results demonstrate that carotid body chemoreceptors play a role in the development of hemodynamic and sympathetic responses to acute HS infusion.

Coronary artery bypass surgery and longitudinal evaluation of the autonomic cardiovascular function.

INTRODUCTION: Imbalance in autonomic cardiovascular function increases the risk for sudden death in patients with coronary artery disease (CAD), but the time course of the impact of coronary artery bypass grafting (CABG) on autonomic function has been little studied. Thus, the purpose of the present study was to determine the effects of the CABG on the cardiovascular autonomic function. METHODS: Patients undergoing CABG (n = 13) and two matched control groups (patients with CAD who refused surgical treatment [n = 9], and healthy volunteers [n = 9]) underwent a prospective longitudinal study consisting of autonomic evaluation before and after (3, 6, 15, 30, 60, and 90 days) surgery, including measurement of heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and Valsalva maneuver. RESULTS: After CABG there was a decrease in, and a later recovery of, (1) the HRV in the time domain and in the frequency domain, (2) RSA, and (3) Valsalva maneuver. CONCLUSIONS: CABG caused an impairment, reversible after 60 days, of cardiovascular autonomic function, with a maximal decrease on about the sixth day after surgery.

Cardiovascular responses induced by obstructive apnea are enhanced in hypertensive rats due to enhanced chemoreceptor responsivity.

Spontaneously hypertensive rats (SHR), like patients with sleep apnea, have hypertension, increased sympathetic activity, and increased chemoreceptor drive. We investigated the role of carotid chemoreceptors in cardiovascular responses induced by obstructive apnea in awake SHR. A tracheal balloon and vascular cannulas were implanted, and a week later, apneas of 15 s each were induced. The effects of apnea were more pronounced in SHR than in control rats (Wistar Kyoto; WKY). Blood pressure increased by 57±3 mmHg during apnea in SHR and by 28±3 mmHg in WKY (p<0.05, n = 14/13). The respiratory effort increased by 53±6 mmHg in SHR and by 34±5 mmHg in WKY. The heart rate fell by 209±19 bpm in SHR and by 155±16 bpm in WKY. The carotid chemoreceptors were then inactivated by the ligation of the carotid body artery, and apneas were induced two days later. The inactivation of chemoreceptors reduced the responses to apnea and abolished the difference between SHR and controls. The apnea-induced hypertension was 11±4 mmHg in SHR and 8±4 mmHg in WKY. The respiratory effort was 15±2 mmHg in SHR and 15±2 mmHg in WKY. The heart rate fell 63±18 bpm in SHR and 52±14 bpm in WKY. Similarly, when the chemoreceptors were unloaded by the administration of 100% oxygen, the responses to apnea were reduced. In conclusion, arterial chemoreceptors contribute to the responses induced by apnea in both strains, but they are more important in SHR and account for the exaggerated responses of this strain to apnea.