Carotid Sinus Nerve Stimulation Research Articles

Right‐sided Vagus Nerve Stimulation

To the Editor: We enjoyed the recent article entitled “Right-sided vagus nerve stimulation as a treatment for refractory epilepsy in humans” by McGregor et al. (1). We agree that right vagus nerve stimulation may be used in humans with epilepsy, as prior reports of cardiac effects after right-sided vagus nerve stimulation were based on experiments in dogs (2). Although complications with vagus nerve stimulation are low, as found in our report of 74 children undergoing this procedure (3), as surgeons, the option of left versus right side for vagus nerve stimulation is appealing, especially in cases of concomitant left-sided ventriculoperitoneal shunts, so that additional hardware (i.e., vagus nerve stimulator) is moved farther away from the shunt system, thus decreasing the risk of infection of the shunt. Our experience also has shown that another cardiovascular nerve (the carotid sinus nerve) can be stimulated on both left and right sides in a dog model with equal effect on causing cessation of cortically induced seizures (4). Furthermore, we found no significant cardiovascular effects when this nerve (carotid sinus nerve) was stimulated with parameters comparable to those used for vagus nerve stimulation in humans (4). Interestingly, both of these nerves synapse proximally in the cardiorespiratory part of the nucleus tractus solitarius. After right-sided vagus nerve stimulation, we have been unable to alter the cardiorespiratory system in a porcine model (5). These data imply, whether with vagus or carotid sinus nerve stimulation, that nerve stimulation responses (e.g., right-sided cardiorespiratory responses) may be species specific. We also agree with the authors' statement that the right vagus nerve may be desired for stimulation when a left-sided vagus nerve has been used and removed after infection. Indeed, we have shown in a single case that a left-sided vagus nerve that was often stimulated and removed at autopsy had severe demyelination (6).

Neonatal maternal separation enhances phrenic responses to hypoxia and carotid sinus nerve stimulation in the adult anesthetized rat

In awake animals, our laboratory recently showed that the hypoxic ventilatory response of adult male (but not female) rats previously subjected to neonatal maternal separation (NMS) is 25% greater than controls (Genest SE, Gulemetova R, Laforest S, Drolet G, and Kinkead R. J Physiol 554: 543-557, 2004). To begin mechanistic investigations of the effects of this neonatal stress on respiratory control development, we tested the hypothesis that, in male rats, NMS enhances central integration of carotid body chemoafferent signals. Experiments were performed on two groups of adult male rats. Pups subjected to NMS were placed in a temperature-controlled incubator 3 h/day from postnatal day 3 to postnatal day 12. Control pups were undisturbed. At adulthood (8-10 wk), rats were anesthetized (urethane; 1.6 g/kg), paralyzed, and ventilated with a hyperoxic gas mixture [inspired O2 fraction (Fi(O2)) = 0.5], and phrenic nerve activity was recorded. The first series of experiments aimed to demonstrate that NMS-related enhancement of the inspiratory motor output (phrenic) response to hypoxia occurs in anesthetized animals also. In this series, rats were exposed to moderate, followed by severe, isocapnic hypoxia (Fi(O2) = 0.12 and 0.08, respectively, 5 min each). NMS enhanced both the frequency and amplitude components of the phrenic response to hypoxia relative to controls, thereby validating the use of this approach. In a second series of experiments, NMS increased the amplitude (but not the frequency) response to unilateral carotid sinus nerve stimulation (stimulation frequency range: 0.5-33 Hz). We conclude that enhancement of central integration of carotid body afferent signal contributes to the larger hypoxic ventilatory response observed in NMS rats.

Chronic hypoxia abolishes expiratory prolongation following carotid sinus nerve stimulation in the anesthetized rat

In anesthetized rats, increases in phrenic nerve (PN) amplitude and frequency during brief periods of hypoxia or electrical stimulation of the carotid sinus nerve (CSN) are followed by an increase in expiratory duration. We investigated the effects of chronic exposure to hypoxia on PN responses to CSN stimulation. In Inactin anesthetized (100 mg/kg) Sprague-Dawley rats PN discharge and arterial pressure responses to 10-120 s of CSN stimulation (20 Hz, 0.2 ms duration pulses) were recorded after 7-10 days exposure to hypoxia (10 +/- .5% O2). In normoxic rats, the degree of CSN-evoked expiratory prolongation was dependent upon the duration of CSN stimulation. CSN-evoked increases in PN burst amplitude were not different comparing chronic hypoxic rats to rats maintained at normoxia while CSN-evoked increases in PN burst frequency were greater in chronic hypoxic rats (p<.05). CSN-evoked expiratory prolongation was abolished in chronic hypoxic rats. Following chronic hypoxia, changes occur within the central processing of arterial chemoreceptor inputs so that CSN stimulation evokes an enhanced PN frequency response and no expiratory prolongation.

Serotonin receptor subtypes involved in vagus nerve stimulation-induced phrenic long-term facilitation in rats

Episodic vagus nerve stimulation (VNS) induces phrenic long-term facilitation (LTF, a persistent augmentation of phrenic nerve activity after the stimulation ends), sensitive to the serotonin 5-HT 1,2,5,6,7 receptor antagonist methysergide and similar to that elicited by episodic hypoxia or carotid sinus nerve stimulation. This study examined the effect of ketanserin (5-HT 2 antagonist) or clozapine (5-HT 2,6,7 antagonist) on VNS-induced LTF in anesthetized, vagotomized, paralyzed and ventilated rats to determine which receptor subtype(s) is involved. Three episodes of 5 min VNS (50 Hz, 0.1 ms, ∼500 μA) with 5 min intervals elicited phrenic LTF in control (amplitude: 38% above baseline at 60 min post-VNS) and ketanserin (2 mg·kg −1, i.p.) pre-treated rats (45%), but not clozapine (3 mg·kg −1) rats (8%). These data suggest that unlike hypoxia-induced LTF (5-HT 2 receptor-dependent), VNS-induced LTF requires non-5-HT 2 serotonin receptors, perhaps 5-HT 6 and/or 5-HT 7 subtype(s).

Episodic phrenic-inhibitory vagus nerve stimulation paradoxically induces phrenic long-term facilitation in rats

Accumulating evidence suggests that the respiratory control system exhibits an impressive degree of plasticity, as do many other neural networks in the central nervous system (Eldridge & Millhorn, 1986; McCrimmon et al. 1995; Ling et al. 1997a; Powell et al. 1998; Mitchell et al. 2001). For example, episodic hypoxia induces a persistent augmentation of respiratory activity (Cao et al. 1992; Bach & Mitchell, 1996; Turner & Mitchell, 1997; Olson et al. 2001; McGuire et al. 2002), known as long-term facilitation (LTF). Episodic carotid sinus nerve (CNS) stimulation (CSNS) also elicits phrenic LTF in anaesthetized animals (Millhorn et al. 1980a; Hayashi et al. 1993; Ling et al. 1997b), which is not abolished by decerebration or spinal transection at the C7-T1 level (Eldridge & Millhorn, 1986). These results suggest that LTF is elicited by central mechanisms located in the brainstem and/or cervical spinal cord, and that the carotid body, respiratory mechanics, systemic hypoxia, forebrain and the lower spinal cord are not necessary for its expression (Eldridge & Millhorn, 1986). Both hypoxia- and CSNS-induced LTF are serotonin-dependent (Millhorn et al. 1980b; Bach & Mitchell, 1996). Recent evidence further suggests that spinal serotonin receptors (Baker-Herman & Mitchell, 2002) and the synapses transmitting bulbospinal, inspiratory drive to the phrenic motoneurons (Fuller et al. 2002) play key roles in phrenic LTF. In these experiments, respiratory LTF is always preceded by repeated inspiratory augmentation. This fact suggests that induction of respiratory LTF is somehow related to inspiratory augmentation, and more specifically, that phrenic LTF relies heavily on an activity-dependent Hebbian mechanism (coincident pre- and post-synaptic activity strengthens synapses) in the synapses on the phrenic motoneurons. However, as all LTF to date has been induced by episodic inspiratory-excitatory stimulation, it has been difficult to directly test these hypotheses by separating the LTF from inspiratory augmentation. In contrast, vagus nerve (VN) stimulation (VNS) suppresses inspiration during stimulation, and induces a reduction (< 1 min duration) in phrenic amplitude and frequency after stimulation (0.5 min duration; Eldridge & Millhorn, 1986). We speculate that a relatively longer post-stimulation inhibitory memory is possible if using episodic and longer VNS. VNS has also been used as a tool in brain research (e.g. evoked potentials recorded from the cerebral cortex, hippocampus, thalamus and cerebellum; Rutecki, 1990) and neurophysiological studies of several reflexes (e.g. cough, swallow and Hering-Breuer reflex or inspiratory off-switch mechanisms) because vagal afferents provide an easily accessible, peripheral route by which to modulate the central nervous system function. However, these investigators all used brief VNS and focused mainly on immediate or short-term (< several min) effects, during and/or after VNS. For many years, episodic VNS has been used clinically as a common treatment for patients with medically intractable epilepsy (Schachter, 2002). However, the precise underlying mechanisms and the consequence of long-term VNS remain unclear. The aims of the present study were to (1) examine the long-term effects of episodic phrenic-inhibitory VNS on phrenic nerve activity and compare them with those elicited by phrenic-excitatory CSNS and (2) explore the possibility of using VNS as a tool to suppress phrenic motor neurons during LTF elicitation. We hypothesized that episodic VNS would induce phrenic long-term depression, but that phrenic activity would eventually return to baseline in less than 60 min.

Episodic phrenic-inhibitory vagus nerve stimulation paradoxically induces phrenic long-term facilitation in rats.

All respiratory long-term facilitation (LTF) is induced by inspiratory-excitatory stimulation, suggesting that LTF needs inspiratory augmentation and is the result of a Hebbian mechanism (coincident pre- and post-synaptic activity strengthens synapses). The present study examined the long-term effects of episodic inspiratory-inhibitory vagus nerve stimulation (VNS) on phrenic nerve activity. We hypothesized that episodic VNS would induce phrenic long-term depression. The results are compared with those obtained following serotonin receptor antagonism or episodic carotid sinus nerve stimulation (CSNS). Integrated phrenic neurograms were measured before, during and after three episodes of 5 min VNS (50 Hz, 0.1 ms), each separated by a 5 min interval, at a low (approximately 50 microA), medium (approximately 200 microA) or high (approximately 500 microA) stimulus intensity in anaesthetized, vagotomized, neuromuscularly blocked and artificially ventilated rats. Medium- and high-intensity VNS eliminated rhythmic phrenic activity during VNS, while low-intensity VNS only reduced phrenic burst frequency. At 60 min post-VNS, phrenic amplitude was higher than baseline (35 +/- 5% above baseline, mean +/- S.E.M., P < 0.05) in the high-intensity group but not in the low- (-4 +/- 4%) or medium-intensity groups (-10 +/- 15%), or in the high-intensity with methysergide group (4 mg kg(-1), i.p.) (-11 +/- 5%). These data, which are inconsistent with our hypothesis, indicate that phrenic-inhibitory VNS induces a serotonin-dependent phrenic LTF similar to that induced by phrenic-excitatory CSNS (33 +/- 7%) and may require activation of high-threshold afferent fibres. These data also suggest that the synapses on phrenic motoneurons do not use the Hebbian mechanism in this LTF, as these motoneurons were suppressed during VNS.

Complete vasomotor collapse: an unusual manifestation of the carotid sinus reflex.

Complete vasomotor collapse: an unusual manifestation of the carotid sinus reflex.

Life-long impairment of hypoxic phrenic responses in rats following 1 month of developmental hyperoxia.

Hypoxic ventilatory and phrenic responses are reduced in adult rats (3-5 months old) exposed to hyperoxia for the first month of life (hyperoxia treated). We previously reported that hypoxic phrenic responses were normal in a small sample of 14- to 15-month-old hyperoxia-treated rats, suggesting slow, spontaneous recovery. Subsequent attempts to identify the mechanism(s) underlying this spontaneous recovery of hypoxic phrenic responses led us to re-evaluate our earlier conclusion. Experiments were conducted in two groups of aged Sprague-Dawley rats (14-15 months old) which were anaesthetized, vagotomized, neuromuscularly blocked and ventilated: (1) a hyperoxia-treated group raised in 60 % O2 for the first 28 postnatal days; and (2) an age-matched control group raised in normoxia. Increases in minute phrenic activity and integrated phrenic nerve amplitude (integral Phr) during isocapnic hypoxia (arterial partial pressures of O2, 60, 50 and 40 +/- 1 mmHg) were greater in aged control (n = 15) than hyperoxia-treated rats (n = 11; P < or = 0.01). Phrenic burst frequency during hypoxia was not different between groups. To examine the central integration of carotid chemoafferent inputs, steady-state relationships between carotid sinus nerve (electrical) stimulation frequency and phrenic nerve activity were compared in aged control (n = 7) and hyperoxia-treated rats (n = 7). Minute phrenic activity, integral Phr and burst frequency were not different between groups at any stimulation frequency between 0.5 and 20 Hz. Carotid body chemoreceptor function was examined by recording whole carotid sinus nerve responses to cessation of ventilation or injection of cyanide in aged control and hyperoxia-treated rats. Electrical activity of the carotid sinus nerve did not change in five out of five hyperoxia-treated rats in response to stimuli that evoked robust increases in carotid sinus nerve activity in five out of five control rats. Estimates of carotid body volume were lower in aged hyperoxia-treated rats (4.4 (+/- 0.2) x 10(6) microm3) compared to controls (17.4 (+/- 1.6) x 10(6) microm3; P <0.01). We conclude that exposure to hyperoxia for the first month of life causes life-long impairment of carotid chemoreceptor function and, consequently, blunted phrenic responses to hypoxia.

Chronic hypoxia induces changes in the central nervous system processing of arterial chemoreceptor input.

Chronic hypoxia increases the hypoxic ventilatory response (HVR) in awake rats and the phrenic nerve response to carotid sinus nerve stimulation in anesthetized rats. An increased O2 sensitivity of the arterial chemoreceptors contributes to the increase in the HVR, but changes in the CNS processing of afferent information from arterial chemoreceptors are also involved. Adult male Sprague-Dawley rats were exposed to 0-7 days of hypobaric hypoxia (PIO2 = 80 Torr). Ventilation was measured in rats exposed to 0, 2 and 7 days of hypoxia using whole-body plethysmography. Ventilation increased after 2 days and remained elevated after 7 days of hypoxia. Following dopamine D2 receptor (D2-R) blockade in the CNS, frequency significantly decreased after 0 and 7 days of hypoxia, but did not change significantly after 2 days of hypoxia. In anesthetized rats, the phrenic nerve response to carotid sinus nerve stimulation was reduced following systemic D2-R blockade in control rats and those exposed to 7 days of hypoxia. After 2 days of hypoxia, there was no effect of blocking systemic D2-R. To determine whether changes in D2-R mRNA precede physiological changes, competitive RT-PCR was used to quantify D2-R mRNA in micropunches from the nucleus tractus solitarius (NTS) in normoxic and chronically hypoxic rats. In hypoxia, D2-R mRNA in the caudal NTS initially increased (6-12 hours) and then decreased below control levels (24 hours-7 days). These results show that chronic hypoxia causes time-dependent changes in D2-R that could result in changes in the ventilatory response to hypoxia.

Short-term potentiation of carotid chemoreflex: an NMDAR-dependent neural integrator.

Repetitive stimulation of the carotid sinus nerve (CSN) elicits a short-term potentiation (STP) of the reflex response in respiratory motor output in mammals. The input-output transformation approximates a leaky integrator with a time constant of several seconds. Here, we showed that STP induced by CSN stimulation in rats was manifested in the reflex response in the amplitude of rhythmic phrenic nerve activity as well as its duration. Moreover, pharmacological blockade of NMDA receptors (NMDAR) resulted in marked increases in the time constants of the equivalent neural integrator in both the STP induction phase (by 10- to 20-fold) and recovery phase (by 1- to 5-fold). Thus, NMDAR serves as a molecular switch that facilitates the integrative processing of CSN inputs by STP.

Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats.

Chronic exposure to hypoxia results in a time-dependent increase in ventilation called ventilatory acclimatization to hypoxia. Increased O(2) sensitivity of arterial chemoreceptors contributes to ventilatory acclimatization to hypoxia, but other mechanisms have also been hypothesized. We designed this experiment to determine whether central nervous system processing of peripheral chemoreceptor input is affected by chronic hypoxic exposure. The carotid sinus nerve was stimulated supramaximally at different frequencies (0.5-20 Hz, 0.2-ms duration) during recording of phrenic nerve activity in two groups of anesthetized, ventilated, vagotomized rats. In the chronically hypoxic group (7 days at 80 Torr inspired PO(2)), phrenic burst frequency (f(R), bursts/min) was significantly higher than in the normoxic control group with carotid sinus nerve stimulation frequencies >5 Hz. In the chronically hypoxic group, peak amplitude of integrated phrenic nerve activity ( integral Phr, percent baseline) or change in integral Phr was significantly greater at stimulation frequencies between 5 and 17 Hz, and minute phrenic activity ( integral Phr x f(R)) was significantly greater at stimulation frequencies >5 Hz. These experiments show that chronic hypoxia facilitates the translation of arterial chemoreceptor afferent input to ventilatory efferent output through a mechanism in the central nervous system.

Hereditarily elongated carotid sinus nerve in a rat colony

A specific colony of Wistar rats was found in which the common carotid artery bifurcates at an unusually caudal position, thereby the carotid sinus nerve that originates from the bifurcation is elongated. The present study was done to determine whether this elongated nerve carries baro- and chemosensations in the same manner as the carotid sinus nerve of conventional rats or of other species. In chloralose-urethane anesthetized rats of this specific colony, the afferent discharges were recorded from the elongated carotid sinus nerve in response to a phenylephrine-induced rise in blood pressure and a fall in oxygen tension, as well as an increase in carbon dioxide tension in the respiratory gas. Reflex effects of electrical stimulation of the nerve were also examined. In nerve recording, the afferent discharges of the elongated carotid sinus nerve were increased by any of the perturbations, hypertensive, hypoxic or hypercapnic. Electrical stimulation of the elongated carotid sinus nerve caused an initial rise and a subsequent fall in blood pressure, bradycardia, and an increase of respiratory volume and rate. These results confirmed that the elongated carotid sinus nerve of rats in this colony contains both baroreceptor and chemoreceptor afferent fibers. It seems that this colony of rats proffers a beneficial material which will facilitate the studies to analyze the features and reflex functions of carotid body chemoreceptors and/or carotid sinus baroreceptors.

Phase resetting of the respiratory oscillator by carotid sinus nerve stimulation in cats.

1. Stimulation of the carotid sinus nerve causes an increase in inspiratory (I) and expiratory (E) neural activities. If central respiratory oscillation is generated by an attractor-cycle process, an increase in its activity can be caused by a centrifugal perturbation of state. We evaluated this hypothesis by comparing the respiratory oscillator's phase responses to carotid sinus nerve stimulations in cats to the phase responses of an attractor-cycle oscillator, the Bonhoeffer-van der Pol (BvP) equations, subjected to centrifugal perturbations. 2. We recorded phrenic activity in seven anaesthetized, vagotomized, glomectomized, paralysed and servo-ventilated cats. Carotid sinus nerve (CSN) stimulation with 0.5-0.8 s electrical pulse trains increased the immediate cycle period and delayed the onset of breaths after stimulation in a highly predictable manner, with the exception that strong stimuli (25 Hz, 0.25-0.90 V) caused unpredictable responses when given at the I-E or the E-I transitions. The resetting plots exhibited focal gaps corresponding to these unpredictable responses, and the size of the gaps increased with increases in the strength of CSN stimulation. Type 0 resetting was not achieved despite the large perturbations in rhythm induced by CSN stimulation. 3. Centrifugal perturbations of the BvP oscillator resulted in phase responses which were similar to those found in the animal experiments. The BvP cycle had two critical phases at which phase resetting was highly irregular and neighbouring state trajectories were highly divergent. The resetting plots had focal gaps that increased in size with increases in the strength of perturbation. The gaps did not represent true discontinuity because at higher computational resolution the resetting plots appeared to be steep but smooth portions of topological Type 1 resetting curves. 4. These studies support the concept that brief carotid sinus nerve stimulations cause a transient outward displacement of the central respiratory state away from its attractor cycle, in contrast to the unidirectional displacements that accompany midbrain reticular or superior laryngeal nerve stimulations. The findings define particular geometrical relationships between oscillatory state trajectories of the rhythm generator and perturbed state trajectories induced by inputs to the oscillator. These relationships provide a framework for developing and testing the validity of neural models of the respiratory oscillator.

Local injection of NaCN into the nucleus locus ceruleus of the rat brain induces respiratory depression.

The central inhibitory effect of systemic hypoxia on respiration can be explained by different mechanisms including withdrawal of excitatory inputs to respiratory related neurons. It has been shown that several groups of catecholamine containing neurons, including the locus ceruleus (LC), express chemosensitive properties. Different stimuli like hypercapnia, hypoxia or electrical stimulation of carotid sinus nerve, induce c-fos protein expression in the LC neurons.1,2 Furthermore, their activation by increased hydrogen ions causes elevation of respiratory drive.3 KeywordsExcitatory InputRespiratory DriveLocus CeruleusNucleus LocusSodium CyanideThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Phase resetting of the respiratory oscillator by carotid sinus nerve stimulation in cats

Phase resetting of the respiratory oscillator by carotid sinus nerve stimulation in cats

Short-term potentiation of carotid sinus nerve inputs to neurons in the nucleus of the solitary tract

Reflex studies have shown that the effects of afferent stimulation can persist beyond the period of stimulation. To determine if some form of `short-term potentiation' occurs during the initial integration of afferent inputs within the nucleus of the solitary tract (NTS), the synaptic responses of NTS neurons to high frequency carotid sinus nerve (CSN) stimulation were examined in anesthetized rats. In extracellular recording experiments, high frequency CSN stimulation (1–3 sec, 100–300 Hz) increased the number of action potentials evoked by 30 CSN stimuli from 31±3 to 38±4 ( P<0.05, n=11). In this population, evoked discharge was enhanced in six cells, not altered in three cells and reduced in two cells. Spontaneous discharge was increased in the five cells in which it was present ( P<0.05). In intracellular recording experiments, high frequency CSN stimulation increased EPSP amplitude from 5.1±0.4 to 6.1±0.4 mV ( P<0.01, n=21). In this population, amplitude was enhanced in 13 cells, not altered in four cells and reduced in four cells. The enhanced EPSP occurred in the absence of any change in membrane potential in five cells and during a 3–5 mV depolarization in eight cells. In both the intra- and extra-cellular experiments, the effects of high frequency stimulation were over within 5 min. The results indicate that brief, intense periods of visceral afferent activation can alter the responses of NTS neurons to subsequent afferent inputs.

Co-localization of c-Fos and neurotransmitter immunoreactivities in the cat brain stem after carotid sinus nerve stimulation

To reveal neurones in the cat medulla oblongata involved in carotid baroreceptor/chemoreceptor reflexes, the distribution of c-Fos oncoprotein immunoreactivity was studied following electrical stimulation of the right carotid sinus nerve. The neurochemistry of the activated neurones was investigated using antisera to tyrosine hydroxylase, neuropeptide Y, somatostatin, and glutamate. Nitric oxide containing neurones were identified using antiserum to nitric oxide synthase (NOS) and by the histochemical localization of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase. Following sinus nerve stimulation numerous c-Fos-IR cells were detected both ipsilaterally and contralaterally in the nucleus tractus solitarii, the area postrema and throughout the ventrolateral medulla. Dual labelling studies revealed that 3.3% of c-Fos- immunoreactive cells in the nucleus tractus solitarii were also immunoreactive for tyrosine hydroxylase. The double labelled cells were scattered within the medial and ventrolateral subnuclei, predominantly rostral to obex. A higher proportion (10.3%) of c-Fos-IR cells in the ventrolateral medulla also showed tyrosine hydroxylase immunoreactivity. Caudal to obex, these were scattered in the reticular formation between the spinal trigeminal nucleus and the lateral reticular nucleus, while more rostrally they were found within the lateral reticular nucleus, the nucleus ambiguus and the lateral tegmental field. Cells expressing c-fos and reactive for glutamate, neuropeptide Y or NADPH-diaphorase (or NOS) were only rarely seen, and co-localization of c-Fos and somatostatin immunoreactivities was not seen. These results suggest that of the neurones forming pathways within the medulla activated on carotid sinus nerve stimulation, presumably mediating baro- and chemoreceptor reflexes, relatively few utilize catecholamines, glutamate, neuropeptide Y or nitric oxide as their transmitter substance.

Integrated phrenic responses to carotid afferent stimulation in adult rats following perinatal hyperoxia.

1. Hypoxic ventilatory responses are greatly attenuated in adult rats exposed to moderate hyperoxia (60% O2) during the first month of life (perinatal treated rats). The present study was designed to test the hypothesis that perinatal hyperoxia impairs central integration of carotid chemoreceptor afferent inputs, thereby diminishing the hypoxic ventilatory response. 2. Time-dependent phrenic nerve responses to electrical stimulation of the carotid sinus nerve (CSN) and steady-state relationships between CSN stimulation frequency and phrenic nerve output were compared in control and perinatal treated rats. The rats were urethane anaesthetized, vagotomized, paralysed and artificially ventilated. End-tidal CO2 was monitored and maintained at isocapnic levels; arterial blood gases were determined. 3. Two stimulation protocols were used: (1) three 2 min episodes of CSN stimulation (20 Hz, 0.2 ms duration, 3 x threshold), separated by 5 min intervals; and (2) nine 45 s episodes of CSN stimulation with stimulus frequencies ranging from 0.5 to 20 Hz (0.2 ms duration, 3 x threshold), separated by 4 min intervals. 4. The mean threshold currents to elicit phrenic responses were similar between groups. Burst frequency (f, burst min-1), peak amplitude of integrated phrenic activity (integral of Phr), and minute phrenic activity (integral of Phr x f) during and after CSN stimulation were not distinguishable between groups in either protocol at any time or at any stimulus intensity (P > 0.05). 5. Perinatal hyperoxia does not alter temporal or steady-state phrenic responses to CSN stimulation, suggesting that the central integration of carotid chemoreceptor afferent inputs is not impaired in perinatal treated rats. It is speculated that carotid chemoreceptors per se are impaired in perinatal treated rats.

This Month in the Journal

This Month in the Journal

Baroreflex frequency-response characteristics to aortic depressor and carotid sinus nerve stimulation in rats.

Dynamic cardiovascular regulation depends on baroreflexes and the processing of sensory information. We evaluated the influence of choice of anesthetic on the frequency-response characteristics of the baroreflex of rats by electrical stimulation of two major baroreceptor-containing nerves, the carotid sinus (CSN) and aortic depressor nerves (ADN). The ADN contains baroreceptors alone, and the CSN has both chemoreceptors and baroreceptors. Most studies were performed under pentobarbital sodium (PB; 65 mg/kg) anesthesia. We compared this to a combination of alpha-chloralose (80 mg/kg) and urethan (800 mg/kg) (CU). Stimulus trains were fixed at 60-s periods (0.1-ms shocks, supramaximal intensities, 1-200 Hz) and delivered in steady and burst patterns. Unilateral steady-frequency ADN stimulation in PB-anesthetized rats evoked reflex decreases in mean arterial pressure and heart rate that increased with frequencies between 1 and approximately 10 Hz before reaching a maximum. From 10 to 200 Hz, PB ADN reflex responses were sustained at these maximal levels. Cutting the opposite ADN or both CSNs did not alter ADN baroreflex relationships. Heart rate and mean arterial pressure depressor responses evoked by CSN stimulation in PB-anesthetized rats were smaller compared with ADN stimulation and were biphasic, with small pressor responses at 1 Hz. Maximal CSN depressor responses in PB-anesthetized rats occurred at approximately 20 Hz and were sustained at 20-200 Hz. Baroreflex responses for ADN stimulation in CU-anesthetized rats were similar to those in PB-anesthetized rats. In contrast, in CU-anesthetized rats, maximal CSN responses occurred at 20 Hz but declined at 50-200 Hz. Constant- and burst-stimulation responses were equivalent. The results suggest that rat aortic baroreflex responses are sustained even at very high input frequencies (> 100 Hz). The sustained high-frequency baroreflex responses seem to present a paradox in understanding central integration because other studies show substantial depression of sensory transmission at the first synapse in the nucleus tractus solitarius at frequencies as low as 10 Hz.