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1 Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil
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Abstract |
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-methyl-4-carboxyphenylglycine (MCPG, 100 mM), or KYN plus MCPG into the cNTS were performed in three different groups. These microinjections into the cNTS did not affect the increase in the thoracic sympathetic nerve activity elicited by chemoreflex activation (KYN, 54 ± 3 versus 51 ± 2%, n= 11; MCPG, 48 ± 5 versus 54 ± 5%, n= 7; and KYN plus MCPG, 57 ± 6 versus 55 ± 3%, n= 5). The increase in the frequency of the phrenic nerve discharge in response to chemoreflex activation was also not affected by KYN (0.28 ± 0.02 versus 0.30 ± 0.04 Hz), MCPG (0.27 ± 0.03 versus 0.27 ± 0.04 Hz), or KYN plus MCPG (0.30 ± 0.04 versus 0.20 ± 0.03 Hz). The bradycardic response to chemoreflex activation was significantly reduced after microinjection of KYN at 2 (–220 ± 16 versus–50 ± 6 beats min–1) and 10 min (–220 ± 16 versus–65 ± 9 beats min–1) and after microinjection of KYN plus MCPG into the NTS it was abolished at 2 (–192 ± 14 versus–2 ± 1 beats min–1) and 10 min (–192 ± 14 versus–4 ± 2 beats min–1). These data support the hypothesis that the neurotransmission of the sympathoexcitatory and respiratory components of the chemoreflex in the cNTS involves neurotransmitters other than L-glutamate and also the concept that the parasympathetic component of this reflex is mediated by L-glutamate.
(Received 19 December 2005;
accepted after revision 26 January 2006; first published online 1 February 2006)
Corresponding author B. H. Machado: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil. Email: bhmachad{at}fmrp.usp.br
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Introduction |
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In the present study the experiments were performed in an in situ decerebrated working heart–brainstem preparation (WHBP), which allowed us to evaluate the changes in the heart rate, frequency of the phrenic nerve discharge (PND) and, mostly importantly, the direct record of the thoracic sympathetic nerve activity before and after microinjections of ionotropic and metabotropic glutamate receptor antagonists into the cNTS. The WHBP is a suitable model to evaluate the responses to chemoreflex activation because it presents patterns of autonomic and respiratory responses that are quite similar to those seen in awake rats (Paton et al. 2002; Antunes et al. 2005). In addition, the use of the WHBP avoids the undesirable changes in the baseline of the mean arterial pressure produced by different glutamate receptor antagonists because the WHBP is artificially perfused and the perfusion pressure is kept at low levels (50–70 mmHg). Therefore, the main purpose of the present study was to evaluate whether or not the increase in the sympathoexcitation in response to chemoreflex activation would be prevented by the antagonism of the glutamate receptors in the cNTS.
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Methods |
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The Ethical Committee for Animal Experimentation of the School of Medicine of Ribeirão Preto, University of São Paulo approved all procedures and experimental protocols used in this study during the ordinary meeting on December 1st, 2003.
General surgical procedures
The experiments were performed in an in situ unanaesthetized decerebrated WHBP as previously described by Paton (1996). Twenty-three male Wistar rats (70–90 g) were used in our experiments and provided by the Animal Care House of the University of São Paulo. Rats were anaesthetized deeply with halothane (AstraZeneca do Brazil Ltda, Cotia, SP, Brazil) in a small chamber, and the level of anaesthesia was assessed by absence of response to a noxious pinch of either the paw or the tail. Following subdiaphragmatic transection, the rostral half of the animal was submerged in cooled artificial cerebrospinal fluid (ACSF) that was carbogen gassed (95% O2 and 5% CO2), decerebrated at the precollicular level and skinned. The descending aorta was isolated, and the heart exposed by removal of the left ribs and the lungs. The dorsal surface of the brainstem was exposed by removal of the occipital bone and cerebellum. The WHBP was moved to a recording chamber; then the descending aorta was cannulated and perfused retrogradely with ACSF (mM): NaCl, 125; NaHCO3, 24; KCl, 5; CaCl2, 2.5; MgSO4, 1.25; KH2PO4, 1.25; dextrose, 10; and oncotic agent (Ficoll® 70, 1.25%; Sigma, St Louis, MO, USA) using a roller pump (Watson-Marlow 502s, Falmouth, UK) via a double-lumen cannula. A neuromuscular blocker (vecuronium bromide, 0.04 mg ml–1, Norcuron, Organon Teknika, São Paulo, Brazil) was used to prevent the chest wall respiratory movements. Perfusion pressure was maintained in a narrow range (50–70 mmHg) by adjusting flow rate of the perfusion pump. The perfusate was gassed with carbogen continuously, warmed to 32°C and filtered using a nylon mesh (pore size, 25 µm, Millipore, Billerica, MA, USA).
Recordings of electrocardiogram and nerve activities
Left phrenic nerve activity was recorded from its central end using a glass suction electrode held in a micromanipulator (Narishige, Tokyo, Japan). Rhythmic ramping phrenic nerve discharge (PND) gave a continuous physiological index of the preparation viability. The electrocardiogram (ECG) was visible on the phrenic nerve recording, which allowed us to evaluate the heart rate (HR) by using a low-pass filter. Sympathetic nerve activity was recorded from the thoracic sympathetic chain (tSNA) at the level of T5–T10 using a second glass suction bipolar electrode. Signals were AC amplified, bandpass filtered (8 Hz to 3 kHz) and displayed on a computer using the software Spike 2 (Cambridge Electronic Design, Cambridge, UK).
Activation of peripheral chemoreceptors
Potassium cyanide solution (KCN, 0.05 ml of 0.05% solution) was injected into the descending aorta via the perfusion cannula to excite peripheral chemoreceptors as used previously (Paton et al. 1999; Antunes et al. 2005).
Microinjections into the cNTS
The calamus scriptorius (CS) was used as a landmark for the determination of the sites of microinjections into the cNTS. Drugs were microinjected bilaterally via a three-barrelled micropipette (tip diameter, 20–30 µm). The tip of the micropipette was driven into the medulla to a depth of 0.3–0.4 mm ventral to the dorsal surface, 0.2–0.4 mm caudal relative to CS and between 0.25 and 0.35 mm from the mid-line (bilaterally). The injected volume for all drugs (
20 nl) was determined by previous calibration of the pico-pump system (Picospritzer II, Parker Instruments, Dayton, OH, USA). At the end of the experiments the brain was removed, fixed in 10% buffered formalin for 1 week, and serial coronal sections (16 µm) were cut and stained by the Nissl method in order to verify the micropipette track and the centre of microinjections in the cNTS.
Antagonists microinjected into the cNTS
Kynurenic acid (KYN) and (+/–)--methyl-4-carboxyphenylglycine (MCPG) were obtained from Sigma. Drugs were dissolved in saline (0.9% NaCl) and adjusted to pH 7.4. Concentrations are expressed as the free base of each drug. In preliminary experiments (data not shown) we verified that concentrations of KYN lower than 250 mM were not effective in blocking the responses to microinjection of L-glutamate into the cNTS in the WHBP. The concentration of MCPG (100 mM) was used in accordance with previous studies from our laboratory in which this concentration was effective in blocking the responses elicited by microinjection of trans-[15,3R]-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) into the NTS of awake rats (Antunes & Machado, 2003).
Data analysis
All data were analysed off-line using Spike 2 software with custom-written programs. Baseline and peak reflex responses in HR were measured. Phrenic burst frequency (i.e. respiratory cycle frequency) was measured, and the changes were evaluated by comparing the phrenic burst frequency observed at the peak of the response during chemoreflex activation to the baseline values. These data were expressed as change in the frequency of the PND (
Hz). The rectified and integrated signal of the tSNA (100 ms time constant) was measured for a period covering 20 s before and 20 s after chemoreflex activation. Data of tSNA were normalized as percentage of control values, and changes in the tSNA during chemoreflex stimulation were calculated as the difference between the peak of the response and the baseline measured before each stimulus. The significance of effects was assessed by one-way ANOVA followed by Tukey's post hoc test (P < 0.05) to evaluate the changes in the frequency of the PND as well as to evaluate changes in tSNA and HR after chemoreflex activations. All values are expressed as the mean ±S.E.M., and n is the number of preparations.
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Results |
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Figure 1 shows representative tracings that summarize the changes in tSNA, HR and frequency of the PND in response to chemoreflex activation before and at 2, 10, 30 and 45 min after the antagonism of the ionotropic glutamate receptors with kynurenic acid (KYN, 250 mM) in the cNTS bilaterally. Control chemoreflex activation elicited a striking increase in the thoracic sympathetic nerve activity (54 ± 3%; Fig. 2A). Chemoreflex activation at 2 (51 ± 2%), 10 (51 ± 3%), 30 (51 ± 3%) and 45 min (52 ± 1%) after bilateral microinjection of KYN into the cNTS produced no changes in the increase in the thoracic sympathetic nerve activity. Regarding the HR (Fig. 2B), the bradycardia produced by chemoreflex activation was significantly reduced at 2 (from –220 ± 16 to –50 ± 6 beats min–1), 10 (from –220 ± 16 to –65 ± 9 beats min–1) and 30 min (from –220 ± 16 to –113 ± 15 beats min–1) after the antagonism of the ionotropic glutamate receptors with KYN microinjected bilaterally into the cNTS.
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Hz) in response to chemoreflex activation before and at 2 (0.30 ± 0.04 Hz), 10 (0.24 ± 0.02 Hz), 30 (0.25 ± 0.02 Hz) and 45 min (0.23 ± 0.02 Hz) after antagonism of ionotropic glutamate receptors with KYN, which produced no changes in the increase in the frequency of the PND compared to the control chemoreflex activation (0.28 ± 0.02 Hz). Microinjection of the KYN produced no changes in the baseline of the frequency of PND (n= 11, n.s.). Changes in tSNA, HR and frequency of PND in response to chemoreflex activation before and after bilateral microinjection of MCPG (100 mM) into the cNTS
Figure 3 shows representative tracings that summarize the changes in tSNA, HR and frequency of the PND in response to chemoreflex activation before and at 2, 10, 30 and 45 min after the antagonism of the metabotropic glutamate receptors with MCPG (100 mM) in the cNTS. Control chemoreflex activation elicited a striking increase in the thoracic sympathetic nerve activity (48 ± 5%; Fig. 4A). Chemoreflex activation at 2 (54 ± 5%), 10 (56 ± 5%), 30 (52 ± 2%) and 45 min (56 ± 6%) after bilateral microinjection of MCPG into the cNTS produced no changes in the increase in the thoracic sympathetic nerve activity. Regarding the HR (Fig. 4B), the bradycardia produced by chemoreflex activation at 2 (–201 ± 27 beats min–1), 10 (–175 ± 27 beats min–1), 30 (–217 ± 22 beats min–1) and 45 min (–210 ± 22 beats min–1) after the antagonism of the metabotropic glutamate receptors with MCPG microinjected bilaterally into the cNTS was not different compared with the control response (–205 ± 26 beats min–1).
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Hz) in response to chemoreflex activation before and at 2 (0.27 ± 0.04 Hz), 10 (0.27 ± 0.05 Hz), 30 (0.25 ± 0.04 Hz) and 45 min (0.27 ± 0.03 Hz) after the antagonism of metabotropic glutamate receptors with MCPG, which produced no change in the increase in the frequency of PND compared to the control chemoreflex activation (0.27 ± 0.03 Hz). Microinjection of the MCPG produced no changes in the baseline of the frequency of PND (n= 7, n.s.). Changes in tSNA, HR and frequency of PND in response to chemoreflex activation before and after bilateral microinjection of kynurenic acid (250 mM) and MCPG (100 mM) into the cNTS
Figure 5 shows representative tracings of one preparation, representative of the group, summarizing the changes in tSNA, HR and frequency of the PND in response to chemoreflex activation before and at 2, 10, 30 and 45 min after the antagonism of ionotropic and metabotropic glutamate receptors with KYN (250 mM) and MCPG (100 mM) in the cNTS. Control chemoreflex activation elicited a striking increase in the thoracic sympathetic nerve activity (57 ± 6%; Fig. 6A), and subsequent chemoreflex activations at 2 (55 ± 3%), 10 (51 ± 4%), 30 (47 ± 4%) and 45 min (49 ± 3%) after bilateral microinjection of KYN plus MCPG into the cNTS produced an increase in the thoracic sympathetic nerve activity which was similar to control values (57 ± 6%). Regarding the HR (Fig. 6B), the bradycardia produced by chemoreflex activation was abolished at 2 (from –192 ± 14 to –2 ± 1 beats min–1) and 10 min (from –192 ± 14 to –4 ± 2 beats min–1) after bilateral microinjection KYN plus MCPG into the cNTS.
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Hz) in response to chemoreflex activation before and at 2 (0.20 ± 0.03 Hz), 10 (0.22 ± 0.03 Hz), 30 (0.18 ± 0.04 Hz) and 45 min (0.28 ± 0.04 Hz) after antagonism of ionotropic and metabotropic glutamate receptors with KYN plus MCPG, which produced no change in the peak of the increase in the frequency of PND compared to the control chemoreflex activation (0.30 ± 0.04 Hz). Microinjection of KYN plus MCPG produced an increase in baseline of the frequency of PND at 2 and 10 min, which was statistically different from control baseline values (n= 5, P < 0.05). |
Discussion |
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With respect to the sympathoexcitation elicited by activation of peripheral chemoreceptors in the WHBP, our data show that the blockade of all subtypes of ionotropic and metabotropic glutamate receptors using non-selective glutamate receptor antagonists (KYN and MCPG) microinjected into the cNTS did not affect the striking increase in the thoracic sympathetic nerve activity, which is in accordance with previous studies from our laboratory performed in awake rats (Haibara et al. 1995, 1999; Machado & Bonagamba, 2005). The most important contribution of the present study to this issue is the evaluation of the role of L-glutamate and its ionotropic and metabotropic receptors in the neurotransmission of the sympathoexcitatory component of the chemoreflex in the cNTS, taking advantage of the recordings of direct sympathetic nerve and phrenic nerve discharge as indices of the autonomic and respiratory responses, respectively, to chemoreflex activation.
Previous studies performed in anaesthetized rats documented that the pressor response to chemoreflex activation was significantly reduced by the blockade of ionotropic glutamate receptors in the same subregion of the NTS explored in the present study (Zhang & Mifflin, 1993; Vardhan et al. 1993). However, those studies were performed under anaesthesia, which could compromise the chemoreflex responses, since we have reported that anaesthesia profoundly affects the responses to microinjection of L-glutamate into the NTS (Machado & Bonagamba, 1992).
Studies by Haibara et al. (1995, 1999) performed in awake rats have shown that ionotropic glutamate receptor antagonists such as DNQX and KYN produce significant changes in the baseline of the mean arterial pressure, probably by blocking neurones involved in the sympathoinhibitory pathways of the baroreflex. Thus, in a previous study, Haibara et al. (1999) verified that the magnitude of the pressor response to chemoreflex activation after microinjections of KYN into the commissural NTS was significantly reduced, which might be explained, at least in part, by the large increase in the baseline of the mean arterial pressure. Furthermore, in a recent study we verified that the infusion of sodium nitroprusside (I.V.) in order to normalize the mean arterial pressure, previously increased in response to kynurenic acid microinjection into the NTS, showed that the magnitude of the pressor response to chemoreflex activation was similar to the control responses, suggesting that L-glutamate does not have a major role in the neurotransmission of the sympathoexcitatory component of the chemoreflex (Machado & Bonagamba, 2005).
The present data strongly support the hypothesis that L-glutamate and its receptors might not be involved in the neurotransmission of the sympathoexcitatory component of the chemoreflex in the cNTS. First, the concentration of antagonists used in our experiments was effective in blocking the response elicited by the microinjection of L-glutamate into the cNTS in the WHBP (data not shown). Second, although there is anatomical evidence that carotid body afferents have a fairly termination field in the NTS and some of these afferents even appear to go beyond the NTS to caudal ventrolateral medulla (Finley & Katz, 1992), physiological evidence supports the concept that the cNTS is the NTS subnucleus essential for the processing of chemoreflex responses (Chitravanshi et al. 1994; Chitravanshi & Sapru, 1995; Sapru, 1996; Colombari et al. 1996; Sato et al. 2003). Studies by Colombari et al. (1996), for example, showed that electrolytic lesion of the cNTS abolishes the bradycardic response and significantly reduces the pressor response elicited by chemoreflex activation.
With respect to the bradycardic response to peripheral chemoreflex activation, previous studies from our laboratory documented that the parasympathetic component of the chemoreflex is mediated by ionotropic NMDA glutamate receptors at the cNTS level (Haibara et al. 1995, 1999). The data of the present study are consistent with this previous study, since KYN almost abolished the bradycardic response elicited by chemoreflex activation. In addition to the role of ionotropic NMDA glutamate receptors in mediating the parasympathetic response to chemoreflex activation, our results show that there is a role for metabotropic glutamate receptors in the parasympathetic pathway as well, because the bradycardic response was attenuated by KYN and completely abolished when KYN was combined with MCPG. Interestingly, MCPG alone had no effect on the bradycardic response elicited by chemoreflex activation.
Regarding the respiratory responses to activation of peripheral chemoreceptors, our data show that chemoreflex activation in the WHBP produced an increase in the frequency of PND. The magnitude of the increase in the frequency of PND was not affected by blockade with KYN, MCPG, or KYN + MCPG, which is in accordance with studies performed by Haibara et al. (1995) showing that (+/–)-2-amino-5-phosphonopentanoic acid (AP-5), a selective NMDA glutamate receptor antagonist, microinjected into the cNTS did not affect the increase in respiratory frequency elicited by chemoreflex activation in awake rats. In addition, there is evidence in the literature that during hypoxia L-glutamate is released in the NTS and somehow participates in the increase in respiration, since previous microinjection of (–)-MK-801 Hydrogen Maleate (MK801) or KYN into the cNTS decreased the tidal volume without affecting the increase in the respiratory frequency elicited by hypoxia in vivo (Mizusawa et al. 1994). Our data are in agreement with these findings, since we were not able to block the increase in the frequency of the PND elicited by peripheral chemoreflex activation, although under KYN we qualitatively observed a reduction in the amplitude of the PND in the control recordings as well as in the response to chemoreflex activation (Figs 1 and 5).
Previous studies from our laboratory performed in the WHBP (Braga et al. 2005) have shown that the microinjection of glutamate into the cNTS activates ionotropic glutamate receptors, resulting in a decrease in the frequency of PND and sympathoexcitation, which were prevented by previous microinjection of kynurenic acid. Considering that L-glutamate microinjected into the cNTS produces a decrease in the PND, these data suggest that this neurotransmitter would not be involved in the tachypnoeic response elicited by chemoreflex activation, while the tSNA was increased by the microinjection of this excitatory amino acid (EAA). In contrast, the sympathoexcitation elicited by chemoreflex activation was not affected by the blockade of the cNTS with KYN. In this way, we might suggest that L-glutamate would be activating neurones in the cNTS which may send projections to RVLM in order to increase the sympathetic outflow. However, these neurones and projections apparently are not integral to the chemoreflex pathways since KYN had no effect on the sympathoexcitatory response of the chemoreflex.
In conclusion, the data of the present study support the hypothesis that L-glutamate and its receptors are not involved in the neurotransmission of the sympathoexcitatory component of the chemoreflex in the commissural subnucleus of the NTS and are in accordance with previous data obtained in awake rats. In contrast, the parasympathetic component of the chemoreflex seems to be mediated by both ionotropic and metabotropic glutamate receptors. The increase in the frequency of phrenic nerve discharge in response to chemoreflex activation apparently does not involve glutamate receptors, although we cannot exclude a role for glutamate in the modulation of the amplitude of the PND which in vivo may contribute to the changes in tidal volume. The possible involvement of neurotransmitters other than L-glutamate, such as ATP, in the processing of the sympathoexcitatory and respiratory components of the chemoreflex, is an open field to be explored further.
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References |
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Antunes VR & Machado BH (2003). Antagonism of glutamatergic metabotropic receptors in the NTS of awake rats does not affect the gain of the baroreflex. Auton Neurosci 103, 65–71.[CrossRef][Medline]
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Colombari E, Menani JV & Talman WT (1996). Commissural NTS contributes to pressor responses to glutamate injected into medial NTS of awake rats. Am J Physiol 270, R1220–R1225.[Medline]
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tSNA), heart rate (HR) and frequency of phrenic nerve discharge (
