Am J Physiol Heart Circ Physiol 292: H408-H414, 2007.
First published September 22, 2006; doi:10.1152/ajpheart.00881.2006
0363-6135/07 $8.00
Differential responsiveness of RVLM sympathetic premotor neurons to hypoxia in rabbits
Tadachika Koganezawa and
Naohito Terui
Department of Physiology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
Submitted 15 August 2006
; accepted in final form 17 September 2006
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ABSTRACT
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To determine whether differential sympathetic nerve responses to hypoxia are explained by opposing effects of hypoxia upon sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), the cardiac sympathetic nerve and the renal sympathetic nerve were recorded in anesthetized and vagotomized rabbits. Renal sympathetic nerve was activated by the injection of sodium cyanide solution close to the bifurcation of the common carotid artery and/or by inhalation of hypoxic gas (3% oxygen-97% nitrogen). On the other hand, cardiac sympathetic nerve was inhibited by these stimuli. Barosensitive (inhibited by the stimulation of baroreceptor afferents) reticulospinal (antidromically activated by the stimulation of the spinal cord) neurons in the RVLM were divided into three groups according to their responses to hypoxic stimulation: neurons (Type I, n = 25), the activity of which was inhibited by the injection of sodium cyanide solution close to the bifurcation of the common carotid artery and/or by inhalation of hypoxic gas, neurons (Type II, n = 99), the activity of which was facilitated by the same stimulation, and neurons (Type III, n = 11), the activity of which was not changed. These data indicated that the differential responses of cardiac and renal sympathetic nerves might be due to opposing effects of hypoxia on individual RVLM neurons.
rostral ventrolateral medulla; cardiac sympathetic nerve; renal sympathetic nerve; chemoreceptor; regional different response
PREMOTOR NEURONS for cardiovascular sympathetic nerves are located in the rostral ventrolateral medulla (RVLM) and have been called RVLM neurons (6, 8, 15). In almost all of the previous papers, the consensus is that RVLM neurons have tonic activity; receive information from baroreceptors, chemoreceptors, and other peripheral and central sources; and control vasoconstrictors and cardiac sympathetic nerve activity (CSNA) that control heart function and arterial pressure (15). Because the activities of cardiac accelerators and vasoconstrictors usually proceed in the same direction, for instance, in the case of the baroreceptor reflex, it has not been established whether a single premotor neuron innervates both of the preganglionic neurons of cardiac accelerators and vasoconstrictors or premotor neurons differentially control functionally different target neurons.
Generally, a hypoxic stimulation is believed to excite sympathetic nerves, as well as visceral vasoconstrictors and muscle vasoconstrictors (12). However, it has been known that hypoxia produces different responses in sympathetic nerves. For example, hypoxia induces inactivation of cutaneous vasoconstrictors in cats, rats, and rabbits (7, 9). Furthermore, at least in the rabbit, hypoxia induces bradycardia through the inhibition of the activity of the cardiac sympathetic nerve (10). Therefore, by hypoxic stimulation of rabbits, barosensitive reticulospinal neurons could be divided into two groups; one group shows inhibitory responses to hypoxia and consists of premotor neurons for the cardiac sympathetic nerve and/or sympathetic nerves, which are inhibited by hypoxia, and the other shows excitatory responses to hypoxia and is those for visceral and/or muscle vasoconstrictors.
In our present study, we first confirmed the inhibitory responses of the cardiac sympathetic nerve and bradycardia to hypoxic stimuli in vagotomized animals. Second, we analyzed the responses of barosensitive reticulospinal neurons in the RVLM to hypoxia, and then we attempted to determine whether differential sympathetic responses to hypoxia are explained by opposing effects of hypoxia upon sympathetic premotor neurons.
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MATERIALS AND METHODS
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Animal preparation.
Experiments were performed on 27 Japanese white rabbits of both sexes weighing between 3.0 and 5.0 kg. Three percent halothane (Takeda) administered through a face mask was used to induce anesthesia, and then urethane (1 g/kg body wt, Tokyo Kasei) was intravenously administered through a polyethylene catheter (SP61, Natsume) inserted into the right femoral vein. While the fluctuations of arterial pressure and heart rate were monitored, an additional dose of the anesthetic was administered when necessary. The Animal Experimental Committee of the University of Tsukuba approved the protocol for these experiments. After the trachea was cannulated, the animals were administered with gallamine triethiodide (Sigma) to cause paralysis, initially 30 mg iv, and thereafter 20 mg/h iv with an infusion pump (STC-521, Terumo). The vagus nerves of both sides were cut at the neck level to prevent vagally mediated changes in heart rate with hypoxia. Animals were ventilated artificially with a respiratory pump (661, Harvard) with a gas mixture of room air and O2 (20%). End-expiratory CO2 concentration was monitored (Respina IH26, Sanei-NEC) and maintained between 3.5% and 4.5% by adjusting the ventilation volume. In a single experiment, end-expiratory CO2 maintained within ± 0.1%. Rectal temperature was maintained at 39.0 ± 0.5°C using a thermostatically regulated heating pad, and an infrared lamp was connected to a rectal thermosensor probe. The animals were mounted prone in a stereotaxic frame. To confirm whether the evoked bradycardia was mediated through the withdrawal of activity of the cardiac sympathetic nerve, a 
-blocker (propranolol hydrochloride, 1 mg/ml, 0.5 mg/kg body wt iv, Astra Zeneca) was injected through the catheter of the femoral vein in vagotomized animals.
Measurement of cardiovascular parameters.
Instantaneous arterial pressure (AP) was monitored continuously in all experiments. AP was monitored from the abdominal aorta by using a polyethylene catheter (SP70, Natsume) inserted through the right femoral artery and connected with a transducer (MPU-0.5,Nihon Kohden) to a carrier amplifier (AP-621G, Nihon Kohden). An amplified AP signal was fed to a tachometer (AT-600G, Nihon Kohden) for counting heart rate.
Recording of activities of the single neurons and nerves.
The head of an animal was fixed to a stereotaxic frame with the head tilted forward. The angle was adjusted such that the bregma was set 10 mm below the lambda. The floor of the fourth ventricle was exposed near the obex through the dorsal aspect. Single unit activity of neurons in the left ventral medulla was recorded using micropipettes filled with 0.5 M sodium acetate and 2% pontamine sky blue for marking and mounted in a hydraulic micromanipulator (M0-81, Narishige). The tip resistance of the electrode was between 8 and 10 M
. Single unit activity was amplified (MEZ-8201, Nihon Kohden) with reference to a ground plate attached to a neck muscle. The site of unit recording was marked by the dye that was expelled following the passage of 10–20 µA current (electrode negative) for about 10 min. The stereotaxic coordinates of the point of entry were determined visually with reference to the rostral margin of the area postrema in the midline, that is, the obex, which was defined as stereotaxic zero. The area explored for single unit recording extended between 1.5 and 4 mm rostral to the obex, between 2.5 and 4 mm to the left of the midsagittal plane, and between 0 and 2.5 mm above the ventral surface of the medulla. We searched for all neurons in the left medulla. Recording procedures were as follows: when a spontaneously active neuron in the rostral ventrolateral medulla was encountered, we tested the response of the neuron to electrical stimulation of the left aortic nerve (AN, see Stimulation of chemoreceptors, the AN, and the spinal cord). If the neuron was inhibited by the AN stimulation, we then determined its spinal projection by the electrical stimulation of the dorsolateral funiculus of the second cervical spinal cord. After the neuron was confirmed as a barosensitive reticulospinal neuron, we started recordings.
After the heads of the left first and second ribs were removed, the cardiac sympathetic nerve was identified near the aorta and then isolated from the surrounding tissue. The left renal nerve was approached retroperitoneally by a left flank incision and prepared for recording near the renal artery. The central cut end of each nerve was placed across a pair of silver-wire electrodes connected to an amplifier. The low and high cutoff frequencies of this recording system were 100 and 5,000 Hz, respectively. The multifiber activities of the CSNA and the renal sympathetic nerve (RSNA), as well as the spikes of reticulospinal neurons (see Stimulation of chemoreceptors, the AN, and the spinal cord), were converted to standard pulses using window discriminators (EN-601J, Nihon Kohden). The threshold of a window discriminator was adjusted to be slightly higher than the noise level. Responses were analyzed by counting these pulses. All of the exposed nerves (including the AN, Stimulation of chemoreceptors, the AN, and the spinal cord) were covered with mineral oil or a mixture of mineral oil and petroleum jelly to prevent drying.
Stimulation of chemoreceptors, the AN, and the spinal cord.
In nine animals, a thin polyethylene tube (PE-10, outer diameter, 0.61 mm, Becton Dickinson) was inserted through the left thyroid artery. The tip of this tube was located at the bifurcation of the common carotid artery. A small amount (0.2 ml) of sodium cyanide (25 µg/ml heparinized saline) was injected to activate peripheral chemoreceptors.
In all animals, hypoxic gas (3% O2-97% N2) was applied through the artificial respirator for 1 min to activate peripheral chemoreceptors.
The left AN was exposed by a flank incision of the neck and isolated from the surrounding tissue. The central cut end of the AN was placed across a pair of silver wire electrodes spaced 2–3 mm apart. Electrical stimuli for the AN were square-wave pulses of 0.2 ms and 100 Hz. To activate AN A-fibers selectively, the stimulus intensity was set at <1.5 V (19). Aortic nerve A-fibers of rabbits are devoid of chemoreceptor afferents (5). All these stimulus pulses were delivered to the animal from a pulse generator (SEN 7103, Nihon Kohden) through an isolation unit (Ss-401J, Nihon Kohden).
To examine whether neurons in the RVLM sent descending bulbospinal projections, they were tested for antidromic activation. Unipolar polyurethane-coated tungsten wire electrodes (<10 µm tip diameter) were placed in the dorsolateral funiculus of both sides by direct vision following laminectomy at the second segment of the cervical spinal cord. Electrodes were inserted immediately lateral to the dorsal root entry and 0.75–1.5 mm below the dorsal surface of the spinal cord. The stimulation site was determined such that the maximum excitation of the cardiac and/or renal sympathetic nerve was elicited by stimulation using three pulses with an intensity of 50 µA, 0.2 ms in duration at intervals of 10 ms. The reason for stimulating the dorsolateral funiculus of the spinal cord at the second cervical segment for the antidromic excitation of neurons in the ventral medulla, rather than the intermediolateral cell column as in previous studies (1, 2), is given in the paper by Terui et al. (27). Briefly, if the stimulation was applied to the thoracic spinal cord, most of the antidromic spikes would collide with a spontaneously occurring spike because of a slow conduction velocity and a long distance from the stimulus site to the medulla. For the antidromic activation of medullary neurons, single-pulse stimulation of which intensity was adjusted to be 1.2–1.5 times the threshold, was usually lower than 500 µA (range 30–1,500 µA). The conduction velocity of a descending axon was estimated on the basis of the onset latency for the antidromic spike and distance between the stimulation and recording sites, both at the points of entry of electrodes. Antidromic spikes were identified by the collision test (16) in all cases.
Data analysis.
The discharges of reticulospinal neurons and nerves, various cardiovascular parameters, stimulus temperature, and stimulus marks were recorded directly onto a computer hard drive through an AD converter (1401 plus, Cambridge Electronic Design) and analyzed using data capture and analysis software (Spike2, Cambridge Electronic Design).
The peristimulus time histograms of single neuronal activity, CSNA, and RSNA were constructed using the same analysis software (Spike2, Cambridge Electronic Design). Perievent time histograms, the bin width of which was 5 ms, were constructed from 128 to 256 trials.
The maximal response magnitude of the sympathetic nerves or reticulospinal neurons for hypoxic gas inhalation for 1 min was expressed as the percent change from the prestimulus level (100%). The mean frequency of the pulses of the nerves or neurons (outputs of the window discriminators) for 120 s immediately before stimulation was defined as the control (prestimulus level). Although the maximal response was evoked almost at the end of stimulation (see Table 2), its latency varied in each experiment. After the onset of stimulation, the records were delimited every 10 s, and the time point where the maximal change was observed was determined. The mean frequency of this span of time was defined as the maximal response, and the time of this address was also used as the peak latency. The maximal response magnitude was defined as (maximal response – control) x 100/control (%). A negative sign means an inhibitory response. In the case of neurons, the activity (counts in every 10 s) of which was within ±15% of the control during stimulation, we considered that no response was evoked. The response magnitude of the activity of the sympathetic nerves or reticulospinal neurons to electrical stimulation of the AN (for 10 s stimulation) was calculated similarly by comparing the mean pulse frequency for 10 s immediately before the stimulation and that for 5 s after the start of stimulation. In the case of stimulation with a short train of pulses stimulation, perievent time histograms were constructed. Because the response latencies of the neurons were different from those of the nerves, response magnitude was calculated at different times. The mean frequency for 50–100 ms (neurons), 175–225 ms (CSNA), or 200–250 ms (RSNA) after the start of stimulation was compared with that for 100 ms immediately before stimulation. The onset latencies of responses of neurons and nerves were determined by the time when the activities reached 20% of the maximal response. Time resolutions were 10 s for the stimulation by hypoxic gas inhalation, 1 s for continuous stimulation of the AN, and 5 ms for stimulation of the AN with a short train of pulses.
Numerical data were expressed as range and/or means ± SD. To statistically compare two different groups, we used Student's t-test. To compare more than three groups, we used one-way ANOVA. To study the correlation of two different groups, we used regression analysis. The level of significance was at P < 0.05.
Histological examination.
At the end of each experiment, the rabbit was perfused with 2 liters of physiological saline followed by 2 liters of 10% formaldehyde (WAKO) through the heart. The brain was removed and immersed in 10% formaldehyde for 2–5 days. The medulla was coronally sliced into sections and then stained with neutral red, so that the recording and stimulation sites could be assessed microscopically.
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RESULTS
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Cardiovascular responses to injected sodium cyanide and inhaled hypoxic gas.
It is well known that the application of sodium cyanide close to the bifurcation of the common carotid artery excites peripheral chemoreceptors. In vagotomized rabbits (n = 3), the injection of sodium cyanide into the carotid artery induced bradycardia (–27.0 ± 7.5 beats/min) and pressor responses (17.8 ± 3.7 mmHg) (Fig. 1A). The inhalation of the hypoxic gas for 1 min produced a much larger bradycardia response (–64.7 ± 13.8 beats/min) and pressor responses (29.7 ± 6.4 mmHg) (Fig. 1B). Both of the bradycardia responses were completely abolished by a systemic administration of the -blocker propranolol (0.5 mg/kg iv) (cyanide; –5.2 ± 0.9 beats/min, hypoxia; –8.9 ± 3.8 beats/min), but pressor responses persisted (cyanide: 20.2 ± 4.6 mmHg, hypoxia: 37.0 ± 11.7 mmHg) (Fig. 1, C and D).
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Fig. 1. Effects of injection of sodium cyanide into the bifurcation of the common carotid artery and inhalation of hypoxic gas. Each panel depicts heart rate (HR, top trace) and arterial blood pressure (AP, bottom trace). Arrows in A and C show injection timings of sodium cyanide. Horizontal bars in B and D show a period of hypoxic gas inhalation. A and B before and C and D after intravenous injection of propranolol are represented.
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Barosensitive reticulospinal neurons.
One hundred thirty-five barosensitive reticulospinal neurons in the RVLM (RVLM neurons) were recorded. Because the following parameters were not significantly different among the three neuronal groups (see Responses of RVLM neurons and sympathetic nerves to inhaled hypoxic gas), we summarized them here collectively as one. Details are shown in Table 1. All neurons were spontaneously active (firing rate 16.4 ± 10.4 Hz, n = 135) and inhibited following the continuous and short-train pulse stimulations of the AN, which inhibited CSNA and RSNA (Fig. 2, A and B). For the continuous stimulation (for 10 s) of the AN, the response magnitude of neurons, CSNA, and RSNA were –56.1 ± 20.7%, –59.9 ± 9.7%, and –73.3 ± 18.0%, respectively. For the short-train pulse stimulations (for 100 ms) of the AN, the response magnitude of neurons, CSNA, and RSNA were –78.0 ± 16.5%, –79.3 ± 19.5%, and –81.0 ± 18.6%, respectively. A sample of collision test for the identification of spinal projection is shown in Fig. 2C.
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Table 1. Onset latencies to the short train pulses stimulation of the aortic nerve, spontaneous activities, and conduction velocities of Type I, II, and II neurons
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Fig. 2. Identified barosensitive reticulospinal neuron (rostral ventrolateral medulla neuron). A: response of a neuron to continuous (10 s) stimulation of the aortic nerve (AN). From top to bottom, activities of single neuron (Neuron), the cardiac sympathetic nerve (CSNA), the renal sympathetic nerve (RSNA), HR, and AP. Stimulus (horizontal bar) was applied to the AN (1.5 V, 0.2 ms, 100 Hz for 10 s). Activities of single neuron and multifibers of the sympathetic nerves were counted every 1 s. B: responses of a neuron to short train pulses stimulation of the AN. Stimulus (horizontal bars) was applied to the AN (1.5 V, 0.2 ms, 10 pulses, 100 Hz). Number of trials was 128. One bin was 5 ms. C: collision test. Five superimposed traces for the collision test. Stimuli (arrows) were applied 4.5 ms (top traces) and 4.8 ms (bottom traces) after spontaneous occurring spikes (open circles) to the dorsolateral funiculus of the second segment of the cervical spinal cord. *Antidromic spikes were evoked only after a critical delay after spontaneously occurring spikes.
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Responses of RVLM neurons and sympathetic nerve to injected sodium cyanide.
With injection of sodium cyanide close to the bifurcation of the common carotid artery, the CSNA was inactivated but the RSNA was activated (Fig. 3). We tested the effect of sodium cyanide injection on 40 RVLM neurons. After the injection of sodium cyanide, five RVLM neurons were inactivated (Fig. 3A), and 34 neurons were excited (Fig. 3B). One neuron did not respond to this stimulation.
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Fig. 3. Responses of a Type I neuron (A) and a Type II neuron (B) to injection of sodium cyanide into the bifurcation of the common carotid artery. Activities of a single neuron and multifibers of the sympathetic nerves were counted every 1 s. Arrows show injection timings of sodium cyanide.
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Responses of RVLM neurons and sympathetic nerves to inhaled hypoxic gas.
Of the 40 RVLM neurons described in the previous section, we also examined the effect of hypoxic gas inhalation. The directions of responses of these neurons to the inhaled hypoxic gas were same as those to the injected sodium cyanide. Because responses to the cyanide solution injected into the common carotid artery were small and the activities of neurons and nerves always fluctuated spontaneously, we needed larger responses to identify the response to hypoxia. Therefore, we determined the effect of hypoxic gas inhalation on the remaining 95 RVLM neurons (total, 135 RVLM neurons). The CSNA was inactivated but the RSNA was excited following the inhalation of hypoxic gas (Fig. 4). Onset of these responses usually preceded that of the hypoxia-induced depressor response. One hundred and twenty-four (92%)-barosensitive reticulospinal neurons responded to this hypoxic stimulation. Among them, 25 neurons were inactivated (Fig. 4A), and 99 neurons were excited (Fig. 4B). Eleven neurons did not respond to hypoxic stimulation. We termed these neurons Type I, Type II, and Type III neurons, respectively. The onset and peak latencies and the response magnitudes of RVLM neurons, the CSNA, and the RSNA are summarized in Table 2. There were no significant differences between the onset latencies of inhibitory responses of single neurons and those of the CSNA, and between the onset latencies of excitation of single neurons and those of the RSNA. In 4 of 25 Type I neurons, a small and a short period of excitation preceded the inhibitory response. In some cases, an early small excitation was also observed in the CSNA.
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Fig. 4. Responses of a Type I neuron (A) and a Type II neuron (B) to hypoxic gas inhalation. Activities of a single neuron and multifibers of the sympathetic nerves were counted every 10 s. Horizontal bars show periods of hypoxic gas inhalation.
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Projection and location of Type I, II, and III neurons.
Twenty of the Type I neurons (80%) projected to the ipsilateral spinal cord and the remaining projected to the contralateral side. Seventy five of the Type II neurons (76%) and six of the Type III neurons (55%) projected to the ipsilateral side. The estimated conduction velocities of axons of Type I, Type II, and Type III neurons projecting to the spinal cord are summarized in Table 1 and Fig. 5A. There were no significant differences between conduction velocities of Type I and Type II neurons, and between those of Type I and Type III neurons. Type III neurons, however, were significantly slower compared with Type II neurons (P < 0.05).
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Fig. 5. Conduction velocities and recording sites of Type I and Type II neurons. A: histograms of conduction velocities of the Type I neurons (open bars) and the Type II neurons (solid bars). B: recording sites of 25 Type I neurons (open circles), 99 Type II neurons (solid circles), and 11 Type III neurons (shaded circles) were illustrated on four successive coronal sections (2.0, 2.5, 3.0, and 3.5 mm rostral to the obex) of the medulla oblongata. 7; nucleus nervi facialis, Amb; nucleus ambiguus, IO; nucleus olivaris, py; tractus pyramidalis.
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The recording sites of Type I, II, and III neurons are summarized in Fig. 5B. All of the neurons were distributed at the rostral ventrolateral medulla. This extended from the area ventral to the facial nucleus and continued caudally in the region ventral to the nucleus ambiguus. The locations of the neurons were consistent with those of the RVLM neurons reported in a previous paper (27).
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DISCUSSION
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The most important findings of this study are that the barosensitive reticulospinal neurons in the RVLM were classified into three groups and differential sympathetic nerve responses to hypoxia may be explained by opposing effects of hypoxia upon sympathetic premotor neurons in the RVLM.
In the present study, we identified 135 reticulospinal neurons that were inactivated by the electrical stimulation of the AN. These barosensitive reticulospinal neurons are considered the same as the conventional "RVLM neurons" (6, 8) because all of the characteristics of the barosensitive reticulospinal neurons agreed with those of RVLM neurons previously reported, in terms of inhibition evoked by the activation of baroreceptors, the onset latency of the inhibitory response to the AN stimulation, conduction velocity, axonal projections (some of them projected to the contralateral spinal cord), and location in the ventral medulla (27).
RVLM neurons show heterogeneity in their response to stimulation of chemoreceptors in cats or cholecystokinin in rats (17, 25). However, it is still unclear what the different responses of RVLM neurons functionally mean. We simultaneously recorded the activities of RVLM neurons along with the cardiac and renal sympathetic outflows and observed their responses to hypoxia to investigate their functional significance.
In vagotomized rabbits, inhalation of hypoxic gas induced bradycardia, cardiac sympathoinhibition, and splanchnic sympathoexcitation (11). In the present study, with the use of vagotomized rabbits, the same stimulation also induced the activation of the renal sympathetic nerve, inactivation of the cardiac sympathetic nerve, and bradycardia that was abolished by -adrenoceptor blockade. To confirm whether these responses resulted from the activation of peripheral chemoreceptors, we examined the effect of sodium cyanide injection into the carotid artery and observed the same directions of sympathetic responses that were induced by the inhalation of hypoxic gas. These observations suggested that the inhalation of hypoxic gas produced these responses via the activation of the peripheral chemoreceptors.
Using microinjection of 
-aminobutyric acid (GABA) into the RVLM, Ootsuka and Terui (22) provided evidence that suggested that functionally different RVLM sympathetic premotor neurons are organized topographically. However, in the present study, Type I, Type II, and Type III neurons were intermingled in the RVLM. This result does not necessarily deny the previous report. We recorded from RVLM neurons in 24 rabbits in the present study and identified their locations histologically. Although topographical differences in RVLM neuron location may be detected in a single rabbit, such a difference may not be apparent when these are represented collectively, such as in Fig. 5. Some studies have suggested that sympathetic premotor neurons for cutaneous vasoconstrictors are located in the RVLM, at sites medial to the RVLM or nucleus raphé of the medulla (13, 18, 20, 24, 26). Chemoreceptor stimulation or hypoxia inhibits activity of cutaneous vasoconstrictors, including the supply to the rabbit's ear, which is a specialized heat exchanger (7, 9). Premotor neurons may also be inhibited by hypoxia. However, rabbit ear vasoconstrictor neurons are not barosensitive and do not respond to stimulation of the aortic nerve (13, 21). Therefore, there is little possibility that neurons recorded in the present study regulate cutaneous vasoconstrictors activity of the rabbit ear. In cats and rats, it has been reported that cutaneous vasoconstrictors are moderately barosensitive (7, 23). Type I neurons might include sympathetic premotor neurons for cutaneous vasoconstrictors, except for the ear skin.
Recently, it has been proposed that premotor neurons for the cardiac sympathetic nerve are located in the raphe nucleus. These neurons in the nucleus raphé were suggested to convey information from the hypothalamus to the spinal cord and do not participate in the baroreceptor reflex (3, 4). Our present study does not deny this theory. It is not surprising that premotor neurons of different functions for the cardiac sympathetic nerve exist in regions other than the RVLM.
At present, the function of Type III neurons was not clarified. In cats, the vasoconstrictors of muscles are activated by hypoxic stimulation (12). As far as we know, the responses of muscular vasoconstrictors of rabbits to hypoxic stimulation have not been clarified. A study of blood flow responses of the muscular bed to prolonged hypoxia (40 min) in rabbits showed that the contribution of the neural component is less in the muscular bed, at least the initial part of responses, than in the heart, skin, and visceral beds (14). Therefore, these Type III neurons had the possibility of controlling the vasoconstrictors for the muscular bed. The ratio (8% of the RVLM neurons), however, seemed to be too small if this type of neuron-innervated preganglionic neurons for muscular vasoconstrictors.
In conclusion, we found three groups of barosensitive reticulospinal neurons in the RVLM. One group of neurons showed inhibitory responses to hypoxic gas inhalation. Because these responses were very similar to those of the cardiac sympathetic nerve, it was concluded that these neurons might participate in controlling cardiac accelerators and other sympathetic nerves that are inhibited by hypoxia.
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GRANTS
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This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.
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ACKNOWLEDGMENTS
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We thank Kazumi Bunzui for technical assistance.
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FOOTNOTES
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Address for reprint requests and other correspondence: N. Terui, Dept. of Physiology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Univ. of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan (e-mail: terui{at}md.tsukuba.ac.jp)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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