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J Appl Physiol 90: 248-260, 2001;
8750-7587/01 $5.00
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Vol. 90, Issue 1, 248-260, January 2001

Dorsomedial medulla is more susceptible than rostral ventrolateral medulla to hypoxic insult in cats

Ling-Zong Hong1,2, Jon-Son Kuo2, Mao-Hsiung Yen1, and Chok-Yung Chai1,3

1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 100; 3 Institute of Biomedical Sciences, Academia Sinica, Taipei 115; and 2 Department of Education and Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We investigated the responses of systemic arterial pressure and vertebral sympathetic nerve activity to glutamate microinjections (0.1 M, 70 nl) in the dorsomedial (DM) and the rostral ventrolateral medulla (RVLM) before hypoxia and after reoxygenation (posthypoxia) after various degrees of hypoxia in anesthetized cats. Hypoxia was produced by ventilating 5% O2 and 95% N2 for different durations (hypoxia I-III). In intact cats, the glutamate-induced systemic arterial pressure and vertebral nerve activity responses of the DM were depressed after all degrees of hypoxia. Posthypoxic depression in the RVLM, however, was not observed until hypoxia II and III. Precollicular decerebration prevented depression in the RVLM, but, for the DM, it was effective only for hypoxia I. Baro- and chemoreceptor denervation abolished all posthypoxic depression in both the DM and the RVLM. Pressor responses to tyramine (100-400 µg/kg iv) remained unchanged after all degrees of hypoxia. These results suggest that the DM is more susceptible to hypoxia than the RVLM. The peripheral baro- and chemoreceptors and the suprapontine structures apparently play an important role in posthypoxic depression. Moreover, the depression is not due to the postganglionic norepinephrine depletion.

vertebral sympathetic nerve; reoxygenation; decerebration; baroreceptor; chemoreceptor


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE PRESSOR AREAS in the dorsomedial (DM) and the rostral ventrolateral medulla (RVLM) have been known to play an important role in cardiovascular integration (5, 6, 9, 32). Neurons in both areas provide tonic sympathoexcitatory influence on cardiovascular functions, although the RVLM apparently is more prominent (6, 32).

The central nervous system (CNS) of mammals is extremely sensitive to oxygen deprivation (hypoxia). Hypoxia triggers enormous biochemical and functional changes (24, 44). Severe hypoxia may lead to neuron injury or even death (24).

It is also well known that both central and peripheral mechanisms may mediate a wide variety of cardiovascular and sympathoexcitatory changes in response to hypoxia. The sympathoexcitatory responses may be mediated by a dramatic increase in the RVLM neuron discharge, consequent to the influx of calcium into the neurons directly responsive to hypoxia (39, 40, 43). The increases of the sympathetic efferent activity in hypoxia may be related to the excitation of the peripheral chemoreceptors, which cause transmitter releases and ion current changes in the carotid glomus cells (10, 19, 25). In addition to the RVLM, the DM is also known to be able to mediate peripheral baro- and chemoreceptor reflex functions and to mediate cardiovascular integration (11, 30). However, the DM has received much less attention than other areas of the brain as far as hypoxia is concerned.

It has been reported that neurons can acclimatize to some level of hypoxia, thus preventing hypoxic insult (46). In brain slices taken from two groups of rats preexposed to hypoxia (10% O2) for 4-5 days and 9-10 days, respectively, the basal pattern of discharge rate of the RVLM neurons was unchanged compared with the normoxic group. However, when the same preparations were challenged with hypoxia (10% O2 for 90 s) again, a greater increase in the neuron discharge was observed in the group preexposed to hypoxia for 4-5 days. The response of the neurons preexposed to hypoxia for 9-10 days remained the same as in the normoxic group. These data indicate that changes might have occurred in the RVLM neurons during the first 4-5 days, which is consistent with acclimatization to the hypoxic condition (28).

On the other hand, the responses to hypoxia of the RVLM neurons could be reproduced without adaptation during either systemic hypoxia produced by inhalation of 100% N2 for 12 or 20 s (26, 40) or local chemical hypoxia induced by iontophoretical application of sodium cyanide to the RVLM (37). The data suggest that a shorter period (in seconds) of hypoxia repeated a few times may not alter the function of the RVLM neurons. The glutamate-induced firing of the RVLM neurons after hypoxia was also found to be reversible (37, 42).

However, it is not known whether neurons in the DM would respond to hypoxia in the same way as in the RVLM. It is also not known what degree of hypoxia would cause significant change in the function of the neurons in the DM and the RVLM.

In the present study, functional changes to cardiovascular control related neurons in the DM and the RVLM after different degrees of hypoxia were investigated. By microinjection of glutamate into the DM and the RVLM, the induced responses of systemic arterial pressure (SAP) and vertebral nerve activity (VNA) were used as indexes for assessing neuronal function. The influences of suprapontine structures and peripheral baro- and chemoreceptors were also evaluated.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General Procedures

Cats of either sex, weighing 2.6-3.4 kg, were anesthetized with intraperitoneal alpha -chloralose (40 mg/kg) and urethane (400 mg/kg). The depth of anesthesia was determined by the smoothness of SAP, regularity of cardiac and sympathetic rhythm, and size of the pupil. When signs of light anesthesia were observed, one-tenth of the original dose of urethane and alpha -chloralose was supplemented intravenously as required. Cats were divided into three groups as follows: the intact cats (n = 18), containing intact brain and intact peripheral baro- and chemoreceptors; the precollicular decerebrate cats (n = 12); and the peripheral baro- and chemoreceptor-denervated cats (BC-receptor denervated, n = 12).

General preparation was as described previously (5, 6). Briefly, mechanical ventilation was maintained at an end-tidal CO2 of 3.5-4.0%. Rectal temperature was kept at 37.0 ± 0.5°C with a servo-controlled heating pad. Both femoral arteries were cannulated, one for monitoring SAP, mean SAP (MSAP), and heart rate, and the other for collecting blood samples for blood-gas measurements (ABL300/4, Radiometer). Blood samples were drawn before hypoxia, at the end of each episode of hypoxia, and after the 30-40 min of reoxygenation. All parameters were recorded with a Gould ES-1000 polygraph (Cleveland, OH). A femoral vein was cannulated for drug administration. Gallamine triethiodide (dissolved in saline, initially 5 mg/kg, supplemented with 5 mg · kg-1 · h-1; Sigma Chemical, St. Louis, MO) was used to paralyze the animal during the course of the experiments.

VNA Recording

The VNA, which is better correlated with the change in blood pressure than other sympathetic nerves in cats (8, 33), was used as an index for sympathetic nerve responses. The left sympathetic vertebral nerve was exposed and desheathed for whole bundle nerve recording, as described previously (8, 33). The electrophysiological setup, including a bipolar platinum electrode and a differential amplifier (band pass: 10-3 kHz), was used to amplify and record efferent activities of the nerve bundle. Nerve activities were rectified and integrated (Gould integrator 13-4615-70) with a reset time of 5 s. The signals were monitored with an oscilloscope (model 5113, Tektronix, Beaverton, OR) and stored on a tape recorder (model DR-890, Neuro Data, New York, NY) for later analysis. At the end of the experiments, the background noise, measured by integrating the null nerve activity 10 min after the animal had been killed, was subtracted from the raw nerve activity to calculate the actual nerve activity. The resting VNA was also calculated by integrating the actual nerve activity for 5 min before hypoxia and after reoxygenation after each episode of hypoxia.

Brain Stimulation

The head of the animal was fixed in a David-Kopf stereotaxic instrument. After occipital craniotomy, the pressor areas of the DM and the RVLM were explored as described previously (5, 6). The stereotaxic coordinates for the DM were 3.0-4.0 mm rostral to the obex, 2.0-2.5 mm lateral to the midline, and 0-2.0 mm ventral to the dorsal surface of the medulla. For the RVLM, the coordinates were 4.0-5.0 mm rostral to the obex, 3.5-4.0 mm lateral to the midline, and 3.5-4.5 mm ventral to the dorsal surface of the medulla. Brain stimulation was carried out with a double-barreled glass micropipette (outside-tip diameter, 25 µm). One barrel of the pipette was filled with 3 M NaCl and inserted with a platinum wire to serve as a monopolar electrode for electrical stimulation. The other barrel was filled with monosodium L-glutamate (Glu, 0.1 M, containing 1% pontamine sky blue dissolved in artificial cerebrospinal fluid at pH 7.4; Sigma Chemical) for chemical stimulation. The target sites for stimulation were initially explored by electrical stimulation (rectangular train pulses, 0.5 ms, 80 Hz, 100 µA, 10-15 s), followed by microinjection of Glu (70 nl over 5-10 s) with a pneumatic pump (Neuro Phore PPS-2 System, Medical Systems, Greenvale, NY). Glu injection was performed at a single point (either in the DM or in the RVLM) in most cats. In a few others, the injection was carried out bilaterally in the same cat with stimulation of the DM and the RVLM on each side but in random order. No significant difference was noted in such arrangement. The increased SAP and VNA after Glu injection usually took ~30-40 min to return to their resting levels. With such an interval, Glu injection could be repeated at least four times at the same point, either in the DM or in the RVLM, without significant change in the magnitude of the induced responses. This repeatability was also demonstrated in the cats with Glu stimulation in bilateral DM and RVLM in the same cat.

Precollicular Decerebration

Decerebration was accomplished by surgical transection of the brain stem rostral to the level of the superior colliculi after ligation of both external carotid arteries above the carotid bifurcation (5). This procedure removed influences from higher levels of the CNS.

Denervation of the Peripheral Baro- and Chemoreceptors

Denervation of the peripheral baro- and chemoreceptors was completed by bilateral section of both glossopharyngeal and vagal nerves at the cervical level. Complete denervation was verified by the loss of chemoreflex responses to sodium cyanide (100 µg/cat iv; Sigma Chemical) (25) and of baroreflex responses to phenylephrine (10 µg/kg iv; Sigma Chemical) and sodium nitroprusside (5 µg/kg iv; Merck, Darmstadt, Germany).

Hypoxia

Hypoxia was induced by switching the inspired gas of the ventilator from room air to a gas mixture of 5% O2 and 95% N2, which was verified by an oxygen monitor (MAXO2, model OM-25ME, Ceramatec, UT). After hypoxia was successfully induced, reoxygenation was initiated by allowing the cat to be ventilated with room air again. Reoxygenation for 30-40 min was sufficient to restore the blood gases, SAP, and VNA to their prehypoxic levels.

Three degrees of hypoxia (I, II, and III) were produced in all three groups of cats. For intact and decerebrate cats, the degree of hypoxia was defined as follows: hypoxia I, SAP increased and reached a maximal peak level; hypoxia II, SAP increased, maintained a period of time at its plateau, and then declined to reach the resting SAP level; hypoxia III, SAP continued to fall to a level of 50 mmHg (Fig. 1). Reoxygenation started immediately after each episode of hypoxia. The durations of hypoxia required for the intact and decerebrate cats were 72 ± 4 and 71 ± 4 s for hypoxia I, 141 ± 22 and 148 ± 14 s for hypoxia II, and 254 ± 43 and 250 ± 42 s for hypoxia III, respectively. For peripheral BC-receptor-denervated cats, the SAP responses to hypoxia did not follow the same pattern as for the intact and decerebrate cats; therefore, the maximal duration required to induce the level of hypoxia in intact cats was used. This was 80 s for hypoxia I, 180 s for hypoxia II, and 300 s for hypoxia III.


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  		Fig. 1.   Effects of different degrees of hypoxia on the cardiovascular functions and vertebral nerve activities (VNAs). In intact (top) and decerebrate (middle) cats, the rapidly increased systemic arterial pressure (SAP) during hypoxia I subsequently returned to its prehypoxic level after reoxygenation. A longer duration of hypoxia (II and III) was required to produce the typical SAP and VNA changes. On the contrary, in baro- and chemoreceptor-denervated (BC-receptor-denervated) cats (bottom), hypoxia induced a decrease in SAP against an increase in VNA. The extent of hypotension was proportional to the duration of hypoxia. A transient rebound of SAP and silence of VNA right after reoxygenation were noted. MSAP, mean systemic arterial pressure; HR, heart rate; b/min, beats/min; INT, integrated. Thick horizontal bar indicates the duration of hypoxia.

The following variables were also determined. The "onset time" was defined as the time from the beginning of hypoxia to the appearance of SAP or VNA responses. The "time to reach maximal change" was the time from the beginning of the response to the maximal change. The "maximal percent change" was calculated by dividing the maximal value of the response by the value before hypoxia (Table 1).

                              
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  		Table 1.   Onset time, time to reach maximal change, and maximal percent change of MSAP and VNA in response to hypoxia in intact, decerebrate, and peripheral BC-receptor-denervated cats

Experimental Protocol

Single-point microinjection in either the DM or the RVLM. For experiments in which a single-point microinjection in either the DM or the RVLM was performed, a control response to Glu microinjection was determined (the first injection, control). Hypoxia I was induced 30-40 min after Glu injection to allow a sufficient recovery from the stimulation. After hypoxia I, reoxygenation for 30-40 min was started immediately, and then the same dose of Glu was injected again into the same point for comparison (the second injection, posthypoxia I). After the second injection of Glu, similar procedures were performed for hypoxia II and III. Each episode of hypoxia was also followed by reoxygenation, posthypoxic Glu injection (i.e., the third injection, posthypoxia II, and the fourth injection, posthypoxia III), and recovery from each Glu stimulation. During the entire procedure, the micropipette was kept undisturbed in the same position. In short, each animal received a control microinjection of Glu and then was sequentially exposed to different degrees of hypoxia in an increasing order from degree I to degree III. After each episode of hypoxia, Glu stimulation was given each after 30-40 min of reoxygenation. The protocol is illustrated in the following time table
where Hp is hypoxia.

Bilateral microinjections in both the DM and the RVLM in the same cat. A control Glu injection was carried out in the DM (or the RVLM) on one side of the medulla, and then another control Glu injection was given in the RVLM (or the DM) on the other side of medulla. The sequence of injections for the DM or the RVLM was randomly chosen. After each Glu injection, 30-40 min were allowed for recovery from the stimulation. After the recovery, hypoxia I and reoxygenation were performed. A second Glu microinjection (posthypoxia I) was then given into the DM and the RVLM in the same sequence as that of the control Glu stimulation. A similar protocol was followed for hypoxia II and III at the following time table
In another series of experiments (intact cat, n = 6), tyramine (Tyr; 100, 200, and 400 µg/kg) was administered intravenously instead of Glu injections before hypoxia (control) and after reoxygenation (posthypoxia I-III) after each episode of hypoxia, to assess the norepinephrine store and release in the peripheral sympathetic nerve endings.

Histology

On completion of the experiments, the animals were killed by an overdose of saturated KCl administered intravenously. Brain sections of 50-µm thickness were cut with a cryostat microtome and stained with cresyl violet (5, 6). The sites receiving chemical stimulation were verified by pontamine sky blue staining.

Data Analysis

The influences of different degrees of hypoxia on blood gases were analyzed by one-way ANOVA with repeated measures. To compare the influences of different degrees of hypoxia and the effects of precollicular decerebration or denervation of peripheral baro- and chemoreceptors, the resting, the hypoxia-induced, and the Glu-induced SAP and VNA responses were analyzed by two-way ANOVA with repeated measures. The Student-Newman-Keuls test was employed for multiple comparisons. All values are expressed as means ± SE. A P value of < 0.05 was considered statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of Different Degrees of Hypoxia on Arterial Blood Gases

Changes in arterial blood-gas measurements (pH, PO2, and PCO2) before, during, and after hypoxia in eight intact cats, which had completed the entire course of the experiment from hypoxia I to III, are summarized in Table 2. Hypoxia resulted in a significant reduction in arterial blood PO2 from a prehypoxic level of 96.3 ± 3.9 to 19.5 ± 1.5 Torr in hypoxia III. The reduction was more apparent in severe hypoxia (II and III) than in hypoxia I. However, no significant difference was found between hypoxia II and III. A slight but significant increase in pH (from 7.31 ± 0.02 before hypoxia to 7.35 ± 0.03 during hypoxia III; P < 0.05) was also observed during all phases of hypoxia (I-III). PCO2 was significantly reduced only in hypoxia III (25.7 ± 0.8 vs. 28.7 ± 1.6 Torr before hypoxia; P < 0.05). With the termination of hypoxia followed by reoxygenation, all of the blood-gas measurements returned to approximately the same levels as before hypoxia. Blood gases were not examined in decerebrate and BC-receptor-denervated cats.

                              
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  		Table 2.   Arterial blood pH, PO2, and PCO2 before hypoxia, during hypoxia, and after reoxygenation for 30-40 min after each episode of hypoxia (I, II, and III) in intact cats

Effects of Different Degrees of Hypoxia on SAP and VNA

SAP changes. Figure 1 shows a typical example of the effects of different degrees of hypoxia on the SAP and VNA responses. For intact and decerebrate cats, hypoxia originally produced a rapid increase in SAP and soon reached a maximum (hypoxia I). When hypoxia was prolonged (as in hypoxia II), the elevated SAP was not maintained. Instead, SAP gradually declined to the resting level. If hypoxia continued (as in hypoxia III), SAP declined further and subsequently reached the level of 50 mmHg (Fig. 1, intact and decerebrate). Table 1 summarizes the onset time, the time to reach maximal change, and the maximal percent change of the MSAP and VNA responses of all three groups of cats to the three degrees of hypoxia. The onset time, the time to reach maximal change, and the maximal percent change in MSAP in response to hypoxia were not significantly different between intact and decerebrate cats nor among cats subjected to different degrees of hypoxia within the same group (Table 1). The resting values of the MSAP and VNA used for comparison of the maximal percent change are shown in Table 3.

                              
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  		Table 3.   Resting MSAP and VNA before hypoxia and after reoxygenation for 30-40 min after each episode of hypoxia (I, II, and III) in intact, decerebrate, and BC-receptor-denervated cats

In BC-receptor-denervated cats, hypoxia I produced a significant decrease in MSAP by -46.7 ± 6.0% (Table 1) from a resting level of 105.0 ± 4.5 mmHg (Table 3). The decrease in MSAP was more apparent in hypoxia II and III (Table 1). In this group, the onset time and the time to reach a maximal change for different degrees of hypoxia were significantly longer than those in intact or decerebrate cats (Table 1).

VNA changes. In all three groups, hypoxia induced an immediate increase in VNA, irrespective of the change in SAP. The magnitude of the VNA increase was gradually reduced as hypoxia continued but still remained higher than the resting value even at the end of hypoxia III (Fig. 1). The onset time of VNA in response to hypoxia in BC-receptor-denervated cats was longer than that of intact or decerebrate cats (Table 1).

As shown in Fig. 1, reoxygenation always induced a transient rebound in SAP and a silence in VNA before these variables gradually returned to the prehypoxic levels. The resting levels of MSAP and VNA within the group were not significantly different, either before hypoxia or after 30-40 min of reoxygenation after each episode of hypoxia (Table 3). In other words, each degree of hypoxia was started from about the same levels of SAP and VNA in the same group. The resting VNA of BC-receptor-denervated cats, however, was significantly higher than that of intact and decerebrate cats under all conditions (Table 3).

Effects of Different Degrees of Hypoxia on Responses Induced by Glu Stimulation in the DM

Figure 2 shows representative recordings of the Glu-induced responses of the DM before and after different degrees of hypoxia in intact, decerebrate, and BC-receptor-denervated cats. The averaged data are summarized in Fig. 3. Before hypoxia, microinjection of Glu into the DM elicited significant increases in SAP (intact: +51.3 ± 5.2% from a resting level of 111.3 ± 4.3 mmHg; decerebrate: +77.9 ± 8.1% from 103.9 ± 7.7 mmHg; and BC-receptor denervated: +50.4 ± 7.2% from 101.3 ± 6.7 mmHg). Glu-induced VNA increases were +162.8 ± 19.6% (from a resting level of 74.8 ± 6.2 µV · s), +237.0 ± 28.7% (from 85.3 ± 6.2 µV · s), and +93.3 ± 25.3% (from 162.7 ± 16.5 µV · s) for intact, decerebrate, and BC-receptor-denervated cats, respectively. The Glu-induced SAP and VNA responses were significantly augmented in decerebrate cats (Fig. 3, control). In contrast, in BC-receptor-denervated cats, VNA increases were smaller compared with those in intact cats (Fig. 3, control).


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  		Fig. 2.   Effects of different degrees of hypoxia on the pressor and sympathoexcitatory responses to microinjection of monosodium L-glutamate (Glu; 0.1 M, 70 nl) into the dorsomedial (DM) of intact (top), decerebrate (middle), and BC-receptor-denervated (bottom) cats. Glu was microinjected before hypoxia (control) and after reoxygenation for 30-40 min (posthypoxia I-III) after different degrees of hypoxia. On the brain drawings (right),  show the sites of Glu injection. Glu-induced increases in SAP and VNA were notably depressed after hypoxia I and more so after hypoxia II and III in intact cats (top). This depression, however, was not so apparent in decerebrate cats (middle) and even less so in BC-receptor-denervated cats (bottom). PH, nucleus praepositus hypoglossi; ION, inferior olivary nucleus.



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  		Fig. 3.   Effects of different degrees of hypoxia on the percent change of MSAP (top) and VNA (bottom) in response to microinjection of Glu (0.1 M, 70 nl) in the DM of intact, decerebrate, and BC-receptor-denervated cats. Control: Glu was microinjected before hypoxia; Posthypoxia I, II, and III: the same dose of Glu was microinjected after reoxygenation for 30-40 min after each episode of hypoxia. Values are means ± SE; n, no. of points receiving microinjection of Glu. * Significant difference between the values of control and the corresponding values of posthypoxia I-III, P < 0.05; dagger  Significant difference between the values of control in intact group and the corresponding values of control in decerebrate and BC-receptor-denervated group, P < 0.05.

In intact cats, the Glu-induced increases in SAP and VNA were significantly depressed after hypoxia I and almost abolished after hypoxia II and III (Figs. 2 and 3, intact). In decerebrate cats, however, SAP and VNA increases were not changed after hypoxia I but were depressed significantly after hypoxia II and III (Figs. 2 and 3, decerebrate). Unlike intact and decerebrate cats, the SAP and VNA responses were not depressed after any phase of hypoxia (I, II, or III) in BC-receptor-denervated cats (Figs. 2 and 3, BC-receptor denervated).

Effects of Different Degrees of Hypoxia on Responses Induced by Glu Stimulation in the RVLM

Figure 4 shows the original recordings of the effects of different degrees of hypoxia on the Glu-induced RVLM responses in intact, decerebrate, and BC-receptor-denervated cats. The results are summarized in Fig. 5. Before hypoxia, microinjection of Glu into the RVLM also elicited increases in SAP and VNA in all three groups of cats, and the magnitude of these increases was similar to that observed in the DM. These increases in SAP and VNA were not statistically different among the three groups (Fig. 5, control).


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  		Fig. 4.   Effects of different degrees of hypoxia on the pressor and sympathoexcitatory responses to microinjection of Glu (0.1 M, 70 nl) into the rostral ventrolateral medulla (RVLM) of intact (top), decerebrate (middle), and BC-receptor-denervated (bottom) cats. Glu was microinjected before hypoxia (control) and after reoxygenation for 30-40 min (posthypoxia I-III) after different degrees of hypoxia. On the brain drawings (right),  show the sites of Glu injection. Unlike the DM, Glu stimulation in the RVLM of intact cats (top) appeared not to be affected by hypoxia I. A longer duration of hypoxia (II and III) resulted in only a minor attenuation that was not as severe as that in the DM. In decerebrate (middle) and BC-receptor-denervated cats (bottom), the Glu-induced increases in SAP and VNA were not significantly affected by hypoxia.



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  		Fig. 5.   Effects of different degrees of hypoxia on the percent change of MSAP (top) and VNA (bottom) in response to microinjection of Glu (0.1 M, 70 nl) in the RVLM of intact, decerebrate, and BC-receptor-denervated cats. Control: Glu was microinjected before hypoxia; Posthypoxia I, II, and III: the same dose of Glu was microinjected after reoxygenation for 30-40 min after each episode of hypoxia. Values are means ± SE; n, no. of points receiving microinjection of Glu. All statistical symbols are the same as in Fig. 3.

In the RVLM, posthypoxic depression was observed only in intact cats. In intact cats, the Glu-induced SAP increases in the RVLM remained unchanged after hypoxia I and even after hypoxia II but were significantly depressed after hypoxia III (+31.0 ± 7.8 vs. +54.8 ± 7.6%, hypoxia III vs. control; P < 0.05). The VNA responses were significantly depressed after hypoxia II and III (+97.0 ± 33.6 and +70.7 ± 33.0%, respectively, vs. +210.1 ± 33.0% in control; P < 0.05) (Fig. 5, intact). In decerebrate and BC-receptor-denervated cats, the Glu-induced VNA and SAP responses remained unchanged regardless of the degree of hypoxia (Fig. 5, decerebrate, BC-receptor denervated).

The Glu-reactive points of the DM and the RVLM are shown in Fig. 6. The most sensitive site of the DM was distributed in the area 3.0-4.0 mm rostral to the obex, whereas the most sensitive site of the RVLM was mainly concentrated in the region 4.0 mm rostral to the obex.


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  		Fig. 6.   Distribution of Glu-reactive sites in intact, decerebrate, and BC-receptor-denervated cats subjected to different degrees of hypoxia (I-III). The level was from 5.0 mm (A5) to 3.0 mm (A3) rostral to the obex. Points receiving microinjection of Glu before hypoxia and after reoxygenation for 30-40 min after each episode of hypoxia in intact (), decerebrate (triangle ), and BC-receptor-denervated () cats were marked. All Glu-induced responses refer to the changes in MSAP and VNA. 12 N, hypoglossal nucleus; 5ST, spinal trigeminal tract; 5SP, spinal trigeminal nucleus, parvocellular division; AN, ambiguus nucleus; DMV, dorsal motor nucleus of vagus; NTS, nucleus tractus solitarius; RB, restiform body; VIN, inferior vestibular nucleus; VMN, medial vestibular nucleus.

Effects of Different Degrees of Hypoxia on Responses Induced by Tyr

In intact cats, submaximum doses of Tyr were administered intravenously to produce pressor and tachycardiac responses. Although at the highest dose (400 µg/kg) the primary tachycardiac effect was slightly suppressed (probably secondary to the hypertension-induced baroreflex), responses were dose dependent and were not significantly different before and after any degree of hypoxia (Fig. 7).


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  		Fig. 7.   Effects of different degrees of hypoxia on the percent change of MSAP (top) and HR (bottom) produced by tyramine (100, 200, and 400 µg/kg iv) in intact cats (n = 6). The pressor and tachycardiac responses induced by tyramine were not significantly different between control and any posthypoxia phase. Values are means ± SE.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The major findings of the present study are as follows. 1) In intact cats, the posthypoxic depression of Glu-induced SAP and VNA responses is more apparent in the DM than in the RVLM (Fig. 3 vs. Fig. 5, intact). 2) Precollicular decerebration slightly ameliorated the posthypoxic depression in the DM (Fig. 3, intact vs. decerebrate), but it almost completely abolished the posthypoxic depression in the RVLM (Fig. 5, intact vs. decerebrate). 3) Posthypoxic depression in both the DM and the RVLM was not observed after denervation of the peripheral baro- and chemoreceptors (Figs. 3 and 5, intact vs. BC-receptor denervated).

In the present study, the arterial blood-gas measurements (Table 2) and the resting levels of MSAP and VNA before hypoxia and after reoxygenation after each episode of hypoxia (Table 3) were not significantly different in intact cats. The onset time, the time to reach maximal change, and the magnitude of maximal percent change in MSAP and VNA of intact cats in response to hypoxia also did not differ among hypoxia I, II, and III (Table 1). These data indicate that reoxygenation for 30-40 min after hypoxia is sufficient, based on the fact that deviation of blood gases, SAP, and VNA had all returned to their prehypoxic levels. Thus the Glu-induced responses before and after each hypoxia in the present study were compared based on the similar starting levels of SAP and VNA.

Furthermore, the results from BC-receptor-denervated cats showed that responses of repeated Glu stimulation in the DM (Figs. 2 and 3, BC-receptor denervated) and the RVLM (Figs. 4 and 5, BC-receptor denervated) were not altered throughout the three degrees of hypoxia. This finding suggests that the Glu-induced SAP and VNA responses in the DM and the RVLM are indeed reversible and repeatable. Our time control study also confirmed this assumption (data not shown). Accordingly, in the present study, the graded posthypoxic depression in the DM as well as in the RVLM was attributed to the hypoxia itself. Other factors, such as the surgical procedure and changes in physiological conditions, i.e., blood gases, the resting blood pressure, the resting sympathetic tone, or the repetition of exposures to hypoxia, could be excluded.

Arterial Blood-Gas Changes

In the present study, blood-gas values before hypoxia were similar to those reported by others in decerebrate, nonanesthetized, mechanically ventilated cats (21). During hypoxia, PO2 was significantly decreased and correlated to the severity of hypoxia, although it was not significantly different between hypoxia II and III. This may be attributed to a very low level of PO2 (21.8 ± 1.8 Torr) in hypoxia II, which was not much affected by a longer duration of hypoxia (19.5 ± 1.5 Torr in hypoxia III).

PCO2 was significantly lowered only in hypoxia III. With constant minute ventilation maintained artificially, it is expected that arterial blood PCO2 will be held constant, provided that CO2 production is not changed. However, a significant decrease in cellular oxygen uptake in this phase of hypoxia might have affected the normal CO2 production.

Contrary to the expectation that hypoxia would cause production of acidic anaerobic metabolites, the pH was slightly elevated during hypoxia. This finding may be attributed to the lowered production of PCO2, which resulted in an imbalance in the buffer system. In the present study, the severity of hypoxia was correlated with the duration of hypoxia, in which arterial PO2, PCO2, and pH were all affected.

Although the blood gases were not examined in decerebrate or BC-receptor-denervated cats, a sufficient recovery in the resting MSAP and VNA after hypoxia occurred among these three groups of cats (Table 3). This finding suggests that, in the mechanically ventilated decerebrate or BC-receptor-denervated cats, the blood-gas levels could be comparable with those of the intact cats before each Glu stimulation, despite lack of blood-gas measurements.

Cardiovascular and Sympathetic Nerve Responses During Different Degrees of Hypoxia

In the present study, hypoxia induced notable increases in SAP and VNA during hypoxia I and during the early phases of hypoxia II and III in intact and decerebrate cats. However, during the late phases of hypoxia II and III in intact and decerebrate cats and during all three degrees of hypoxia in BC-receptor-denervated cats, VNA remained elevated, despite the reduction in SAP (Fig. 1). The overall VNA response can be explained either by the rapid activation of peripheral chemoreceptors during hypoxia (25) or by a direct action of hypoxia on the CNS (12, 38, 40, 43). The reduction in SAP response during hypoxia in all three groups may be partly attributed to a direct hypoxic effect on peripheral vessels (12, 18).

After hypoxia, reoxygenation immediately evoked a transient rebound of SAP. It was most likely due to the washout of metabolic vasodilators, produced and accumulated under the anaerobic condition (hypoxia), by the reperfusion of reoxygenated blood (4, 14). On the other hand, a short period of silence in VNA was observed right after reoxygenation in all three groups. It has been shown that, during apnea, chemoreceptor activation is a predominant factor in the activation of renal sympathetic nerve activity, whereas, during the second and third breaths of the postapneic periods, arterial baroreceptor inputs become predominant and inhibit renal sympathetic nerve activity (29). Therefore, the silence of VNA on reoxygenation may be a result of the sudden loss of both central and peripheral chemoreceptor activities because of the elevation of arterial PO2 and, consequently, the release of the baroreceptor function from the override activation of chemoreceptors during hypoxia (1). However, although both peripheral chemoreceptors and baroreceptors were removed in BC-receptor-denervated cats, the silence of VNA during the early period of reoxygenation was still observed. This result suggests that the silence of VNA during reoxygenation may involve mainly a central mechanism. For example, the RVLM, a powerful mechanism for central sympathetic control, can directly and rapidly respond to O2 change (38, 40, 43) but not baroreceptor function.

The Glu-Induced SAP and VNA Responses in the DM and the RVLM Were Depressed after Hypoxia in Intact Cats

In intact cats, a notable depression of the Glu-induced responses in the DM was observed after all degrees of hypoxia. In the RVLM, the depression in SAP was observed after hypoxia III, and in VNA it was observed after hypoxia II and III. Thus neurons of the RVLM, in the presence of an intact CNS and peripheral baro- and chemoreceptor mechanisms, are apparently more resistant to hypoxia than are those of the DM.

Our laboratory's previous studies have shown that the increases in SAP and VNA induced by microinjection of Glu into the DM arise from the combined action of N-methyl-D-aspartic acid (NMDA) and alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, whereas in the RVLM the action is mediated primarily through AMPA receptors (8).

AMPA receptors possess the characteristics of rapid desensitization and quick recovery from stimulation (45). The rapid desensitization of AMPA receptors may provide neuroprotection against overactivation and injury (27, 47). Conversely, NMDA receptors exhibit a slow onset and prolonged delay of recovery (22, 23). As a matter of fact, NMDA receptors are activated by the enormous release of Glu during hypoxia (24), and this activation may slowly decay or persist by the spontaneous release of Glu during reoxygenation, which would cause more neurotoxicity (44). Thus it is very likely that, during reoxygenation, neurons in the DM with NMDA receptors cannot respond well when stimulated by exogenous Glu. Therefore, in the present study, the depressed responses of the DM to Glu stimulation after hypoxia might have been due to the depression of the DM neurons containing NMDA receptors.

In contrast to the DM, the RVLM contains mostly AMPA receptors for the glutamatergic action (8). It also has a much higher density of cell bodies and more nerve fibers than the DM (5). Significantly higher glucose utilization, blood flow, and capillary density are also found in the RVLM (13). Consequently, neurons in the RVLM, which exhibit a high activity of synaptic inputs and a high metabolic rate, would be more capable of rapidly sensing the change in arterial O2 content and washing out the hypoxic products than those in the DM. Therefore, neurons in the RVLM are less affected by hypoxia.

However, the RVLM did show some depression in SAP responses after hypoxia III and in VNA responses after hypoxia II and III. Under such a severe hypoxia, besides the release of excitatory amino acids, other modulators, such as adenosine (24), GABA, and glycine, might also have been massively produced or released in the brain. These compounds may directly modulate Glu receptors or influence the neurons in this area.

Suprapontine Structures Partially Contribute to the Depression of the Glu-Induced Responses in the DM and the RVLM after Hypoxia

The resting MSAP and VNA (Table 3, decerebrate) and the hypoxia-induced MSAP and VNA responses (Fig. 1 and Table 1, decerebrate) in precollicular decerebrate cats were similar to those in intact cats. These findings are consistent with the results of other studies using rats (41) or cats (15), indicating the importance of the medulla in maintaining and integrating cardiovascular functions.

It is interesting to note that decerebration could ameliorate the posthypoxic depression of the RVLM after hypoxia II and III. As a matter of fact, the Glu-induced responses of the RVLM were not attenuated by hypoxia after precollicular decerebration. However, in the DM, the improvement of depression by precollicular decerebration was minor and could be seen only after hypoxia I (Fig. 3, decerebrate). Thus suprapontine neurons may exert more influence over the Glu receptors in the RVLM than in the DM during hypoxia.

It has been shown that the descending sympathoexcitatory pathways from suprapontine structures, such as the lateral hypothalamus, exhibit glutamatergic synapses with neurons of the nucleus paragigantocellularis lateralis (corresponding to vasomotor neurons of the anterior ventrolateral medulla) (35). These pathways also project to the periaqueductal gray region (2). The fibers from the periaqueductal gray region also project to the DM and even more predominantly to the RVLM in cats (7). Some of the descending inhibitory pathways from the prefrontal cortex would produce hypotension (17). The GABAergic pathway, for example, from the prefrontal cortex has been shown to project to the vasomotor neurons in the RVLM (34). Thus precollicular decerebration, interrupting the suprapontine descending pathways, would alter the release of many neurotransmitters (e.g., Glu, GABA) in their synaptic sites in the DM and in the RVLM. Such a procedure also eliminates the possible effects of suprapontine neuron excitation induced by hypoxia. These actions may explain why precollicular decerebration prevented the RVLM (for hypoxia II and III) and the DM (for hypoxia I) from posthypoxia depression (Figs. 3 and 5, decerebrate) in the present study.

Peripheral Baro- and Chemoreceptors Mainly Contribute to the Depression of Glu-Induced Responses in the DM and the RVLM after Hypoxia

In normoxic conditions, cardiovascular and sympathetic nerve functions are mainly regulated by arterial baroreceptors, rather than by chemoreceptors (16). Therefore, denervation of peripheral baro- and chemoreceptors would eliminate the baroreflex control on the sympathetic nerve activity and consequently enhance its basal activity (25). It was also shown in this study that the resting VNA of BC-receptor-denervated cats was higher than that of intact and decerebrate cats (Table 3). The RVLM receives baroreceptor-activated GABAergic inputs from the caudal ventrolateral medulla (3, 36), whereas the DM receives only a few barosensitive inputs from the nucleus tractus solitarii (11, 30). Denervation of peripheral baro- and chemoreceptors may elevate the basal activities of neurons in the DM and the RVLM because of disinhibition resulting from the loss of baroreceptor restraint. It is likely that such disinhibition and the enhanced resting VNA prevented further increases in VNA in the DM and the RVLM when stimulated by Glu. Thus in BC-receptor-denervated cats, the Glu-induced VNA responses in the DM and the RVLM before hypoxia were less than those in intact cats (Figs. 3 and 5, control).

On the other hand, hypoxia causes a widespread influence on the CNS (38). For instance, both the DM (11, 30) and the RVLM (31, 38) receive chemoreflex-mediated glutamatergic inputs from the nucleus tractus solitarii. Activation of peripheral chemoreceptors could produce pressor and sympathoexcitatory responses mediated via excitation of the Glu receptors in the RVLM (26, 42). In addition, peripheral chemoreceptor denervation would reduce brain glutamatergic activities, and this reduction is more apparent during hypoxia (20). Thus hypoxia may increase brain glutamatergic activities via the activation of peripheral chemoreceptors. Indeed, in the present study, denervation of peripheral baro- and chemoreceptors significantly delayed the onset time of VNA responses to hypoxia (Table 1) and prevented the depression of Glu-induced responses in the DM and the RVLM after all degrees of hypoxia. The denervation of peripheral chemoreceptors may decrease excitatory synaptic transmission and result in less overexcitation of brain Glu receptors during hypoxia, consequently promoting a quicker recovery of neuronal functions during reoxygenation.

Hypoxia Did Not Affect Norepinephrine Store in Peripheral Sympathetic Nerve Terminals

Tyr is known to induce norepinephrine release from postganglionic sympathetic nerve terminals. In the present study, the Tyr-induced pressor and tachycardiac responses were not changed after hypoxia I, II, or III. Thus hypoxia-induced sympathetic discharge does not reduce the norepinephrine store in peripheral sympathetic nerve terminals.

Limitation of the Technique

Glu is not the sole chemical during the natural process in the DM or the RVLM activation. The use of Glu-induced SAP and VNA responses to represent the activity of the sympathetic pressor neurons in the DM and the RVLM may not be a direct measure. However, Glu microinjection after electrical stimulation had been a routine practice in localization of the sympathetic pressor neurons in the DM or the RVLM to induce SAP and VNA responses (5-8). On the basis of our results with Glu stimulation, the posthypoxic depression in the RVLM and the DM could be improved by removal of influences either from the rostral brain structures (with intact peripheral baro- and chemoreceptor inputs) or from the peripheral baro- and chemoreceptors (with intact rostral brain neurons). In both cases, neurons in the downstream pathway from the sympathetic neurons of DM and RVLM were subjected to the same hypoxic exposure, but the posthypoxic depression of SAP and VNA responses was not observed. These results indicate that the downstream neurons are less affected by the hypoxia applied in our experiments. In other words, the Glu-induced SAP and VNA responses represented a reliable parameter to illustrate the activity of the DM and the RVLM neurons in the present study.

In conclusion, the pressor and sympathoexcitatory responses elicited by Glu stimulation in the DM were depressed after a short period of hypoxia in the present study. For the RVLM, the depression was minor unless a longer duration of hypoxia was experienced. Neurons in the DM are more susceptible to hypoxia than are neurons in the RVLM. These results imply that neurons in the DM and the RVLM exhibit a differential response to hypoxia. The posthypoxic depression is apparently due to multiple causes and is not related directly to the depletion of norepinephrine store in postganglionic sympathetic nerve terminals. Both influences from suprapontine structures and peripheral baro- and chemoreceptor inputs may be involved. However, the peripheral baro- and chemoreceptor inputs contribute more significantly to the modulation of the DM and the RVLM during hypoxia.


    ACKNOWLEDGEMENTS

The authors thank Dr. C. K. Su for invaluable comments regarding this study. We are also grateful to Dr. K. H. Lee at the Univ. of North Carolina for critical reading of the manuscript.


    FOOTNOTES

This study was supported by the Shih-Chun Wang Research Memorial Fund, and by grants from the National Science Council of ROC (NSC 88-2314-B-001-002) and Taichung Veterans General Hospital (TCVGH-887315C).

Address for reprint requests and other correspondence: C.-Y. Chai, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 115, ROC (E-mail: lzhong{at}ughtc.ughtc.gov.tw).

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.

Received 10 December 1999; accepted in final form 10 August 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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