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Am J Physiol Heart Circ Physiol 281: H1233-H1241, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 3, H1233-H1241, September 2001

Paraventricular nucleus bicuculline alters frequency components of sympathetic nerve discharge bursts

Michael J. Kenney, Mark L. Weiss, Kaushik P. Patel, Yan Wang, and Richard J. Fels

Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas 66506; and Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska 68198


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Autospectral and coherence analyses were used to determine the effect of paraventricular nucleus (PVN) GABAA receptor antagonism [microinfusion or microinjections of bicuculline methiodide (BMI) 100 pmoles] on sympathetic nerve discharge (SND) frequency components (bursting pattern and relationships between discharges in regionally selective nerves) in alpha -chloralose-anesthetized rats. SND was recorded from the renal, splenic, and lumbar nerves. The following observations were made. First, PVN BMI microinjections, but not PVN saline or cortical BMI microinjections, transformed the cardiac-related SND bursting pattern in baroreceptor-innervated rats to one characterized by the presence of low-frequency bursts not synchronized to the cardiac cycle or phrenic nerve discharge bursts. Second, SND pattern changes were similar in the renal, splenic, and lumbar nerves, and peak coherence values relating low-frequency bursts in sympathetic nerve pairs (renal-splenic, renal-lumbar, and splenic-lumbar) were significantly increased from preinjection control after PVN BMI microinjection. Third, PVN BMI microinjections significantly increased the coupling between low-frequency SND bursts in baroreceptor-denervated rats. Finally, PVN BMI-induced changes in the SND bursting pattern were not observed after PVN pretreatment with muscimol (GABA agonist, 1 nmole). We conclude that PVN GABAA receptor antagonism profoundly alters the frequency components in sympathetic nerves.

sympathetic nerve activity; autospectral analysis; coherence function; Sprague-Dawley rats


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

IT IS WELL ESTABLISHED that GABA plays a role in the central regulation of arterial blood pressure and sympathetic nerve discharge (SND) (10). Microinjection of muscimol, a GABA agonist, into the paraventricular nucleus (PVN) of the hypothalamus decreases arterial pressure and renal SND (28). In contrast, microinfusion or microinjection of bicuculline methiodide (BMI), a GABAA receptor antagonist, into the PVN increases arterial pressure (7, 20-22, 26, 28), heart rate (HR) (7, 20-22, 26), cardiac index (20), plasma concentrations of norepinephrine and epinephrine (21, 22), and renal SND (26, 28). These findings suggest that a PVN GABAergic system exerts a tonic inhibitory effect on efferent SND (20, 22).

The role of the PVN GABAergic system in control of the pattern of SND is not known. This is an important omission because the SND bursting pattern represents the signature output of central sympathetic neural circuits (1, 8, 9) and can be changed during a variety of experimental interventions (3, 12, 14, 15). In addition, the effect of PVN GABAA receptor antagonism on the frequency-domain relationships between discharges in sympathetic nerve pairs is not known. Importantly, synchronized discharges in sympathetic nerves can uncouple during various experimental interventions (3, 12), demonstrating one form of sympathetic selectivity. Because the PVN is an important central nervous system site for autonomic and endocrine regulation (19, 23, 25), we hypothesized that PVN BMI microinjection would alter the SND bursting pattern and the frequency-domain coupling between discharges in sympathetic nerve pairs (i.e., renal-splenic, renal-lumbar, and splenic-lumbar).

With the exception of renal SND (26, 28), the effect of PVN GABAA receptor antagonism on the level of activity in other sympathetic nerves is not well established. This is an important omission because it is widely accepted that the sympathetic nervous system can selectively change the level of activity in nerves that innervate different target organs (2, 4, 11, 13, 15, 27). Relative to this point, Deering and Coote (6) reported that in anesthetized rabbits, PVN injections of DL-homocysteic acid decreased the level of renal SND but increased splanchnic, adrenal, and cardiac SND. We hypothesized that PVN microinjection of BMI would produce nonuniform changes in the level of renal, splenic, and lumbar SND (as evidenced by directionally opposite changes in the level of SND and/or differences in the time course of SND responses).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Surgical procedures and experimental protocols were approved by the Institutional Animal Care and Use Committee.

General procedures. Male Sprague-Dawley rats (300 g) were anesthetized (methohexital sodium, 50-60 mg/kg ip, followed by alpha -chloralose 50 mg/kg iv, initial dose), artificially ventilated, and paralyzed with gallamine triethiodide (5-10 mg/kg iv, initial dose). Catheters were placed in the femoral vein for administering drugs, including maintenance doses of alpha -chloralose (35 mg · kg-1 · h-1), methohexital sodium (10-20 mg/kg), and gallamine triethiodide (10-15 mg · kg-1 · h-1). End-tidal CO2 was kept near 4.5% by adjusting the frequency of respiration. Colonic temperature was measured and was kept at 38.0°C during surgery by a temperature-controlled table. Femoral arterial blood pressure and HR were recorded using standard procedures.

Bilateral denervation of the aortic arch was completed by cutting the superior laryngeal nerve near its junction with the vagus nerve and by removing the superior cervical ganglion (18). Bilateral carotid sinus denervation was completed by removing the adventitia from the carotid sinus bifurcation and by applying 10% phenol to this area (18). Bilateral cervical vagotomies were completed by sectioning the vagus nerves at the level of the carotid sinus bifurcation. Sinoaortic denervation (SAD) was considered complete by 1) the loss of coherence between the arterial pulse and SND and/or 2) the absence of a reflex change in SND from control levels during increases in mean arterial pressure (MAP) produced by phenylephrine hydrochloride (5 µg/kg iv) and during decreases in arterial pressure produced by sodium nitroprusside (5 µg/kg iv).

Neural recordings. Activity was recorded biphasically with a platinum bipolar electrode after capacity-coupled preamplification (band pass 30-3,000 Hz) from the central end of cut renal, splenic, and lumbar sympathetic nerves. The renal and splenic nerves were isolated retroperitoneally and the lumbar nerve was isolated after a midline laparotomy. The left phrenic nerve was isolated in the cervical region. The nerve electrode preparations were covered with a silicone gel. The sympathetic and phrenic nerve potentials were full-wave rectified and integrated (time constant 10 ms), which produced a smooth tracing of the synchronized discharges (14-16). The level of activity in sympathetic nerves was quantified after integration as volts times seconds and corrected for background noise after ganglionic blockade (trimethaphan camsylate, 15 mg/kg) or nerve crush (14-16).

Central nervous system microinjections. With the use of stereotaxic methods, microinjections of 100 pmoles of BMI dissolved in phosphate-buffered saline (50 nl) or saline (50 nl, vehicle controls) were made unilaterally into the PVN (target site; 1.8 mm caudal to bregma, 0.7 mm lateral to the midline, 7.7 mm ventral from the surface of the brain). The dorsal parvocellular subdivision of the PVN was targeted because this region contains neurons that project to brain stem regions involved in autonomic regulation and to sympathetic preganglionic neurons of the intermediolateral cell column (19, 23, 25). Anatomic controls were completed by microinjecting BMI (100 pmoles, 50 nl) into the frontoparietal motor cortex (1.8 mm caudal to bregma, 0.7 mm lateral to the midline, 2.0 mm ventral from the surface of the brain), an area of the brain that has not been found to be involved in SND regulation. Sites of microinjection were identified with reference to the location of the tip of the micropipette. Rhodamine-labeled latex microspheres (1:2 dilution with distilled water) were mixed with the BMI to identify the diffusion boundaries of the microinjection.

Midbrain transections. The rat was placed in a stereotaxic apparatus and a portion of the skull was removed. Midbrain transections were completed by performing sequential left and right hemisections at the level of the superior colliculus (16). Transections were completed through the rostral portion of the superior colliculus (16). The completeness and level of transection were verified by gross examination of the brain stem.

Brain histology. At the end of each experiment, the rats received an overdose of methohexital sodium (150 mg/kg iv) and were transcardially perfused with 0.15 M NaCl (containing 3 IU/ml heparin) followed by a fixative solution consisting of 10% buffered neutral formalin (pH 7.4). Brains were removed and blocked, and a fiducial mark was made in the right hemisphere. Brains were postfixed in buffered neutral formalin for at least 2 h and then placed in 20% sucrose for cyroprotection. Once the brains sank in the sucrose, they were frozen, sectioned at 40 µm in the coronal plane, collected into phosphate-buffered saline, and mounted on subbed slides in serial sequence. The sections were rinsed in distilled water, air dried, cleared in xylenes, and coverslipped. The center of the injection site was localized by observing discrete clusters of latex microspheres. Microspheres could be observed in bright field or epifluoresence (rhodamine filter cube: BP 515-560 excitation filter).

Data and statistical analysis. Autospectra and coherence analysis of the arterial pulse, SND, and phrenic nerve discharge (PND) were computed using the methods and programs described earlier (17). Fast Fourier transform was performed on 12-18 contiguous windows of data that were 5 s in duration. Autospectra and coherence functions were computed over a frequency band of 0-15 Hz. Spectral analyses provide the following information (17). The autospectrum of a signal shows the relative power present at each frequency. The coherence function (normalized cross spectrum) provides a measure of the strength of linear correlation of two signals as a function of frequency. The squared coherence value (referred to as coherence value) is 1.0 in the case of a linear system undisturbed by noise and is zero, if the two signals are completely unrelated. Peak coherence values in the 0- to 2-Hz frequency band and at the frequency of HR (cardiac frequency) were quantified.

All values are means ± SE. Control values of SND were taken as 100%. Statistical analysis included Student's t-test for pairwise comparisons and repeated-measures analysis of variance. P < 0.05 indicated statistical significance.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The effect of PVN BMI microinjections (100 pmoles, 50 nl) on SND frequency components, the level of sympathetic nerve activity, MAP, and HR was determined in 15 baroreceptor-innervated rats and four SAD rats. In baroreceptor-innervated rats, SND was recorded simultaneously from three nerves (renal-splenic-lumbar) in five experiments and from two nerves (renal-splenic, n = 7; renal-lumbar, n = 1; splenic-lumbar, n = 2) in 10 experiments. Six of the renal-splenic SND recording experiments also included PND recordings. SND was recorded from renal-splenic sympathetic nerve pairs in SAD rats (n = 4). PVN saline microinjections (50 nl, n = 8, administered before PVN microinjection of BMI) and cortical BMI microinjections (100 pmoles in 50 nl, n = 9) were completed in baroreceptor-innervated rats. Figure 1 shows BMI microinjection sites (as referenced to the tip of the micropipette) in baroreceptor-innervated and SAD rats from the rostral to caudal extent of the PVN and vicinity. In every experiment, the PVN was included within the diffusion boundaries of the microinjection. Therefore, we refer in RESULTS to PVN microinjections.


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  		Fig. 1.   Bicuculline methiodide (BMI) microinjection sites in the paraventricular nucleus (PVN) of the hypothalamus. The location of the micropipette tip is plotted in serial coronal sections for rats with intact arterial baroreceptors (open circles) and for sinoaortic-denervated rats (solid circles). In every case, the diffusion boundary of the microinjection (50 nl saline containing 100 pmoles BMI) included the PVN. fx, Fornix; oc, optic chiasm; ot, optic tract; SAD, sinoaortic denervation.

Figure 2A shows traces of simultaneously recorded SND bursts (renal, splenic, and lumbar) and pulsatile arterial pressure from a representative experiment during control and 45 s, 6 min, and 30 min (recovery) after PVN BMI microinjection. MAP values recorded during each period are shown below the pulsatile arterial pressure traces. During control, the majority of SND bursts were coupled to the arterial pulse. In contrast, renal, splenic, and lumbar nerve recordings were dominated by the presence of low-frequency bursts at 45 s and 6 min postinjection. During recovery, SND bursts were similar to control. MAP was increased from control at 45 s and 6 min after PVN BMI microinjection. PVN BMI-induced changes in the SND bursting pattern were not observed after pretreatment with muscimol (GABA agonist, 1 nmole, n = 4) (see Fig. 2B for one representative example). In contrast, when BMI microinjections were repeated at the same PVN site without an intervening muscimol microinjection, the SND bursting pattern was changed (similar to Fig. 2A) after each PVN BMI microinjection (n = 3). PVN muscimol did not significantly change MAP (-10 ± 4 mmHg, P < 0.09) or the level of renal (+4 ± 3%) and splenic (-2 ± 3%) SND.


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  		Fig. 2.   A: traces of integrated sympathetic nerve discharge (SND) bursts (renal, splenic, and lumbar) and pulsatile arterial pressure (AP) recorded during control and 45 s, 6 min, and 30 min (recovery) after microinjection of BMI (100 pmoles) into the PVN. Mean arterial pressure (MAP) values for each period are shown below pulsatile AP. Horizontal calibration is 500 ms. B: traces of integrated SND bursts (renal and splenic) recorded during control, 5 min after an initial PVN microinjection of BMI (PVN BMI, 100 pmoles), recovery (20 min after the initial PVN BMI microinjection), and 5 min after a second PVN BMI microinjection (100 pmoles) completed after PVN pretreatment with muscimol (1 nmole) (PVN BMI after PVN muscimol). MAP values for each period are shown below the splenic SND traces. Horizontal calibration is 500 ms.

Figure 3 shows the results of autospectral and coherence analyses of lumbar, renal, and splenic SND (12 contiguous windows of data that were 5 s in duration) during control (A) and initiated at 20 s (B), 6 min (C), and 30 min (D) after PVN BMI microinjection from one representative experiment. During control, SND autospectra (Fig. 3, A, left) contained primary peaks at the frequency of the HR (8.0 Hz) and SND coherence functions (Fig. 3, A, right) demonstrated correlations that extended from 0 to ~10 Hz, with peaks at 8 Hz and at frequencies <4 Hz. After PVN BMI microinjection (20 s and 6 min), the primary peaks in the SND autospectra were shifted to <2 Hz (Fig. 3, B-C, left), cardiac-related peaks in the SND coherence functions were reduced (Fig. 3, B-C, right), and peak coherence values relating low-frequency (0-2 Hz) discharges were increased (Fig. 3, B-C, right). SND autospectra (Fig. 3D, left) and coherence functions (Fig. 3D, right) constructed 30 min after PVN BMI were similar to control. Onset of the SND pattern change after PVN BMI microinjection, as documented by a shift in the SND autospectra, was 40 ± 6 s in baroreceptor-innervated rats (n = 15).


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  		Fig. 3.   Frequency-domain relationships among renal, splenic, and lumbar SND bursts during control (A), 20 s (B), 6 min (C), and 30 min (D) after microinjection of BMI (100 pmoles) into the PVN. Left: individual autospectra (total power), right: nerve-to-nerve coherence functions. Frequency band is displayed from 0 to 15 Hz.

Mean data from PVN BMI microinjection experiments in baroreceptor-innervated rats were analyzed at the following three points: 1) preinjection control; 2) after microinjection when changes in SND frequency components (5 ± 1 min), MAP (5 ± 1 min), and the level of sympathetic nerve activity (11 ± 2 min) were maximal (max change); and 3) recovery (19 ± 3 min after microinjection). Peak coherence values relating low-frequency (0- to 2-Hz frequency band) discharges in sympathetic nerve pairs (renal-splenic, renal-lumbar, and splenic-lumbar) were significantly increased, whereas those relating discharges at the cardiac frequency were significantly reduced after PVN BMI (Table 1). Peak coherence values remained unchanged from control after PVN saline and cortex BMI microinjections. MAP and the level of renal and splenic SND were significantly increased, whereas HR and lumbar SND remained unchanged from control after PVN BMI (Table 2). MAP, HR, and the level of SND (renal, splenic, and lumbar) remained unchanged from control after PVN saline and cortex BMI microinjections.

                              
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  		Table 1.   Peak coherence values relating discharges in sympathetic nerve pairs in 0- to 2-Hz frequency band and at CF before and after BMI and saline microinjections in PVN and BMI microinjections in the cortex


                              
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  		Table 2.   MAP, HR, and SND recorded before and after BMI and saline microinjections in the PVN and BMI microinjections in the cortex

The effect of PVN BMI microinjection (100 pmoles) on the coupling between SND and PND bursts (renal-phrenic and splenic-phrenic) was determined in six baroreceptor-innervated rats. Renal, splenic, and phrenic nerve autospectra (Fig. 4, A and B, left) and SND-PND coherence functions (Fig. 4, A and B, right) were constructed before and after PVN BMI microinjection. During control (Fig. 4A), SND autospectra contained peaks at HR (7.6 Hz) and PND (1.2 Hz, small in the renal SND autospectrum and large in the splenic SND autospectrum) frequencies. In addition, SND-PND coherence functions constructed during control had primary peaks (renal-phrenic, 0.44 and splenic-phrenic, 0.83) at 1.2 Hz. After PVN BMI microinjection (Fig. 4B), cardiac-related peaks in the SND autospectra were reduced, and peak coherence values relating SND-PND bursts were virtually eliminated. Peak coherence values relating renal-phrenic (control, 0.56 ± 0.11 and max change, 0.07 ± 0.02, n = 6) and splenic-phrenic (control, 0.61 ± 0.08 and max change, 0.08 ± 0.01, n = 6) were significantly reduced from control after PVN BMI microinjections.


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  		Fig. 4.   Frequency-domain relationships among renal SND, splenic SND, and phrenic nerve discharge (PND) bursts during control (A) and 4 min after (B) microinjection of BMI (100 pmoles) into the PVN. Left: individual autospectra (total power); right: nerve-to-nerve coherence functions. Amplitudes of autospectra are autoscaled to the highest peak. Frequency band is displayed from 0 to 15 Hz.

Midbrain transections were completed after PVN BMI microinjection in three baroreceptor-innervated rats. Figure 5 shows traces of simultaneously recorded renal and splenic SND during control (A), 5 min after PVN BMI microinjection (B), and immediately after decerebration (completed within 10 min after PVN BMI microinjection) (C). Renal and splenic SND were dominated by the presence of low-frequency bursts 5 min after PVN BMI microinjection, whereas immediately after completion of the transection procedure, SND bursts were similar to control. Similar results were observed in each of the midbrain transection experiments.


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  		Fig. 5.   Traces of integrated SND bursts (renal and splenic) and arterial pressure (AP) recorded during control (A), 5 min after microinjection of BMI into the PVN (B), and immediately after midbrain transection (C). Midbrain transection was completed within 10 min after PVN BMI microinjection. Horizontal calibration is 500 ms.

The effect of PVN BMI microinjection (100 pmoles) on SND (renal-splenic) frequency components, the level of SND, MAP, and HR was determined in four SAD rats. The results of autospectral and coherence analyses of renal and splenic SND from a representative experiment are shown in Fig. 6. During control (A), SND autospectra contained primary peaks between 0 and 3 Hz and were devoid of cardiac-related peaks (7.0 Hz in this experiment), and the renal-splenic coherence function had peak values between 0 and 3 Hz. SND autospectra exhibited narrow bands, and peak coherence values were markedly increased after PVN microinjection (Fig. 6B). Onset of the SND pattern change after PVN BMI microinjection was 40 ± 17 s in SAD rats (n = 4). Peak coherence values relating renal-splenic discharges in the 0- to 2-Hz frequency band (control, 0.68 ± 0.5 and 5-7 min after PVN BMI, 0.96 ± 0.01) and MAP (control, 93 ± 16 mmHg and 5-7 min after PVN BMI, 155 ± 28 mmHg) were significantly increased after PVN BMI microinjection in SAD rats. In addition, the level of renal SND was increased by 118 ± 52% (P < 0.05), and the level of splenic SND was increased by 105 ± 54% (P < 0.05) after PVN BMI microinjection in SAD rats.


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  		Fig. 6.   Frequency-domain relationships between renal and splenic SND bursts during control (A) and 6 min after microinjection of BMI (100 pmoles) (B) into the PVN of a sinoaortic-denervated rat. Top and middle, individual SND autospectra (total power) during each period; bottom, nerve-to-nerve coherence functions during each period. Amplitudes of autospectra are autoscaled to the highest peak. Frequency band is displayed from 0 to 15 Hz.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

This study examined the effect of PVN GABAA receptor antagonism on efferent sympathetic nerve outflow in chloralose-anesthetized rats. Our results provide experimental support for three findings that provide insight into the role of the PVN in sympathetic nerve regulation. First, PVN BMI microinjection profoundly altered the SND bursting pattern in baroreceptor-innervated and -denervated rats. PVN BMI-induced changes in the SND bursting pattern were not observed after pretreatment with muscimol. Second, the low-frequency SND bursts recorded after PVN BMI microinjection were not coupled to PND bursts, demonstrating reduced respiratory modulation of efferent sympathetic nerve outflow after PVN GABAA receptor antagonism. Third, SND pattern changes were similar in the renal, splenic, and lumbar nerves and peak coherence values relating low-frequency bursts in sympathetic nerve pairs were significantly increased from control after PVN BMI microinjection, demonstrating a lack of selectivity in SND frequency responses to PVN GABAA receptor antagonism.

Several discharge patterns are evident in recordings from efferent sympathetic nerves, including cardiac- and respiratory-related oscillations (1, 3, 8, 9, 14, 29). The cardiac-related pattern of SND bursts in baroreceptor-innervated animals is considered the signature output of those central neural circuits involved in generation of SND (1, 8, 9). The respiratory-related pattern in efferent sympathetic nerve outflow results from the interaction of central circuits that control phrenic and sympathetic nerves, providing the neural substrate for cooperation between the cardiovascular and respiratory systems (29). The current results demonstrate that PVN BMI microinjections, but not PVN saline or cortical BMI microinjections, transform the cardiac-related SND bursting pattern in baroreceptor-innervated rats to one characterized by the presence of low-frequency bursts that are not synchronized to the cardiac cycle or PND bursts.

Under what physiological conditions might this type of SND bursting pattern be observed? Although the current results do not directly address this question, it is interesting to note that various experimental interventions, including hyperthermia (15) and hypothermia (14), transform the cardiac-related SND bursting pattern to one dominated by low-frequency bursts. Interestingly, low-frequency SND bursts recorded during hyperthermia (14) and mild-to-moderate hypothermia (15) are prominently coupled to PND bursts, whereas those recorded during deep hypothermia (15) and after PVN BMI microinjection (current study) are not. Taken together, these findings demonstrate that central sympathetic neural circuits have the capability of generating a complex array of output patterns and that PVN BMI microinjection profoundly alters the SND bursting pattern. The fact that PVN BMI-induced changes in the SND bursting pattern were not observed after muscimol pretreatment suggests a role for PVN GABAA receptors. However, BMI can exert nonselective cellular effects. For example, Debarbieux et al. (5) reported that BMI directly blocks a current mediated by small conductance channels in thalamic reticular neurons, thereby enhancing the low-threshold calcium spike and the overlying burst of sodium action potentials. Although the current results do not identify the precise cellular mechanism(s) mediating BMI-induced changes in the SND bursting pattern, they do support an important role for the PVN in SND regulation.

What is the physiological significance of SND pattern changes? We (14) have previously demonstrated that heat-induced SND pattern changes contribute significantly to increasing sympathetic nerve activity during progressive elevations in internal body temperature, establishing pattern formation as an important strategy for changing the level of SND during acute heat stress. Alternatively or in addition, it may be that the SND pattern change itself (not the associated change in the level of activity) is physiologically important. Relative to this point, Pernow et al. (24) reported that the pattern of SND bursts influences the amount of neurotransmitter released in the pig spleen. As described by Gebber (8, 9) the presence of a pattern in neuronal discharges is likely an important way to coordinate or synchronize the discharges of central neurons. With regard to the present study, although renal and splenic sympathetic nerve activity were significantly (albeit modestly) increased after PVN BMI microinjection, it may be that transformation to low-frequency SND bursts enhances the effectiveness of nerve activity innervating regionally selective target organs.

The sympathetic nervous system is capable of producing selective changes in efferent nerve outflow (2, 4, 11, 13, 15, 27). For example, nonuniform changes in the frequency-domain coupling between discharge bursts in sympathetic nerve pairs have been observed. As demonstrated using coherence analysis, the synchronized discharges in different sympathetic nerves uncouple during periods of asphyxia (12) and after sustained activation of baroreceptor afferents (3). We reasoned that the uncoupling of discharges in postganglionic nerves (reduced coherence) may provide a neural substrate for sympathetic selectivity and differentiation (12). Because the PVN is an important central nervous system site for autonomic regulation (19, 23, 25), we hypothesized that PVN BMI microinjection would reduce the coupling between discharges in different sympathetic nerves. However, the current results demonstrate similar changes in the renal, splenic, and lumbar SND bursting patterns and prominent coupling between low-frequency discharges in sympathetic nerve pairs after PVN BMI microinjection in baroreceptor-innervated and SAD rats, suggesting little regional selectivity in SND frequency responses to PVN GABAA receptor antagonism. On the other hand, the magnitude of change in the level of activity in sympathetic nerves after PVN BMI microinjection was nonuniform (i.e., renal and splenic SND were significantly increased, whereas lumbar SND was not), suggesting some degree of selectivity in SND regulation after PVN BMI microinjection. However, because MAP increased with BMI injections, variations in responses in different nerves may be indicative of regulatory differences in the baroreflex control of renal, splenic, and lumbar SND rather than reflecting selectivity in the PVN control of efferent SND.

The fact that the low-frequency SND bursts produced by PVN BMI microinjections were eliminated immediately after midbrain transection demonstrates that neural connections between the PVN and postganglionic sympathetic nerves are required for mediating PVN BMI-induced SND pattern changes. Relative to this point, it is well established that both the dorsal and medial parvocellular subdivisions of the PVN project to brain stem regions involved in autonomic regulation and to sympathetic preganglionic neurons of the intermediolateral cell column (19, 23, 25). It should be noted that, despite the fact that the BMI diffusion boundaries in the current study included the PVN, we cannot exclude the possibility that the perinuclear region of the PVN may play a role in mediating BMI-induced changes in the SND bursting pattern.

Perspectives

Central sympathetic neural networks regulate three important functional characteristics of efferent SND: 1) the basal level of activity, 2) the bursting pattern, and 3) the relationships between discharges in regionally selective sympathetic nerves and sympathetic-phrenic nerve pairs. By altering these functional characteristics, the sympathetic nervous system plays a critical role in maintaining physiological homeostasis and mediating physiological responses to acute physical stress. The central neurocircuitry mediating changes in SND functional characteristics is not well described; however, at least three lines of evidence suggest that the PVN of the hypothalamus may be an important component. First, antagonism of PVN GABAA receptors increases the level of renal and splenic sympathetic nerve activity (26, 28, current study) and alters the SND bursting pattern (current study). Second, PVN injections of DL-homocysteic acid produce nonuniform changes in the level of efferent sympathetic nerve activity (6). Third, antagonism of PVN GABAA receptors alters the cardiac- and respiratory-related patterns in efferent sympathetic nerves and enhances the coupling between low-frequency bursts in sympathetic nerve pairs (current study). These results suggest that the PVN of the hypothalamus is an important component of the central neurocircuitry regulating efferent sympathetic nerve outflow.


    ACKNOWLEDGEMENTS

This research was supported by National Heart, Lung, and Blood Institute Grant HL-65346.


    FOOTNOTES

Address for reprint requests and other correspondence: M. J. Kenney, Dept. of Anatomy and Physiology, Coles Hall Rm. 228, Kansas State Univ., 1600 Denison Ave., Manhattan, KS 66506 (E-mail: Kenny{at}vet.ksu.edu).

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 9 February 2001; accepted in final form 10 May 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Barman, SM, and Gebber GL. Sympathetic nerve rhythm of brain stem origin. Am J Physiol Regulatory Integrative Comp Physiol 239: R42-R47, 1980[Free Full Text].

2.   Barman, SM, Gebber GL, and Calaresu FR. Differential control of sympathetic nerve discharge by the brain stem. Am J Physiol Regulatory Integrative Comp Physiol 247: R513-R519, 1984.

3.   Claassen, DE, Fels RJ, and Kenney MJ. Altered frequency characteristics of sympathetic nerve activity after sustained elevation in arterial pressure. Am J Physiol Regulatory Integrative Comp Physiol 274: R694-R703, 1998[Abstract/Free Full Text].

4.   Claassen, DE, Morgan DA, Hirai T, and Kenney MJ. Nonuniform sympathetic nerve responses after sustained elevation in arterial pressure. Am J Physiol Regulatory Integrative Comp Physiol 271: R1264-R1269, 1996[Abstract/Free Full Text].

5.   Debarbieux, F, Brunton J, and Charpak S. Effect of bicuculline on thalamic activity: a direct blockade of IAHP in reticularis neurons. J Neurophysiol 79: 2911-2918, 1998[Abstract/Free Full Text].

6.   Deering, J, and Coote JH. Paraventricular neurons elicit a volume expansion-like change of activity in sympathetic nerve to the heart and kidney in the rabbit. Exp Physiol 85: 177-186, 2000[Abstract].

7.   De Novellis, V, Stotz-Potter EH, Morin SM, Rossi F, and DiMicco JA. Hypothalamic sites mediating cardiovascular effects of microinjected bicuculline and EAAs in rats. Am J Physiol Regulatory Integrative Comp Physiol 269: R131-R140, 1995[Abstract/Free Full Text].

8.   Gebber, GL. Central oscillators responsible for sympathetic nerve discharge. Am J Physiol Heart Circ Physiol 239: H143-H155, 1980[Abstract/Free Full Text].

9.   Gebber, GL. Central determinants of sympathetic nerve discharge. In: Central Regulation of Autonomic Functions, edited by Loewy AD, and Spyer KM.. New York: Oxford University Press, 1990, p. 126-144.

10.   Gillis, RA, Yamada KA, DiMicco JA, Williford DJ, Segal SA, Hamosh P, and Norman WP. Central gamma -aminobutyric acid involvement in blood pressure control. Federation Proc 43: 32-38, 1984[Web of Science][Medline].

11.   Iriki, M, Reidel W, and Simon E. Regional differentiation of sympathetic nerve activity during hypothalamic heating and cooling in anesthetized rabbits. Pflügers Arch 328: 320-331, 1971[Web of Science][Medline].

12.   Kenney, MJ. Frequency characteristics of sympathetic nerve discharge in anesthetized rats. Am J Physiol Regulatory Integrative Comp Physiol 267: R830-R840, 1994[Abstract/Free Full Text].

13.   Kenney, MJ, Barman SM, Gebber GL, and Zhong S. Differential relationships among discharges of postganglionic sympathetic nerves. Am J Physiol Regulatory Integrative Comp Physiol 260: R1159-R1167, 1991[Abstract/Free Full Text].

14.   Kenney, MJ, Claassen DE, Bishop MR, and Fels RJ. Regulation of the sympathetic nerve discharge pattern during heat stress. Am J Physiol Regulatory Integrative Comp Physiol 275: R1992-R2001, 1998[Abstract/Free Full Text].

15.   Kenney, MJ, Claassen DE, Fels RJ, and Saindon CS. Cold stress alters characteristics of sympathetic nerve discharge bursts. J Appl Physiol 87: 732-742, 1999[Abstract/Free Full Text].

16.   Kenney, MJ, Pickar JP, Weiss ML, Saindon CS, and Fels RJ. Effects of midbrain and spinal cord transections on sympathetic nerve responses to heating. Am J Physiol Regulatory Integrative Comp Physiol 278: R1329-R1338, 2000[Abstract/Free Full Text].

17.   Kocsis, B, Gebber GL, Barman SM, and Kenney MJ. Relationships between activity of sympathetic nerve pairs: phase and coherence. Am J Physiol Regulatory Integrative Comp Physiol 259: R549-R560, 1990[Abstract/Free Full Text].

18.   Krieger, EM. Neurogenic hypertension in the rat. Circ Res 15: 511-521, 1964[Abstract/Free Full Text].

19.   Loewy, AD. Central autonomic pathways. In: Central Regulation of Autonomic Functions, edited by Loewy AD, and Spyer KM.. New York: Oxford University Press, 1990, p. 28-43.

20.   Martin, DS, and Haywood JR. Hemodynamic responses to paraventricular nucleus disinhibition with bicuculline in conscious rats. Am J Physiol Heart Circ Physiol 265: H1727-H1733, 1993[Abstract/Free Full Text].

21.   Martin, DS, and Haywood JR. Reduced GABA inhibition of sympathetic function in renal-wrapped hypertensive rats. Am J Physiol Regulatory Integrative Comp Physiol 275: R1523-R1529, 1998[Abstract/Free Full Text].

22.   Martin, DS, Segura T, and Haywood JR. Cardiovascular responses to bicuculline in the paraventricular nucleus of the rat. Hypertension 18: 48-55, 1991[Abstract/Free Full Text].

23.   Miselis, RR, Weiss ML, and Shapiro RE. Modulation of the visceral neuraxis. In: Circumventricular Organs and Body Fluids, edited by Gross PM.. Boca Raton, FL: CRC, 1987, p. 143-162.

24.   Pernow, J, Schwieler J, Kahan T, Hjemdahl P, Oberle J, Gunnar Wallin B, and Lundberg JM. Influence of sympathetic nerve discharge pattern on norepinephrine and neuropeptide Y release. Am J Physiol Heart Circ Physiol 257: H866-H872, 1989[Abstract/Free Full Text].

25.   Swanson, LW, and Sawchenko PE. Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6: 269-324, 1983[Web of Science][Medline].

26.   Tagawa, T, and Dampney RAL AT1 receptors mediate excitatory inputs to rostral ventrolateral medulla pressor neurons from hypothalamus. Hypertension 34: 1301-1307, 1999[Abstract/Free Full Text].

27.   Victor, RG, Thoren P, Morgan DA, and Mark AL. Differential control of adrenal and renal sympathetic nerve activity during hemorrhagic hypotension in rats. Circ Res 64: 686-694, 1989[Abstract/Free Full Text].

28.   Zhang, K, and Patel KP. Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA. Am J Physiol Regulatory Integrative Comp Physiol 275: R728-R734, 1998[Abstract/Free Full Text].

29.   Zhong, S, Zhou SY, Gebber GL, and Barman SM. Coupled oscillators account for the slow rhythms in sympathetic nerve discharge and phrenic nerve activity. Am J Physiol Regulatory Integrative Comp Physiol 272: R1314-R1324, 1997[Abstract/Free Full Text].

Am J Physiol Heart Circ Physiol 281(3):H1233-H1241
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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