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Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat
Neuroscience Letters 179 (1994) 71-74
ELSEVIER
HEUROSClENCE LETTERS
Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat Johannes
Zanzinger*, Jens Doutheil, Jfirgen Czachurski, Horst Seller
L Physiologisehes Institut, Universitiit Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany
Received 4 July 1994; Revised version received 3 August 1994; Accepted 3 August 1994
Abstract
The caudal ventrolateral medulla (CVLM) modulates sympathetic outflow from the rostral ventrolateral medulla (RVLM). We studied the possible role of the CVLM in the transmission of excitatory somato-sympathetic reflexes in baro- and chemoreceptor denervated chloralose-anesthetized cats. Neurotoxic doses of kainate, injected in the CVLM, caused marked increases in baseline sympathetic nerve activity (SNA) and arterial blood pressure (BP). Concomitantly. excitatory somato-sympathetic reflex responses evoked by electrical stimulation of the 4th intercostal nerve disappeared almos pletely. Similar effects on SNA and BP but not on somato-sympathetic reflexes were observed when the GABA-antagonist t,,cuculline was injected in the RVLM. Bicuculline injected in the RVLM after kainate had no additional effects. These results suggest that in addition to a tonic GABA-ergic inhibition on the RVLM, the CVLM controls somato-sympathetic reflex transmission through interneurons located in this region. Key words: Somato-sympathetic reflex; RVLM; CVLM; Sympathetic nerve; Ventrolateral medulla; Cat
The caudal ventrolateral medulla (CVLM) is known to exert an inhibitory input to the rostral ventrolateral medulla (RVLM) which is the final area for generation of sympathetic tone [10]. This inhibition was initially thought to be almost entirely produced by the relay of baroreflex inputs within this area [1,2,4]. Recent studies on rats [3] revealed an additional tonic component of sympathoinhibition after baroreceptor denervation since lesions of the CVLM caused marked increases in sympathetic nerve activity (SNA) and blood pressure (BP) in these animals. Furthermore, modulatory roles for the CVLM in the transmission of inhibitory somato-sympathetic reflexes [6] and the vagal cardiopulmonary (Bezold-Jarisch) reflex [11] have been proposed. The present study was undertaken to characterize possible baroreceptor independent functions of the CVLM in the modulation of SNA in cats. For this purpose we studied the possible role of the CVLM in the generation of basal sympathetic tone in the RVLM and in the trans-
*Corresponding author. Fax: (49) 6221-564561. 0304-3940/94l$7.00© 1994 Elsevier ScienceIreland Ltd. All rights reserved S S D I 0304-3940(94)00612-1
mission of characteristic somato-sympathetic reflexes evoked by electrical stimulation of the 4th intercostal nerve [9]. The supraspinal reflex component produced, is known to be relayed in the RVLM and is characterized by a rather generalized activation of the sympathetic nervous system [7]. Experiments were performed on cats (3.5-4.5 kg) initially sedated by ketamine (10 mg/kg i.m.) and subsequently anesthetized by ~-chloralose (50-70 mg/kg i.v.). Catheters were placed into a femoral vein and artery for infusion of drugs and for measurement of arterial BP via a pressure transducer (Statham PD23ID). The cats were paralyzed by 0.2 mg/kg pancuronium bromide per hour and artificially ventilated. Rectal temperature was maintained at 38.5°C by a thermostatically controlled infrared lamp. Arterial baroreceptors and chemoreceptors were denervated by cutting the carotid sinus and vagoaortic nerves, bilaterally. The denervation was subsequently verified by the absence of changes in SNA during BP-increases caused by 1 ¢tg/kg noradrenaline (i.v.). A pneumothorax was performed and the left white ramus of the 3rd thoracic segment and the left intercostal nerve
72
J. Zanzinger et al./Neuroscience Letters 179 (1994) 7l 74
of the 4th thoracic segment were exposed retropleurally. Nerves prepared were kept in a pool of warm paraffin oil. To activate somato-sympathetic reflexes, the central end of the intercostal nerve was placed on bipolar platinum electrodes connected to an isolated stimulator (Digitimer). Electrical stimulation was carried out with short trains of 3-4 pulses of various amplitudes (0.5-15 V), 0.5 ms pulse duration and 300-400 Hz intratrain frequency, representing 2-3 times threshold intensity. Intervals between sucessive trains were 3-4 s. Preganglionic activity was recorded from the central end of the WR-T3 via bipolar platinum electrodes. Neural signals were amplified (20000-50000 x; Tektronix AM 502) and filtered (2 Hz to 3 kHz). SNA was recorded as counted impulses at intervals of 0.3s and is expressed in Fig. 2 as impulses per second (imp/s), Ten consecutive reflex sweeps were routinely averaged at a sample rate of 5 kHz to reduce influence of fluctuations in reflex activities. Measurements of the onset latency were made from the onset of stimulation to the beginning of reflex responses. The magnitude of the potentials was estimated by measuring peak amplitudes. For microinjections in the RVLM the ventral surface of the medulla oblongata was exposed. Injections were performed into the RVLM or CVLM with glass micropipettes having a tip diameter of approximately 20/lm. In cats, the RVLM projects on the ventral surface ca. lmm rostral and the CVLM ca. 3 mm caudal to the most cranial rootlet of the XII cranial nerve, both ca. 4 mm lateral to the midline. Injections (500 nl each site) were made by pneumatic pressure on the ipsilateral (left) side in the center of the areas at depths of 1.2 mm below the ventral surface using a micromanipulator. Measurements were taken when steady state responses were observed, in general after approximately 5 min. For statistical analysis an ANOVA for repeated measurements with Tukey's multiple range test was performed. Differences at P < 0.05 were considered to be significant. Values are reported as mean + S.E.M. Representative reflex responses as recorded from the white ramus are shown in Fig. 1A. Reflexes were classified on the basis of their latency to onset and duration [9]. Latencies are typically 10 15 ms for spinal and 40-50 ms for supraspinal reflexes. Electrical stimulation of short trains of 3-4 pulses at an intensity of 2 5 V, 0.5 ms pulse duration and 400 Hz intratrain frequency, consistently evoked a predominant supraspinal reflex potential with a latency to onset of 45.3 + 5.4 ms (n -- 11 cats). Injection of neurotoxic doses of kainate (5 mM) in the CVLM affecting an approximate distribution area which is shown in Fig. 1B, completely abolished the supraspinal reflex in 6 of 11 cats (see example in Fig. 1) and markedly reduced reflex amplitudes in the other cats. Mean data of all cats are given in Fig. 2. Reflex responses were not significantly affected by concomitant increases in SNA as shown by the unchanged reflex after glutamate stimulation of SNA (50/.tM; 278 vs 110 imp/s at control in this
A
glutamate
kainic acid (CVLM)
_j,o.v 50ms
B
Fig. 1. A: representative reflex responses evoked in the left white ramus WR-T3 following stimulation of the ipsilateral 4th intercostal nerve during control conditions and alter microinjections (500 nl) of either glutamate (50 ,uM) in the rostral ventro-lateral medulla (RVLM) or kainate (5 mM) in the caudal ventrolateral medulla (CVLM). Electrical stimulation was performed using trains of four pulses at 300 Hz, 0.5 ms pulse duration and 5V intensity; the stimulus was repeated every 5s, amplification x 50.000. B: cross-section of the lower brain stem of the cat at the level of the C V L M (marked area). Injections were made in the center of the C V L M causing distribution of the volume throughout the whole CVLM. S = solitary tract, 5ST = spinal trigeminal tract, 5SP = alaminar spinal trigeminal nucleus, parvocellular division, N A = nucleus ambiguus, L R N = lateral reticular nucleus, IO = inferior olive.
cat) in Fig. 1 and by the only slightly reduced reflex amplitudes after injection of bicuculline (40 p M ) in the
£ Zanzinger et al. INeuroscience Letters 179 (1994) 71 74
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Kainic (CVLM)
Fig. 2. Effects of GABA receptor blockade in the RVLM by bicuculline (40/IM) and chemical lesion of the CVLM by kainate (5 mM) on mean arterial blood pressure (MAP), sympathetic nerve activity (SNA) recorded from the 3rd left white ramus and supraspinal reflex amplitudes evoked by stimulation of the 4th ipsilateral intercostal nerve. Data are presented as percentage of the mean control amplitude (= 100%). Asterisks denote significant differences from control values *P < 0.05, **P < 0.01 (n = 11 cats).
RVLM (Fig. 2). On the other hand, the coincidence of marked increases in SNA and disappearance of supraspinal reflexes after kainate in the CVLM shows that possible damage of the RVLM caused by diffusion of kainate from the CVLM did not occur in this study and thus cannot account for the observed effects. Injection of kainate into the RVLM caused elimination of supraspinal
73
reflexes and baseline SNA (data not shown). The removal of inhibitory inputs on the RVLM increased SNA more than 2-fold leading to dramatic rises in BP. The origin of inhibition is probably the CVLM since bicuculline (RVLM) and kainate (CVLM) were equieffective (Fig. 2) and, in addition, when bicuculline was injected after kainate, no further increases occurred in neither SNA nor BP (data not shown). These experiments revealed a so far unknown additional relay for somato-sympathetic reflex transmission. Supraspinal reflexes were not completely abolished in 5 out of 11 cats. This could indicate that the location of the reflex transmitting interneurons may be not strictly confined to the CVLM. However, there are some uncertainties arising from the injection procedure. The CVLM was identified visually by landmarks and deviations of the injection site from the center occurred in some cases because of superficial blood vessels. The injected volume (500 nl) has a spherical diameter of ca. 1 mm plus a diffusion zone which is sufficient to reach the whole RVLM or CVLM as shown in previous studies [8,12]. A greater volume probably would have caused additional effects in the nearby structures (RVLM/CVLM overlapping zone). Nevertheless, since kainate does not block axonal transmission, the consistent blockade of supraspinal refexes after kainate in 6 animals suggests that the CVLM contains interneurons of the excitatory somatosympathetic reflex arc. The reason why these excitatory neurons had not been discovered until now may be that their activity was masked in functional studies by the predominant inhibitory activity of the other CVLM neurons. It is possible that other somato-sympathetic afterents are likewise relayed in the CVLM. In rabbits, a modulation of reflex inhibition of SNA in response to stimulation of the sural nerve (cutaneous afferents) by the CVLM has been recently observed [6]. The study demonstrates further that in acutely baroreceptor denervated cats inactivation of CVLM neurons increases SNA and BP by removal of an obviously tonically active GABA-ergic inhibition on the RVLM, a finding which has been also reported from rats [3]. Thus, it appears that the CVLM modulates SNA in the cat not only through interneurons of the baroreflex arc as previously suggested [1,2,4,10] but also through neurons mediating tonic inhibition and the transmission of excitatory, probably not GABAergic somato-sympathetic reflexes. However, the present experiments cannot rule out the possibility, that populations of CVLM neurons mediating inhibition upon baroreceptor stimulation in intact animals become tonically active after baroreceptor denervation. Previous studies suggest that different cell populations may exist. Specific NMDA-receptor blockade in the CVLM selectively blocks baroreflex responses without producing hypertension and without blocking hypotensive responses to glutamate in this area [4]. Injection of the broad-spectrum glutamate antagonist kynure-
74
J. Zanzinger et al./Neuroscience Letters 179 (1994) 71-74
nate in the CVLM, however, blocked the baroreflex and increased SNA and BP in another study [5]. We conclude, that modulation of sympathetic outflow from the RVLM by the CVLM in vivo may consist of a tonic baseline inhibition and of a co-ordinated control of inhibitory and excitatory sympathetic reflexes as well. This work was supported by the Deutsche Forschungsgemeinschaft within the SFB 320. [1] Agarwal, S.K. and Calaresu, F.R., Monosynaptic connection from caudal to rostral ventrolateral medulla in the baroreceptor reflex pathway, Brain Res., 555 (1991) 7~74. [2] Agarwal, S.K., Gelsema, A.J. and Calaresu, F.R., Inhibition of rostral VLM by baroreceptor activation is relayed through caudal VLM, Am. J. Physiol., 258 (1990) R1271-R1278. [3] Cravo, S.L. and Morrison, S.F., The caudal ventrolateral medulla is a source of tonic sympathoinhibition, Brain Res., 621 (1993) 133-136. [4] Gordon, F.J., Aortic baroreceptor reflexes are mediated by NMDA receptors in caudal ventrolateral medulla, Am. J. Physiol., 252 (1987) R628-R633. [5] Guyenet, P.G., Filtz, T.M. and Donaldson, S.R., Role of excita-
[6]
[7]
[8]
[9]
[10] [11]
[12]
tory amino acids in rat vagal and sympathetic baroreflexes, Brain Res., 407 (1987) 272-284. Masuda, N., Ootsuka, Y. and Terui, N., Neurons in the caudal ventrolateral medulla mediate the somato-sympathetic inhibitory reflex response via GABA receptors in the rostral ventrolateral medulla, J. Auton. Nerv. Syst., 40 (1992) 91-98. McAllen, R.M., Mediation of the fastigial pressor response and a somatosympathetic reflex by ventral medullary neurons in the cat, J. Physiol., 368 (1985) 423433. Offner, B., Dembowsky, K. and Czachurski, J., Characteristics of sympathetic reflexes evoked by electrical stimulation of phrenic nerve afferents, J, Auton. Nerv. Syst., 41 (1992) 103-112. Sato, A. and Schmidt, R.F., Somatosympathetic reflexes: afferent fibers, central pathways, discharge characteristics, Physiol. Rev., 53 (1973) 916-947. Spyer, K.M., Central nervous mechanisms contributing to cardiovascular control, J. Physiol., 474 (1994) 1-19. Verberne, A.J.M., Beart, P.M. and Louis, W.J., Excitatory amino acid receptors in the caudal ventrolateral medulla mediate a vagal cardiopulmonary reflex in the rat, Exp. Brain Res., 78 (1989) 185-192. Zanzinger, J., Czachurski, J., Offner, B. and Seller, H., Somatosympathetic reflex transmission in the ventrolateral medulla oblongata: spatial organization and receptor types, Brain Res., 656 (1994) 353 358.
ELSEVIER
HEUROSClENCE LETTERS
Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat Johannes
Zanzinger*, Jens Doutheil, Jfirgen Czachurski, Horst Seller
L Physiologisehes Institut, Universitiit Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany
Received 4 July 1994; Revised version received 3 August 1994; Accepted 3 August 1994
Abstract
The caudal ventrolateral medulla (CVLM) modulates sympathetic outflow from the rostral ventrolateral medulla (RVLM). We studied the possible role of the CVLM in the transmission of excitatory somato-sympathetic reflexes in baro- and chemoreceptor denervated chloralose-anesthetized cats. Neurotoxic doses of kainate, injected in the CVLM, caused marked increases in baseline sympathetic nerve activity (SNA) and arterial blood pressure (BP). Concomitantly. excitatory somato-sympathetic reflex responses evoked by electrical stimulation of the 4th intercostal nerve disappeared almos pletely. Similar effects on SNA and BP but not on somato-sympathetic reflexes were observed when the GABA-antagonist t,,cuculline was injected in the RVLM. Bicuculline injected in the RVLM after kainate had no additional effects. These results suggest that in addition to a tonic GABA-ergic inhibition on the RVLM, the CVLM controls somato-sympathetic reflex transmission through interneurons located in this region. Key words: Somato-sympathetic reflex; RVLM; CVLM; Sympathetic nerve; Ventrolateral medulla; Cat
The caudal ventrolateral medulla (CVLM) is known to exert an inhibitory input to the rostral ventrolateral medulla (RVLM) which is the final area for generation of sympathetic tone [10]. This inhibition was initially thought to be almost entirely produced by the relay of baroreflex inputs within this area [1,2,4]. Recent studies on rats [3] revealed an additional tonic component of sympathoinhibition after baroreceptor denervation since lesions of the CVLM caused marked increases in sympathetic nerve activity (SNA) and blood pressure (BP) in these animals. Furthermore, modulatory roles for the CVLM in the transmission of inhibitory somato-sympathetic reflexes [6] and the vagal cardiopulmonary (Bezold-Jarisch) reflex [11] have been proposed. The present study was undertaken to characterize possible baroreceptor independent functions of the CVLM in the modulation of SNA in cats. For this purpose we studied the possible role of the CVLM in the generation of basal sympathetic tone in the RVLM and in the trans-
*Corresponding author. Fax: (49) 6221-564561. 0304-3940/94l$7.00© 1994 Elsevier ScienceIreland Ltd. All rights reserved S S D I 0304-3940(94)00612-1
mission of characteristic somato-sympathetic reflexes evoked by electrical stimulation of the 4th intercostal nerve [9]. The supraspinal reflex component produced, is known to be relayed in the RVLM and is characterized by a rather generalized activation of the sympathetic nervous system [7]. Experiments were performed on cats (3.5-4.5 kg) initially sedated by ketamine (10 mg/kg i.m.) and subsequently anesthetized by ~-chloralose (50-70 mg/kg i.v.). Catheters were placed into a femoral vein and artery for infusion of drugs and for measurement of arterial BP via a pressure transducer (Statham PD23ID). The cats were paralyzed by 0.2 mg/kg pancuronium bromide per hour and artificially ventilated. Rectal temperature was maintained at 38.5°C by a thermostatically controlled infrared lamp. Arterial baroreceptors and chemoreceptors were denervated by cutting the carotid sinus and vagoaortic nerves, bilaterally. The denervation was subsequently verified by the absence of changes in SNA during BP-increases caused by 1 ¢tg/kg noradrenaline (i.v.). A pneumothorax was performed and the left white ramus of the 3rd thoracic segment and the left intercostal nerve
72
J. Zanzinger et al./Neuroscience Letters 179 (1994) 7l 74
of the 4th thoracic segment were exposed retropleurally. Nerves prepared were kept in a pool of warm paraffin oil. To activate somato-sympathetic reflexes, the central end of the intercostal nerve was placed on bipolar platinum electrodes connected to an isolated stimulator (Digitimer). Electrical stimulation was carried out with short trains of 3-4 pulses of various amplitudes (0.5-15 V), 0.5 ms pulse duration and 300-400 Hz intratrain frequency, representing 2-3 times threshold intensity. Intervals between sucessive trains were 3-4 s. Preganglionic activity was recorded from the central end of the WR-T3 via bipolar platinum electrodes. Neural signals were amplified (20000-50000 x; Tektronix AM 502) and filtered (2 Hz to 3 kHz). SNA was recorded as counted impulses at intervals of 0.3s and is expressed in Fig. 2 as impulses per second (imp/s), Ten consecutive reflex sweeps were routinely averaged at a sample rate of 5 kHz to reduce influence of fluctuations in reflex activities. Measurements of the onset latency were made from the onset of stimulation to the beginning of reflex responses. The magnitude of the potentials was estimated by measuring peak amplitudes. For microinjections in the RVLM the ventral surface of the medulla oblongata was exposed. Injections were performed into the RVLM or CVLM with glass micropipettes having a tip diameter of approximately 20/lm. In cats, the RVLM projects on the ventral surface ca. lmm rostral and the CVLM ca. 3 mm caudal to the most cranial rootlet of the XII cranial nerve, both ca. 4 mm lateral to the midline. Injections (500 nl each site) were made by pneumatic pressure on the ipsilateral (left) side in the center of the areas at depths of 1.2 mm below the ventral surface using a micromanipulator. Measurements were taken when steady state responses were observed, in general after approximately 5 min. For statistical analysis an ANOVA for repeated measurements with Tukey's multiple range test was performed. Differences at P < 0.05 were considered to be significant. Values are reported as mean + S.E.M. Representative reflex responses as recorded from the white ramus are shown in Fig. 1A. Reflexes were classified on the basis of their latency to onset and duration [9]. Latencies are typically 10 15 ms for spinal and 40-50 ms for supraspinal reflexes. Electrical stimulation of short trains of 3-4 pulses at an intensity of 2 5 V, 0.5 ms pulse duration and 400 Hz intratrain frequency, consistently evoked a predominant supraspinal reflex potential with a latency to onset of 45.3 + 5.4 ms (n -- 11 cats). Injection of neurotoxic doses of kainate (5 mM) in the CVLM affecting an approximate distribution area which is shown in Fig. 1B, completely abolished the supraspinal reflex in 6 of 11 cats (see example in Fig. 1) and markedly reduced reflex amplitudes in the other cats. Mean data of all cats are given in Fig. 2. Reflex responses were not significantly affected by concomitant increases in SNA as shown by the unchanged reflex after glutamate stimulation of SNA (50/.tM; 278 vs 110 imp/s at control in this
A
glutamate
kainic acid (CVLM)
_j,o.v 50ms
B
Fig. 1. A: representative reflex responses evoked in the left white ramus WR-T3 following stimulation of the ipsilateral 4th intercostal nerve during control conditions and alter microinjections (500 nl) of either glutamate (50 ,uM) in the rostral ventro-lateral medulla (RVLM) or kainate (5 mM) in the caudal ventrolateral medulla (CVLM). Electrical stimulation was performed using trains of four pulses at 300 Hz, 0.5 ms pulse duration and 5V intensity; the stimulus was repeated every 5s, amplification x 50.000. B: cross-section of the lower brain stem of the cat at the level of the C V L M (marked area). Injections were made in the center of the C V L M causing distribution of the volume throughout the whole CVLM. S = solitary tract, 5ST = spinal trigeminal tract, 5SP = alaminar spinal trigeminal nucleus, parvocellular division, N A = nucleus ambiguus, L R N = lateral reticular nucleus, IO = inferior olive.
cat) in Fig. 1 and by the only slightly reduced reflex amplitudes after injection of bicuculline (40 p M ) in the
£ Zanzinger et al. INeuroscience Letters 179 (1994) 71 74
200
-o- ) -r"
E E
*
150 100
I:L <: ~;
50 0 400 300
Q.
E
° ~
< z 03
200 100 0 120
v
a)
.10 :3
80
Q.
E
ca x
40
m
0 control
BICU (RVLM)
Kainic (CVLM)
Fig. 2. Effects of GABA receptor blockade in the RVLM by bicuculline (40/IM) and chemical lesion of the CVLM by kainate (5 mM) on mean arterial blood pressure (MAP), sympathetic nerve activity (SNA) recorded from the 3rd left white ramus and supraspinal reflex amplitudes evoked by stimulation of the 4th ipsilateral intercostal nerve. Data are presented as percentage of the mean control amplitude (= 100%). Asterisks denote significant differences from control values *P < 0.05, **P < 0.01 (n = 11 cats).
RVLM (Fig. 2). On the other hand, the coincidence of marked increases in SNA and disappearance of supraspinal reflexes after kainate in the CVLM shows that possible damage of the RVLM caused by diffusion of kainate from the CVLM did not occur in this study and thus cannot account for the observed effects. Injection of kainate into the RVLM caused elimination of supraspinal
73
reflexes and baseline SNA (data not shown). The removal of inhibitory inputs on the RVLM increased SNA more than 2-fold leading to dramatic rises in BP. The origin of inhibition is probably the CVLM since bicuculline (RVLM) and kainate (CVLM) were equieffective (Fig. 2) and, in addition, when bicuculline was injected after kainate, no further increases occurred in neither SNA nor BP (data not shown). These experiments revealed a so far unknown additional relay for somato-sympathetic reflex transmission. Supraspinal reflexes were not completely abolished in 5 out of 11 cats. This could indicate that the location of the reflex transmitting interneurons may be not strictly confined to the CVLM. However, there are some uncertainties arising from the injection procedure. The CVLM was identified visually by landmarks and deviations of the injection site from the center occurred in some cases because of superficial blood vessels. The injected volume (500 nl) has a spherical diameter of ca. 1 mm plus a diffusion zone which is sufficient to reach the whole RVLM or CVLM as shown in previous studies [8,12]. A greater volume probably would have caused additional effects in the nearby structures (RVLM/CVLM overlapping zone). Nevertheless, since kainate does not block axonal transmission, the consistent blockade of supraspinal refexes after kainate in 6 animals suggests that the CVLM contains interneurons of the excitatory somatosympathetic reflex arc. The reason why these excitatory neurons had not been discovered until now may be that their activity was masked in functional studies by the predominant inhibitory activity of the other CVLM neurons. It is possible that other somato-sympathetic afterents are likewise relayed in the CVLM. In rabbits, a modulation of reflex inhibition of SNA in response to stimulation of the sural nerve (cutaneous afferents) by the CVLM has been recently observed [6]. The study demonstrates further that in acutely baroreceptor denervated cats inactivation of CVLM neurons increases SNA and BP by removal of an obviously tonically active GABA-ergic inhibition on the RVLM, a finding which has been also reported from rats [3]. Thus, it appears that the CVLM modulates SNA in the cat not only through interneurons of the baroreflex arc as previously suggested [1,2,4,10] but also through neurons mediating tonic inhibition and the transmission of excitatory, probably not GABAergic somato-sympathetic reflexes. However, the present experiments cannot rule out the possibility, that populations of CVLM neurons mediating inhibition upon baroreceptor stimulation in intact animals become tonically active after baroreceptor denervation. Previous studies suggest that different cell populations may exist. Specific NMDA-receptor blockade in the CVLM selectively blocks baroreflex responses without producing hypertension and without blocking hypotensive responses to glutamate in this area [4]. Injection of the broad-spectrum glutamate antagonist kynure-
74
J. Zanzinger et al./Neuroscience Letters 179 (1994) 71-74
nate in the CVLM, however, blocked the baroreflex and increased SNA and BP in another study [5]. We conclude, that modulation of sympathetic outflow from the RVLM by the CVLM in vivo may consist of a tonic baseline inhibition and of a co-ordinated control of inhibitory and excitatory sympathetic reflexes as well. This work was supported by the Deutsche Forschungsgemeinschaft within the SFB 320. [1] Agarwal, S.K. and Calaresu, F.R., Monosynaptic connection from caudal to rostral ventrolateral medulla in the baroreceptor reflex pathway, Brain Res., 555 (1991) 7~74. [2] Agarwal, S.K., Gelsema, A.J. and Calaresu, F.R., Inhibition of rostral VLM by baroreceptor activation is relayed through caudal VLM, Am. J. Physiol., 258 (1990) R1271-R1278. [3] Cravo, S.L. and Morrison, S.F., The caudal ventrolateral medulla is a source of tonic sympathoinhibition, Brain Res., 621 (1993) 133-136. [4] Gordon, F.J., Aortic baroreceptor reflexes are mediated by NMDA receptors in caudal ventrolateral medulla, Am. J. Physiol., 252 (1987) R628-R633. [5] Guyenet, P.G., Filtz, T.M. and Donaldson, S.R., Role of excita-
[6]
[7]
[8]
[9]
[10] [11]
[12]
tory amino acids in rat vagal and sympathetic baroreflexes, Brain Res., 407 (1987) 272-284. Masuda, N., Ootsuka, Y. and Terui, N., Neurons in the caudal ventrolateral medulla mediate the somato-sympathetic inhibitory reflex response via GABA receptors in the rostral ventrolateral medulla, J. Auton. Nerv. Syst., 40 (1992) 91-98. McAllen, R.M., Mediation of the fastigial pressor response and a somatosympathetic reflex by ventral medullary neurons in the cat, J. Physiol., 368 (1985) 423433. Offner, B., Dembowsky, K. and Czachurski, J., Characteristics of sympathetic reflexes evoked by electrical stimulation of phrenic nerve afferents, J, Auton. Nerv. Syst., 41 (1992) 103-112. Sato, A. and Schmidt, R.F., Somatosympathetic reflexes: afferent fibers, central pathways, discharge characteristics, Physiol. Rev., 53 (1973) 916-947. Spyer, K.M., Central nervous mechanisms contributing to cardiovascular control, J. Physiol., 474 (1994) 1-19. Verberne, A.J.M., Beart, P.M. and Louis, W.J., Excitatory amino acid receptors in the caudal ventrolateral medulla mediate a vagal cardiopulmonary reflex in the rat, Exp. Brain Res., 78 (1989) 185-192. Zanzinger, J., Czachurski, J., Offner, B. and Seller, H., Somatosympathetic reflex transmission in the ventrolateral medulla oblongata: spatial organization and receptor types, Brain Res., 656 (1994) 353 358.