Cerebellar control of the cardiovascular responses during postural changes in conscious rabbits

NEUROSCIEHCE RESEARCH ELSEVIER

Neuroscience Research 32 (1998) 267-271

Cerebellar control of the cardiovascular responses during postural changes in conscious rabbits Naoko

Nisimaru

*, K e i z o O k a h a r a ,

Soroku

Yanai

Department of Physiology, Oita Medical University, Oita 879-5593, Japan

Received 9 August 1998; accepted 9 September 1998

Abstract

In conscious control rabbits, tilting the head 30° up from a position 30° down induced initially an inhibition in the renal sympathetic nerve activity (RSNA), however this inhibition immediately released and became a transient increase. Following these responses in RSNA, blood pressure (BP) initially decreased but recovered to the control level within 3-5 s. After bilateral destruction of the lateral nodulus-uvula in the cerebellum, in contrast, the same tilting of the head caused an immediate large increase in RSNA without early inhibition, which was sustained at a high level. BP increased transiently, but then decreased and remained at a level lower than the control. These results indicate that the timing and duration of this transient increase in RSNA during tilting the head up are controlled by the lateral nodulus-uvula and may be important in the rapid adaptation of blood pressure. In addition, this suggests that the lateral nodulus-uvula may play an important role in the cardiovascular control under conditions of consciousness during changes in head position and body posture. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cerebellar nodulus-uvula; Postural change; Renal sympathetic nerve activity; Blood pressure; Conscious rabbit

1. Introduction

Several investigators demonstrated the important role of the cerebellum in control of the cardiovascular system, and also in coordination of the cardiovascular system with the m o t o r system (Moruzzi, 1950; Ito, 1984; Nisimaru and Watanabe, 1985; Bradley et al., 1991). All of these experiments were performed in anesthetized or decerebrated animals. To determine the role of the cerebellum in cardiovascular control, it is important that we examine the functions of the cerebellum in conscious animals. We reported previously that electrical stimulation of the lateral region of the nodulus and uvula in the cerebellar vermis produced an inhibition of renal sympathetic nerve activity (RSNA) and a fall in blood * Corresponding author. Tel.: + 81-97-5865642; Fax: + 81-975865649; e-mail: [email protected].

pressure (BP) in anesthetized rabbits (Nisimaru and Watanabe, 1985). Since this region receives cardiovascular and vestibular afferent signals (Uchino et al., 1970; Precht et al., 1976; Nisimaru and Katayama, 1996), it may play a role in cardiovascular control during changes in head position and body posture. To examine the above hypothesis, we studied responses in R S N A and BP as indices of cardiovascular activities in both anesthetized and conscious rabbits during postural changes. Part of the present results has been published elsewhere in abstract form (Nisimaru et al., 1993).

2. Materials and methods

Twenty two adult male albino rabbits weighing 2.13.5 kg were used in this study. The method of continuous monitoring of R S N A in conscious, awake rabbits

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N. Nisimaru et al./Neuroscience Research 32 (1998) 267 271

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Fig. 1. Effects on renal sympathetic nerve activity (RSNA) and blood pressure (BP) following the intravenous injection of noradrenaline (8 gg/kg). (A) Effect of noradrenaline on RSNA and BP. (B) RSNA and BP 60 s after injection of noradrenaline. BP, arterial blood pressure; IRSNA, integrated renal sympathetic nerve activity; RSNA, original record of renal sympathetic nerve activity. was based on the procedure described by Miki et al. (1989). Two or 3 days before each experiment, animals were anesthetized with ~-chloralose plus urethane (30 and 600 mg/kg respectively) and a bipolar stainless steel wire electrode (Teflon-coated, outer diameter 0.2 mm, AS633, Cooner, Chatsworth, CA) for recording R S N A was implanted into the left renal nerve and fixed with the silicone rubber (Wacker silicon 604A and 604B mixed, Wacher-Chemie, Munich). A catheter was inserted into the left c o m m o n carotid artery until its tip reached the aortic arc. The catheter was flushed every day and kept filled with heparin sodium solution (20 unit/cc). The nerve electrode and the arterial catheter were exteriorized through the back neck region and protected by a fitted jacket. A platform of dental cement was built onto the skull along the midsagittal line, in which three bolts were embedded in order to provide fixation points. To examine the effect of the destruction of the lateral nodulus-uvula, 0.1% kainic acid was injected into the bilateral local regions of the lateral nodulus and uvula (2 gl for each side) in six rabbits 5 days before the recording electrodes and the catheter were implanted. Two or three days after the operation, the rabbit was mounted on the tilting table (Fig. 2A), the body being contained in a wooden box in a normal position. The head was fixed with a ventral inclination so as to prevent reflecting movement during head-up and headdown tilts. R S N A was amplified, rectified and integrated according to the procedure described previously

(Nisimaru and Watanabe, 1985). During a tilting experiment under either conscious or anesthetized conditions (with ~-chloralose plus urethane), R S N A and BP were recorded on a chart recorder (Nihon Koden) and stored on a data recorder (RD-101T, TEAC) for off-line analysis. Usually, grouped discharges synchronized with heart beat and respiration were observed in the spontaneous activity of the R S N A in both conscious and anesthetized rabbits (Fig. 1). To test whether the recorded signal definitely consists of postganglionic efferent RSNA, either a ganglionic blocking agent (hexamethonium, 2 mg/kg) or noradrenaline ( 5 - 2 0 gg/kg) that induces reduction of R S N A via the sinoaortic baroreceptor reflex, was administered intravenously. As exemplified in Fig. 1 with the injection of noradrenaline (8 gg/kg), these agents reduced R S N A at an almost undetectable level, indicating that the recorded discharges were of postganglionic origin. After this setting of the canula and electrodes, we were able to record R S N A and BP over 3 - 7 days. During these experiments, the animals were treated with care and were without any sign of pain or discomfort.

3. Results

In four rabbits anesthetized with c~-chloralose plus urethane (30 and 600 mg/kg, respectively), tilting the head 30 ° up from position 30 ° down caused inhibition

N. Nisimaru et a l . / Neuroscience Research 32 (1998) 267-271

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Fig. 2. Changes in R S N A and BP following tilting the head 30 ° up from a position 30 ° down. (A) Schematic drawing of the method for tilting and recording in R S N A and BP. (Ba) Under anesthetized conditions responses of mean blood pressure (MBP) and integrated renal sympathetic nerve activity (IRSNA) following tilting the head up. (Bb) Responses in conscious control rabbits. (Bc) Responses after bilateral destruction of the lateral nodulus-uvula in conscious rabbits. All traces are averages of five trials. Horizontal bar indicates 10 s.

269

of the R S N A and concomitant decrease in BP. RSNA recovered to the control level within 2 - 4 s, but BP recovered to the control level gradually within about 20 s (Fig. 2Ba). These responses resembled those previously reported in anesthetized cats, where electrical stimulation of the primary vestibular afferent nerve induced an inhibition of RSNA and a fall in BP (Uchino et al., 1970). It appears that under anesthesia, tilting the head upwards stimulates vestibular afferent nerves, which in turn reflexly inhibit RSNA, leading to the fall in BP. The later gradual recovery of the RSNA and BP could be due to the baroreceptor reflex (Kezdi and Geller, 1970; Ninomiya et al., 1971). Thus, under anesthesia, the responses in R S N A and BP induced by tilting the head up can be explained by a combination of vestibulo-sympathetic and baroreceptor reflexes. In twelve conscious control rabbits, in contrast, tilting the head up induced a transient increase in RSNA and a modest decrease in BP. After this initial phase the R S N A was maintained at a level slightly below the control level, while BP returned to the control level as shown in Fig. 2Bb. These results suggest that the vestibulo-sympathetic and baroreceptor reflex responses, i.e. the changes in RSNA and BP, induced by tilting the head up are substantially modified by a higher brain structure in conscious control rabbits, while the structure is inactivated under anesthesia. To examine whether the cerebellum, especially the lateral region of the nodulus and uvula of the vermal cortex, is involved in the above-described modification of RSNA and BP responses to tilting the head up, similar experiments were conducted in six rabbits 5 7 days after bilateral lesioning of the lateral nodulusuvula with local injection of kainic acid (0.1%). In these lesioned animals, tilting the head up caused an immediate large increase in RSNA, which was maintained at a high level as shown in Fig. 2Bc. BP increased slightly at first, but then decreased and remained at a level lower than the control. These results indicate that in the cerebellar-lesioned animals, vestibulo-sympathetic and baroreceptor reflexes following tilting the head up are still incompletely modified by other higher brain areas. As shown in Fig. 3A, tilting the head 30 ° up from a position 30 ° down in conscious control rabbits initially induced inhibition, immediately followed by a pronounced but temporal increase in RSNA. BP also recovered to the control level within 3 - 5 s. Under anesthesia, however, the increase in RSNA did not occur and BP exhibited a large decrease with a slow recovery. In conscious rabbits with bilaterally-lesioned lateral nodulus-uvula, there was no early inhibition of RSNA; RSNA immediately increased and was maintained at a slightly increased level during tilting the head up as shown in Fig. 3B. BP initially increased mirroring the increase in RSNA, but immediately after this it decreased and did not recover to the control level. These results suggested that in conscious control

270

N. Nisimaru et al. / Neuroscience Research 32 (1998) 267-271

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rabbits the increase after the initial brief inhibition in RSNA following tilting the head up is mediated by the lateral nodulus-uvula in the cerebellum, and that the timing and duration of the increase in RSNA are important for the control of BP during the postural changes. 4.

Discussion

The RSNA and BP responses during tilting the head up in the anesthetized rabbits have been explained by a combination of vestibulo-sympathetic and baroreceptor reflexes in the brainstem (Kezdi and Geller, 1970; Uchino et al., 1970; Ninomiya et al., 1971). These results also indicate that the higher brain structures are inactive under anesthesia. A large number of neurons which directly influence sympathetic outflow have been found in the caudal medullary raphe nucleus (Morrison and Gebber, 1984) and in the subretrofacial portion of the rostral ventrolateral medulla, which has been termed the subretrofacial nucleus by several investigators (McAllen, 1986; Dampney, 1990). Although no direct connection between neurons in the raphe nucleus and the subretrofacial nucleus, and vestibular neurons has been found anatomically, many neurons in these nuclei respond to electrical stimulation of the vestibular nerves (Yates et al., 1991; Yates, 1992). It is probable that the neurons in the raphe and subretrofacial nuclei are involved in relaying vestibular signals to the intermediolateral cell column via interneurons. On the other hand, some neurons in the dorsolateral medullary reticular formation receive vestibular inputs and project to

the subretrofacial nucleus (Dampney et al., 1987). Neurons in the caudal paramedian reticular formation receive inputs from both the vestibular afferent nerve and the carotid sinus nerve (Yates and Yamagata, 1990). These neurons in the reticular formation may constitute a candidate for a brainstem pathway mediating vestibulo-sympathetic and baroreceptor reflexes. Tilting the head up in conscious control rabbits initially induced inhibition, immediately followed by an increase in RSNA. Following these RSNA responses, BP decreased slightly at first and recovered to the control level within 3-5 s. This transient increase after the brief inhibition in RSNA during tilting the head up may have an important role in the immediate adaptation of the cardiovascular responses, especially blood pressure control, and this response in RSNA is probably induced by the higher brain structures. In conscious rabbits with bilaterally-lesioned lateral nodulus-uvula in the cerebellum, RSNA immediately increased but BP did not recover quickly to the control level. These results show that the timing and duration of the increase in RSNA during tilting the head up are important for the adaptive control of blood pressure and are regulated by the lateral nodulus-uvula in the cerebellum. Our previous investigation (Nisimaru and Watanabe, 1985) showed that electrical stimulation of the lateral nodulus-uvula in anesthetized rabbits inhibited RSNA and depressed blood pressure. This area in the cerebellum is projected by vestibular nerves (Precht et al., 1976; Kotchabhakdi and Walberg, 1978) and by cardiovascular afferent nerves (Nisimaru and Katayama, 1996). Sadakane et al. (1996) showed that Purkinje cells in this area projected to the nucleus

N. Nisimaru et al./ Neuroscience Research 32 (1998) 267 271

p a r a b r a c h u m c o n j u n c t i v u m . It is possible that n e u r o n s in the subretrofacial a n d r a p h e nuclei receive i n p u t s from vestibular a n d c a r d i o v a s c u l a r nerves a n d also from P u r k i n j e cells in the cerebellum, especially in the lateral n o d u l u s - u v u l a , a n d integrate i n f o r m a t i o n from these inputs. U n d e r anesthesia i n p u t s from the cerebell u m a n d other higher b r a i n structures b e c o m e silent a n d c a r d i o v a s c u l a r c o n t r o l is m e d i a t e d only by vestibulosympathetic a n d b a r o r e c e p t o r reflexes.

Acknowledgements W e are grateful to Professor Y o s h i a k i H a y a s h i d a , D e p a r t m e n t o f Physiology, School o f Medicine, U n i versity of O c c u p a t i o n a l a n d E n v i r o n m e n t a l Health, for his g u i d a n c e in the m e t h o d of c o n t i n u o u s m o n i t o r i n g of sympathetic nerve activity in conscious animals. W e w o u l d like to t h a n k Professor K a z u h i r o Y a m a d a , Dep a r t m e n t of Physiology, Oita Medical University, for his c o n s t a n t e n c o u r a g e m e n t a n d helpful discussions d u r i n g the course o f this study. This w o r k was supp o r t e d in part b y G r a n t s - i n - A i d from the Japanese M i n i s t r y of E d u c a t i o n , Science, Sport a n d C u l t u r e (No. 01570068 a n d 02670070).

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