Pfliigers Arch. 358, 101--110 (1975) 9 by Springer-Verlag 1975

The Effect of Carotid Sinus Nerve Stimulation on Muscle and Skin Nerve Sympathetic Activity in Man B. G u n n e r W a l l i n , G S r a n SundlSf, a n d W o l f r a m Delius* Departmenf~s of Clinical Neurophysiology and Internal medicine, University Hospital, Uppsala, Sweden Received January 27, 1975

Summary. Microelectrode recordings of multi-unit sympathetic activity were made in the right peroneal nerve of 4 awake human subjects during carotid sinus nerve stimulation. 36 periods of CSN-stimulation gave in all cases an inhibition of the muscle nerve sympathetic activity and there was good temporal agreement between this effect and the reduction of heart rate and blood pressure. The neural inhibition was marked during the first part of the stimulation but with continued stimulation the sympathetic activity reappeared, in most cases with reduced strength. In contrast, 20 periods of CSN-stimulation had no reproducible effect on skin nerve sympathetic activity. In most cases, the neural activity remained unchanged but both increases and decreases could occur. The results demonstrate that stimulation of carotid sinus baroreceptors in man has different effects on sympathetic outflow t~ different regions: A clear inhibition of the outflow to ~he muscles but no diseernable effect on impulses destined to the skin. Key words: Sympathetic Activity -- Baroreceptors -- Carotid Sinus Nerve Stimulation -- Baropaeing. I n m o s t i n v e s t i g a t i o n s concerning t h e influence o f t h e c a r o t i d sinus reflex u p o n different v a s c u l a r beds, v a r i o u s h a e m o d y n a m i c p a r a m e t e r s h a v e been u s e d as indices o f t h e s t r e n g t h o f t h e s y m p a t h e t i c vasoc o n s t r i c t o r outflow to t h e vessels. On t h e basis of such studies i t is n o w g e n e r a l l y a g r e e d t h a t t h e v a s c u l a r b e d of s k e l e t a l muscle is a n i m p o r t a n t t a r g e t of t h e c a r o t i d sinus reflex [1,2,4,11,18,24,25]. I n c o n t r a s t , t h e skin v a s c u l a r b e d has been c o n s i d e r e d u n r e s p o n s i v e t o b a r o r e c e p t o r s t i m u l i [12, 21]. On t h i s point, however, t h e e x p e r i m e n t a l evidences a r e s o m e w h a t conflicting a n d a l t h o u g h t h e conclusion seems to a p p l y for c u t a n e o u s veins [11] a n d a r t e r i o - v e n o u s a n a s t o m o s e s [16] i t has been r e p o r t e d t h a t c a r o t i d sinus s t i m u l i h a v e reflex effects on skin resistance vessels [1,16, 20]. W i t h t h e d e v e l o p m e n t of a t e c h n i q u e for r e c o r d i n g s y m p a t h e t i c a c t i o n p o t e n t i a l s in h u m a n p e r i p h e r a l n e r v e s [14] a n e w w a y o f s t u d y i n g * Present addres: I. Medizinisehe Klinik der Teehnischen Universit~t Miinehen. Klinikum rechts der Isar, 8000 Miinehen, Ismaningerstr. 22, West Germany. 8

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t h e effect of baroreflex s t i m u l i on different v a s c u l a r b e d s in m a n was i n t r o d u c e d . I n such recordings, a n a n a l y s i s of t h e t e m p o r a l p a t t e r n of t h e s p o n t a n e o u s l y occurring muscle n e r v e s y m p a t h e t i c a c t i v i t y (MSA) revealed an intimate correlation between the nerve activity and the a r t e r i a l b l o o d p r e s s u r e v a r i a t i o n s , i n d i c a t i v e of a baroreflex m o d u l a t i o n o f t h e n e u r a l outflow [6, 23]. A l t h o u g h no d i r e c t evidence was a v a i l a b l e f r o m these e x p e r i m e n t s , t h e effects were s u p p o s e d to be b r o u g h t a b o u t to a large e x t e n t b y t h e aortic a r c h a n d c a r o t i d sinus b a r o r e e e p t o r s . I n c o n t r a s t no similar signs of baroreflex m o d u l a t i o n were d e t e c t e d in skin nerve s y m p a t h e t i c a c t i v i t y (SSA) [13]. I n t h e i n v e s t i g a t i o n t o be r e p o r t e d here, MSA a n d S S A h a v e been r e c o r d e d d u r i n g electrical s t i m u l a t i o n o f t h e c a r o t i d sinus nerves in a n g i n a pectoris p a t i e n t s w i t h chronically i m p l a n t e d s t i m u l a t i o n electrodes. The a i m o f t h e e x p e r i m e n t s w a s : a) To p r o v i d e d i r e c t evidence t h a t t h e c a r o t i d sinus b a r o r e e e p t o r s affect t h e outflow o f s y m p a t h e t i c impulses in h u m a n muscle nerves, b) To i n v e s t i g a t e w h e t h e r a n y rep r o d u c i b l e effects of t h e s t i m u l a t i o n could be d e t e c t e d in t h e SSA. A p r e l i m i n a r y r e p o r t o f p a r t of t h e results has been given p r e v i o u s l y [9].

Methods Material. 7 recordings were made on 4 males, 40--51 years of age. They suffered from severe angina pectoris and were selected for treatment with carotid sinus nerve stimulation (CSN-stimulation) because conventional treatment had been inadequate in controlling the chest pain. The CSN-stimulating electrodes were implanted bilaterally at least 6--8 weeks before the recordings were made. At the time of the study the subjects were all in sinus rhythm and showed no clinical symptoms of congestive heart failure. 3 subjects were on Digitalis and 1 on Verapamil. None had fl-adrenergic blocking drugs. The CSN.stimulating system used was the Angistat model 4001 (Medtronic Inc., U.S.A.) generating electric pulses with a duration of 350 ttsee at a fixed frequency of 100Hz. The amplitude of the stimulating pulses could be varied between 1--8volts and was adjusted individually. The nerve recordings were made by insulated tungsten microelectrodes with a tip diameter of a few ~, which were inserted manually through the intact skin into a muscle or skin nerve fascicle in the right peroneal nerve at the fibular head. Details about the technique as well as the methods for storing and displaying the nerve signals have been described previously [6]. The nerve fascicles were identified by the type and site of the peripheral test stimuli required to induce afferent responses. For skin nerve fascicles the receptive field was mapped with touch stimuli and the muscle nerve fascicles were identified by taps on the muscle belly and muscle stretch. After having identified the fascicle minute electrode adjustments were made until a recording position was found where spontaneously occurring sympathetic impulses could be recorded. At rest the multi-unit sympathetic impulses recorded in muscle nerve fascicles occurred in rather distinct pulse synchronous burst sequeneies during temporary blood pressure reductions. In skin nerve fascicles, on the other hand, they occurred in more irregular bursts without sign of pulse synchrony and during all phases of the spontaneous blood pressure variations.

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Because of these characteristic temporal patterns at rest and because of the typical reflex responses during Valsalva's manoeuvre (MSA) and during arousal stimuli (SSA) the multi-unit sympathetic activity was easy to identify and discriminate from mechanoreceptive signals evoked by skin stimuli and muscle stretch or contraction [6--8,13]. During the experiments the subjects were repeatedly instructed to remain relaxed and if minor unintentional muscle contractions occurred in the leg recorded from, the resulting electrical activity was recognized both because such signals occurred continuously without grouping in bursts and because they had different frequency content than the sympathetic impulses when monitoring the nerve activity in a loudspeaker. The evidence for the sympathetic nature of the recorded impulses has been discussed in detail previously and only the most important points will be summarized here: 1. By injections of local anaesthetics around the nerve proximal and distal to the recording point the impulses were found to be efferent [6,14]. 2. The conduction velocity of the impulses was found to be approximately 1 m/see [6,14,15]. 3. In five subjects i.v. infusion of a sympathetic ganglion blocking drug (Trimetaphan) reversibly blocked the impulses [6,13]. 4. Within 1--3 sec changes in nerve activity were regularly followed by typical sympathetic effector organ responses, such as changes of skin electrical resistance, changes in regional vascular resistance, changes of blood pressure [6,13]. I n the illustrations to be presented, the nerve signals are shown as mean voltage neurograms and because of the amplitude distortion inherent in the filtering process nerve signal calibrations axe omitted. Intraarterial blood pressure was monitored through a catheter in the brachiM artery connected to a pressure transducer EMT 35 and an electromanometer EMT 31 (Siemens-Elema Ltd., Sweden). Respiratory movements and ECG were monitored as described previously [6]. Cal/blood flow was sometimes recorded in the left leg (contralateral to the nerve recording) by venous occlusion plethysmography. Details about the recording technique and the method for calculating calf vascular resistance has been described previously [7]. Experimental Procedure. The subjects were in the recumbent position. The nerve recording electrode was inserted into the right peroneal nerve at the fibular head, and a recording site with good signal-to-noise ratio for sympathetic impulses was searched for. When found, the spontaneous sympathetic activity was recorded for a few minutes in parallel with the blood pressure before the CSN-stimulation began. Since it was our purpose to determine an optimal stimulation voltage for each subject to be used after the investigation, the voltage was varied till a level was found that gave adequate blood pressure reduction (10--30 mm I-Ig decrease of systolic pressure) with minimal local discomfort in the neck. Because small variations in voltage could give quite pronounced effects the variation possibilitieswere limited.

Results The E//ect o/ CSN-Stimulation on M S A MSA was recorded d u r i n g 36 periods of C S N - s t i m u l a t i o n i n 3 subjects a n d i n all cases the s t i m u l a t i o n led to a n i n h i b i t i o n of the MSA. I n a given s u b j e c t the degree of i n h i b i t i o n t e n d e d to increase with increasing s t i m u l a t i o n voltage a n d i n general there was good a g r e e m e n t b e t w e e n 8*

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the neural inhibitory effect and the magnitude of the blood pressure and heart rate reduction. Fig. 1 shows two examples of the inhibition, one with weak and one with strong inhibitory effect (different subjects). After the onset of stimulation there was a latency of approximately one second before the inhibition occurred. A more exact determination of the latency was difficult to make because of the uncertainty introduced by the inhibitions normally occurring between successive bursts of sympathetic impulses [6,23]. As a rule the inhibitory effect could be divided into two phases, an early phase when the pulse synchronous sympathetic bursts disappeared more or less completely and a late phase when the bursts reappeared, usually with either reduced incidence (Fig. 1A) or strength (Fig. 1 B). Although small sympathetic bursts could occur during the early phase, in most eases the difference between the two phases was dear enough to make the separation easy. The duration of the early phase, which varied both between subjects and between different stimulation periods in the same subject, ranged between 2.5--25 see. Sometimes during the late inhibitory phase the strength of the MSA tended to return towards the prestimulation level, whereas in other cases (c.f. Fig. 1B) the partial inhibition remained till the end of the stimulation. Fig. 1B also illustrates that if the blood pressure still was reduced when the stimulation was terminated, the lowered baroreceptor drive resulted in a transient increase of the strength of the MSA above the prestimulation level. Following this increase of nerve activity the blood pressure returned towards its original level without overshoot. Repeated stimulation periods in the same subject with constant stimulation voltage did not lead to a decrease of the inhibitory effect and neither did we note variations in the response that could be attributed to mental stress or local discomfort in the neck. For example, in one subject 9 consecutive stimulations were made with an interval of at least 60 see between the periods without any visible difference between the effects of the first and last period. The E//ect o/CNS-Stimulation on S S A

SSA was recorded during 20 periods of CNS-stimulation in 4 subjects. In all cases the stimulation led to a blood pressure reduction but the effect on the nerve varied both between subjects and between different stimulation periods in the same subject. Most of the stimulations did not change the nerve activity but both increases and decreases in the strength of the SSA were seen. The results are summarized in Table 1. The increase of SSA seen in subject S. J. was most prominent during the first stimulation period (Fig.2A) and thereafter it declined and finally disappeared during succeeding stimulations with constant voltage

Carotid Sinus Influence on Sympathetic Activity in Man

105

V C S N - stimulation.~

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Fig. 1A and ]3. Examples of CSN-sfimulation with weak (A) and strong (]3) inhibitory effect on MSA. The early phase with marked inhibition lasts approximately 4 see in A and 20 sec in ]3. Upper tracings: Respiratory movements (inspiration upwards). Second tracings: Integrated MSA (time constant 0.1 see in A and 0.2 sec in B), Third tracing,s: Blood pressure; [ourth tracings: Heart rate; lowest ~raclng in (]3): Calf vascular resistance (in leg eontralateral to the nerve recording) in peripheral resistance units (PI~U)

106

B.G. Wallin et al. Table 1. Effect of CSN-s~imulation on t~e strength of SSA (no of stim. per.)

Subject

Increase

P.B. S.3. H.E.

4

Decrease

No change

1

l 3 3

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Total

4

3

6

10

(Fig. 2 B). When increasing the stimulation voltage, however, the response reappeared. I t is worthy of notice that in this subject the stimulation caused local discomfort in the neck. Fig.3 shows an example of a decrease of SSA seen during CSNstimulation. Again such effects were most prominent during the first stimulation periods in each subject and could not always be reproduced during repeated stimulations. S~nce the subjects regularly were informed of a pending stimulation period, the strength of the SSA was often high prior to the stimulation [8]. We noted that the decrease of activity

~SN-stimulation m m Hg

200

A

F CSN-stimu[ation ] ~

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B

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'10 sec ' Fig.2A and B. Example of increased strength of SSA during CSN-stimulation (A). When the stimulation was repeated with constant stimulation voltage the response declined and could not be detected during the 4th stimulation (B). Upper tracings: Respiratory movements; n~iddle tracings: Integrated SSA (time constant 0.1 sec); lower tracings: Blood pressure. The deflections marked with an asterisk are partly artefacts due to electric interference at the onset of stimulation

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Fig.3. Example of decreased strength of SSA during CSN-stimulation. Same tracings as in Fig.2. * Has the same significance as in Fig.2. occurring during the stimulation period was best seen when this "preparatory reaction" was pronounced. Sometimes the decrease did not occur until 3--4 sec after the onset of stimulation and when terminating the stimulation, the SSA did usually not regain the prestimulation strength. Discussion M S A. The present results prove that stimulation of the carotid sinus nerves in man inhibits the sympathetic outflow to the skeletal muscles. The finding is consistent with the suggestion that the modulation of MSA in the pulse r h y t h m and its correlation to arterial blood pressure variations to a large extent is brought about by reflex effects from the high pressure receptors [6, 23]. As the carotid sinus nerves contain both ehemo- and baroreceptor fibres, both fibre types may have become excited b y t h e CSN-stimulation. However, in animal experiments chemoreceptor stimulation has been found to cause an increased systemic vascular resistance [5,17] and for this and other reasons discussed by Dunning [10] it is unlikely that reflex effects from chemoreceptor fibre stimulation contribute significantly to the inhibition of MSA in the present experiments. The time course of the sympathetic inhibition with an early and a late phase agrees with previous data from sympathetic recordings in anesthetized animals [3,19,22]. Different factors may contribute to the partial return of sympathetic activity during the late phase. First, since blood pressure was lowered by the CSN-stimulation, a reduction of the endogenous baroreceptor inhibition must have occurred which, at a

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sufficiently low blood pressure, could lead to a release of sympathetic impulses from the vasomotor centres. Second, in anesthetized animals Richter et al. [19] showed that a central adaptation took place during prolonged CSN-stimulation and if a similar mechanism operated in man it would also favour a return of the sympathetic activity. S S A . In contrast to the reproducible inhibition seen in the MSA, CSN-stimulation had variable effects on SSA and the experiments gave no clear evidence of barorefiex control of sympathetic outflow to the skin. The increase of activity seen in one subject was most likely a stress response to local discomfort in the neck during the stimulation.As described by Delius et al. [8], any type of novelty stimulus (pleasant or unpleasant) often gives an increase of SSA, and it is also common that the strength of such responses wears off upon repetition. In addition, Delius et al. [8] also showed that when a subject was instructed about a forthcoming manoeuvre the SSA frequently increased prior to the actual onset of the test. Since, in the present experiments a decrease of SSA was seen only when the stimulation was preceded by such preparatory reactions and since the decrease was reduced or disappeared withrepeated stimulation it is unlikely that it was a direct reflex effect of the CS~Tstimulation. We believe it more likely that this type of response was due to a rapid wearing off of the preparatory reaction at or soon after the onset of stimulation. This is supported by the observation that the decrease of activity sometimes was not seen until several seconds after the start of stimulation and that the activity did not return to the prestimulation ]eve] after the end of the stimulation. The absence of reproducible effects of CSN-stimulation on SSA agrees with the fact that the spontaneously occurring SSA lacks pulse synchronous grouping of impulses and shows no correlation to spontaneous blood pressure variations [13]. I t is, however, difficult to conclude with certainty that CSN-stimulation has no reflex effects at all on sympathetic outflow to the skin. The multi-unit SSA recorded in these experiments is comprised of a mixture of vasoconstrictor and sudomotor impulses, the relative proportions of which are unknown. I f only part of the vasoconstrictor impulses were under baroreflex control (e.g. impulses going to the resistance vessels as suggested by Beiser et al. [1], Kendrick et al. [16], Rowell et al. [20]) it cannot be excluded that a reduced activity in such fibres during the stimulation would remain undetected, especially if the impulse traffic, in other fibre groups increased as a result of for example emotional stress. To settle this point single fibre rather than multi-unit recordings will probably be necessary. The investigation was supported by the Swedish BIedieal Research Council, grants no B75-04X-3546-04C. The authors ~re indebted to Dr. A. Hall~n who performed the operations.

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References 1. Beiser, G. D., Zelis, R., Epstein, S. E., Mason, D. T., Braunwald, E. : The role of skin and muscle resistance vessels in reflexes mediated by the baroreceptor system. J. olin. Invest. 49, 225--231 (1970) 2. Beveg~rd, B. S., Shepherd, J. T. : Circulatory effects of stimulating the carotid arterial stretch receptors in man at rest and during exercise, g. elin. Invest. 45, 132-- 142 (1966) 3. Bronk, D. W., Fergusson, C. K., Solandt, D. Y.: Inhibition of cardiac accelerator impulses bythe carotid sinus. Prec. See. exp. Biol. (N. u 81, 579--580 (1934) 4. Carlsten, A., Folkow, B., Grimby, G., Hamberger, C. A., Thulesius, D.: Cardiovascular effects of direct stimulation of the carotid sinus nerve in man. Aeta physiol, scand. 44, 138--145 (1958) 5. Daly, M. de B., Scott, M. J.: The cardiovascular responses to stimulation of the carotid body chemoreceptors in the dog. J. Physiol. (Lend.) 165, 179--197 (1963) 6. Delius, W., Hagbarth, K.-E., Hongell, A., Wallin, B. G.: General characteristics of sympathetic activity in human muscle nerves. Acta physiol, scand. 84, 65--81 (1972a) 7. Delins, W., Hagbarth, K.-E., Hongell, A., Wallin, B. G.: Manoeuvres affecting sympathetic outflow in human muscle nerves. Aeta physiol, scand. 84, 82--94 (1972b) 8. Delius, W., Hagbarth, K.-E., Hongell, A., Wallin, B. G.: Manoeuvres affecting sympathetic outflow in human skin nerves. Aeta physiol, stand. 84, 177--186 (19720) 9. Delius, W., Wallin, G., Hall6n, A., Sundi5f, G.: Registrierung sympatischer Nervenaktivit~t beim Meuschen wiihrend elektriseher Stimulation der Carotissinusnerven. Verh. dtsch. Ges. Kreisl.-Forsch. 89, 240--243 (1973) 10. Dunning, A. J. : Eleetrostimulation of the carotid sinus nerve in angina pectoris. Amsterdam: Exeerpta Mediea 1971 11. Epstein, S. E., Beiser, G. I)., Goldstein, R. E., Stampfer, ~., Weehsler, A. S., Glick, G., Bramlwald, E. : Circulatory effects of electrical stimulation of the carotid sinus nerves in man. Circulation 40, 269--276 (1969) 12. Greenfield, A.D. iV[.: The circulation through the skin. In: Handbook of Physiology, ed. by W. F. Hamilton and P. Dew, sect. 2, vol. 2, pp. 1325--1351. Baltimore: The Williams and Wilkens Co. 1963 13. Hagbarth, K.-E., Hallin, R. G., Hongell, A., TorebjSrk, H. E., Wallin, B. G.: General characteristics of sympathetic activity in human skin nerves. Aeta physiol, seand. 84, 164--176 (1972) 14. Hagbarth, K.-E., Vallbo, 4. B.: Pulse and respiratory grouping of sympathetic impulses in human muscle nerves. Acta physiol, scand. 74, 96--108 (1968) 15. Hallin, R. G., TorebjSrk, H. E.: Single unit sympathetic activity in human skin nerves during rest and various manoeuvres. Acta physiol, stand. 92, 303--317 (1974) 16. Kendriek, E., 0berg, B., Wennergren, G.: Vasoconstrictor fibre discharge to skeletal muscle, kidney, intestine and skin at varying levels of arterial barereceptor activity in the cat. Aeta physiol, seand. 85, 464--476 (1972) 17. Korner, P. I. : The role of the arterial chemoreceptors and baroreceptors in the circulatory response to hypoxia of the rabbit, g. Physiol. (Lend.) 180, 279--303 (1965) 18. Resnicoff, S.A., Harris, J . P . , Hampsey, J . P . , Schwartz, S . J . : Effects of sinus nerve stimulation on arterial resistance and flow patterns of specific vascular beds. Surgery 66, 755--761 (1969)

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19. Richter, D. W., Keck, W., Seller, H.: The course of inhibition of sympathetic activity during various patterns of carotid sinus nerve stimulation. Pfliigers Arch. 817, 110--123 (1970) 20. Rowell, L. B., Craig, R. W., Brengelmann, G. L.: Sustained human skin and muscle vasoconstriction with reduced baroreceptor activity. J. appl. Physiol. 84, 639--643 (1973) 21. Shepherd, J. T. : Physiology of the circulation in human limbs in health and disease. Philadelphia-London: Saunders 1963 22. Tedeschi, R. E., Sherman, S., de Sanctis, N., Davidheiser, S., Schainbaum, J. : Effect of carotid sinus baroreeeptor stimulation on blood pressure and sympathetic outflow. Amer. J. Physiol. 221, 405--412 (1971) 23. Wallin, B.G., Delius, W., Sundl6f, G.: Human muscle nerve sympathetic activity in cardiac arrhythmias. Scand. J. clin. Lab. Invest. 84, 293--300 (1974) 24. Warner, H. R., The frequency dependent nature of blood pressure regulation by the carotid sinus studied with an electrical analog. Circular. Res. 6, 35--40 (1958) 25. Vatner, S.F., Franklin, D., van Citters, R.L., Braunwald, E.: Effects of carotid sinus nerve stimulation on blood-flow distribution in conscious dogs at rest and during exercise. Circular. Res. 27, 495--503 (1970) Gunnar Wallin, M.D. Dept. of Clinical Neurophysiology Academic Hospital 8-750 14 Uppsala Sweden

The effect of carotid sinus nerve stimulation on muscle and skin nerve sympathetic activity in man.

Microelectrode recordings of multi-unit sympathetic activity were made in the right peroneal nerve of 4 awake human subjects during carotid sinus nerv...
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