J. Phy8iol. (1978), 274, pp. 621-637 With 11 text-ftgure8 Printed in Great Britain

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HUMAN MUSCLE NERVE SYMPATHETIC ACTIVITY AT REST. RELATIONSHIP TO BLOOD PRESSURE AND AGE

BY G. SUNDLOF AND B. G. WALLIN From the Department8 of Internal Medicine and Clinical Neurophysioloy, Academic Ho8pital, Upp8ala, Sweden

(Received 17 June 1977) SUMMARY

1. Recordings of multi-unit sympathetic activity were made from median or peroneal muscle nerve fascicles in thirty-three healthy subjects, resting in recumbent position. Simultaneous recordings of intra-arterial blood pressure were made in seventeen subjects. The neural activity, quantified by counting the number of pulse synchronous sympathetic bursts in the mean voltage neurogram (burst incidence), was plotted against the arterial blood pressure level and the age of the subjects. The effects of spontaneous temporary blood pressure fluctuations were studied by correlating different pressure parameters of individual heart beats to the probability of occurrence of a sympathetic burst and to the amplitude of the occurring burst. 2. Between different subjects there were marked differences in burst incidence, from less than 10 to more than 90 bursts/100 heart beats. No correlation was found to interindividual differences in the arterial blood pressure level but there was a slight tendency for increasing burst incidence with increasing age. 3. Irrespective of the magnitude of the burst incidence, the bursts always occurred more frequently during spontaneous transient blood pressure reductions than during transient increases in blood pressure. When, for each heart cycle, the occurrence of a sympathetic burst was correlated with different blood pressure parameters there was regularly a close negative correlation to diastolic pressure, a low correlation to systolic and an intermediary negative correlation to mean blood pressure. There was a positive correlation to pulse pressure and to pulse interval. 4. When measured for individual heart beats, not only the occurrence but also the mean voltage amplitude of the sympathetic bursts tended to increase with decreasing diastolic pressure. 5. In a given subject when comparing heart beats with the same diastolic pressure, the occurrence as well as the amplitude of the sympathetic bursts was higher for heart beats occurring during falling than for heart beats occurring during rising blood pressure. For a given change in diastolic blood pressure, sympathetic activity changed more if pressure was falling than if it was rising. 6. The findings suggest that the sympathetic outflow is modulated by arterial baroreflex mechanisms and that transient variations in the strength of the activity are, to a large extent, determined by diastolic blood pressure fluctuations. The intimate correlation with 'dynamic' variations in blood pressure and the absence of correlation to the 'static' blood pressure level suggests that the sympathetic outflow

6. SUNDLJF AND B. G. WALLIN 622 to skeletal muscles is of importance for buffering acute blood pressure changes but has little influence on the long term blood pressure level. The difference in reflex sensitivity between falling and rising pressure indicates that acute blood pressure decreases may be buffered more efficiently than acute blood pressure increases. 7. In twenty-seven subjects baroreflex latency was calculated from the QRScomplexes in the e.c.g. to the appropriate systolic inhibition in the sympathetic

activity. When recording in the peroneal nerve, the latency ranged between 1 E16 and 1P49 sec and there was a positive correlation with the height of the subjects. It is suggested that such latency measurements may be used clinically to evaluate conduction in sympathetic fibres. INTRODUCTION

Previously multi-unit recordings of muscle nerve sympathetic activity (MSA) in have shown that the sympathetic impulses are grouped in pulse synchronous bursts which occur during spontaneous blood pressure reductions and disappear during temporary blood pressure elevations (Delius, Hagbarth, Hongell & Wallin, 1972; Wallin, Delius & Hagbarth, 1973). The- pulse synchrony and the inverse relationship to blood pressure variations were taken as evidence of arterial baroreflex modulation of the sympathetic outflow and in agreement with this an individually constant reflex delay was demonstrated between blood pressure and neural events. In a study of patients with heart arrhythmias (Wallin, Delius & Sundl6f, 1974) the findings were confirmed and a statistical method was used for determining a blood pressure threshold for the sympathetic outflow. Furthermore sympathetic recordings during carotid sinus nerve stimulation gave direct evidence of arterial baroreceptor inhibition of the MSA (Wallin, Sundlof & Delius, 1975). man

The aim of the present investigation was to extend these previous studies by

measuring and comparing the MSA in different normal subjects, focusing the interest on the following questions. (a) Which pressure parameters (dynamic and/or static) are best related to the occurrence of sympathetic bursts? (b) Can differences in blood pressure or age explain the large interindividual differences in the incidence of

sympathetic bursts recently reported by Sundl6f & Wallin (1977)? METHODS

Material. Recordings of MSA were made on thirty-three healthy volunteers, twenty-five men

and eight women, aged 18-54 years, all of whom gave their informed consent to the investigation.

The recordings were made either in the peroneal nerve at the fibular head (twenty-eight subjects) or in the median nerve at the elbow level (five subjects). On five subjects simultaneous recordings were made in both peroneal nerves and on four subjects recordings were made at two, and on one subject at three different occasions. Intra-arterial blood pressure was recorded together with the sympathetic activity in seventeen subjects. Nerve electrodes, recording and display system. Nerve recordings were made with insulated tungsten micro-electrodes which were manually inserted through intact skin into a muscle nerve fascicle in the appropriate nerve. The electrode was adjusted until a position was found in which sympathetic impulses could be recorded. During the experiment the neural activity was continuously monitored on a storage oscilloscope and a loudspeaker. A RC-integrating network with a time constant of 0.1 sec was used to obtain a mean voltage display of the nerve signals and both original and mean voltage neurograms were stored on an 8 channel FM taperecorder (Precision Instruments, PI 6200) for subsequent analysis. Details of the technique and

SYMPATHETIC ACTIVITY AND BLOOD PRESSURE

623

the evidence for the sympathetic nature of the recorded impulses have been described previously (Delius et al. 1972; Wallin et al. 1975; Sundlof & Wallin, 1977). Arterial blood pressure was monitored through a catheter in the brachial artery connected to a pressure transducer EMT 35 and an electromanometer EMT 31 (Siemens-Elema Ltd, Sweden) and stored on the tape-recorder. E.c.g. was recorded by surface chest electrodes. Data analy~is. For analysis each integrated nerve record was displayed together with other variables on an ink-jet recorder (Mingograph 800, Siemens-Elema Ltd, Sweden) with a paper speed of 3-5 mm/sec. In order to make a beat-to-beat correlation between arterial blood pressure and the occurrence of pulse synchronous sympathetic bursts, records obtained at rest were divided into periods of approximately 3 min duration (range 2-4 min) and all bursts that could be identified by inspection of the integrated neurogram were marked. The "analogue signals of integrated neurogram and blood pressure were then converted into digital form (sampling frequency 100 Hz) and fed into a computer (Siemens 305). In previous recordings of MSA a reflex delay was demonstrated between blood pressure and neural events (Delius et al. 1972; Wallin et al. 1974, 1975). Appropriate compensation for this delay was made by the computer and although the exact reflex delay was related to body height (see Results) it proved practical to use a standard compensation for all subjects of 1-45 see in peroneal and 1-10 see in median nerve recordings. For each heart beat the computer determined pulse interval, systolic, diastolic, mean and pulse pressures and marked which beats were associated with a pulse synchronous burst. As a quantitative measure of their strength, burst amplitudes were also determined by the computer. To summarize the results from each 3 min period, pressures were grouped in 2 mmHg intervals and burst incidence (in bursts/100 heart beats) and mean burst amplitude (in arbitrary units) was calculated for each interval. The relationship was plotted graphically in pressure threshold diagrams as described by Wallin et al. (1974), the only difference being that the experimental points were fitted to a straight line instead of a sigmoid-shaped curve (cf. Fig. 2A and Fig. 3A). Although theoretically less satisfactory the linear regression was preferred, since the results were similar with the two methods but the linear regression easier to perform. Pulse intervals were grouped in 0-02 sec intervals and the relationship to burst incidence was plotted graphically in an analogous way. To compare the amount of MSA in periods of falling and rising arterial blood pressure the computer divided each resting period in two parts, one comprised of beats preceded by heart beats with higher blood pressure and one of heart beats preceded by lower pressure. Beat-tobeat analyses were then performed separately for each population of heart beats. Experimental procedure. Subjects were in a comfortable recumbent position. The nerve recording electrode was inserted and when an optimal signal-to-noise ratio for sympathetic impulses was obtained the spontaneous activity at rest was recorded during a number of 2-4 min long rest periods. Each recording comprised on the average eight rest periods (range five to twelve) which often were separated by manoeuvres such as deep breathing, hand contractions, mental arithmetic etc. The effects of these manoeuvres will be described separately. The first 20 sec after a manoeuvre were excluded from the quantitative analyses. RESULTS

Relationship between transient blood pressure variations and the occurrence of sympathetic bursts Although there were marked interindividual differences in the incidence of pulse synchronous sympathetic bursts, a visual inspection of nerve and blood pressure records always revealed an inverse relationship between the occurrence of bursts and spontaneous blood pressure fluctuations. This is illustrated in Fig. 1 by the records from two subjects, one having a burst incidence of approximately 30 (A) and the other approximately 75 bursts/100 heart beats (B). For subject A only one or two bursts occur during each blood pressure reduction whereas for subject B they occur almost continuously and disappear only during blood pressure peaks. Records of this type suggest that for each individual there is a characteristic blood pressure

G. SUNDLOF AND B. G. WALLIN 624 threshold below which the bursts occur and above which they disappear. To express such a threshold in quantitative terms threshold variability diagrams were constructed for each rest period according to the method described by Wallin et al. (1974). Fig. 2A shows examples of such diagrams for diastolic and systolic pressures from a single rest period. Obviously there is a good correlation between diastolic A

B

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10 sec Fig. 1. The relationship between variations in blood pressure and MSA in one recording with mean burst incidence of approximately 30 bursts/1OO heart beats (A) and one with mean burst incidence of approximately 75 bursts/100 heart beats (B). Different subjects. Both recordings made in the right peroneal nerve. 100

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45

SYMPATHETIC ACTIVITY AND BLOOD PRESSURE 625 pressures and the occurrence of sympathetic bursts (r = - 0-95 for the linear regression) so that low diastolic pressures usually and high diastolic pressures rarely are associated with a burst. To systolic pressures, on the other hand, there is no apparent correlation (r = + 0.21). This kind of threshold variability diagram is conveniently characterized by the blood pressure value at which 50 % of the heart beats were associated with a burst (T50) and the slope of the regression line, which gives a measure of the variability range of the blood pressure threshold. Similar results were obtained in all recordings and regardless of whether the burst incidence was high or low the occurrence of bursts always correlated better to diastolic than to systolic pressures. This is brought out in Fig. 2B which summarizes the correlation coefficients from the threshold variability diagrams in 156 rest periods from sixteen subjects. One subject was excluded from the analysis since she had virtually every heart beat associated with a burst (mean burst incidence 94 bursts/ 100 heart beats) and reliable threshold variability diagrams could not be constructed. 100 a) .0I

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The results of similar analyses made for mean and pulse pressures are shown in Fig. 3. Fig. 3A shows individual examples of how the occurrence of bursts correlated to mean and pulse pressures (same rest periods as in Fig. 2A) and Fig. 3B summarizes the correlation coefficients for all 156 rest periods. In some cases the

G. SUNDLOF AND B. G. WALLIN 626 correlation coefficient for the relationship to mean blood pressures was similar to that for diastolic pressures but for the large majority of rest periods it fell between those for diastolic and systolic pressures. The mean correlation coefficient for the whole material was - 0-81 for diastolic, - 0 73 for mean and - 0*22 for systolic pressures. In contrast to diastolic and mean pressures, pulse pressure showed a positive correlation to the occurrence of sympathetic bursts, i.e. the higher the pulse pressure the higher the probability for the occurrence of a burst (Fig. 3). Numerically the correlation coefficients were similar to those for mean pressure and the mean value for the whole material was + 0-68. A positive correlation was also found to variations in pulse interval (mean value for the whole material + 0.72), implying an increased number of sympathetic bursts with increasing pulse interval. For none of the pressure parameters (systolic, diastolic, mean and pulse pressure) or the pulse interval was there a systematic relationship between the mean burst incidence during a rest period and the magnitude of corresponding correlation coefficient, nor was there any relationship between the mean burst incidence and the slope of the regression line. From the threshold variability diagrams it can be deduced that in rest periods with low mean burst incidence (cf. Fig. 1 A) diastolic blood pressure was above the T50-value in most of the heart beats, whereas in rest periods with high mean burst incidence (Fig. 1 B) pressure was below T50 in most heart beats. Thus, there was a systematic relationship between burst incidence, mean diastolic blood pressure (Dm) and the T50-value so that burst incidence was approximately 50 bursts/100 heart beats when Dm = TrO, greater than 50 when Dm < Tr0 and less than 50 when Dm > T50.

Relationship between transient blood pressure variation and burst amplitude In addition to burst incidence burst amplitude also increased during temporary blood pressure reductions. This was shown by plotting burst amplitudes against corresponding blood pressures (systolic and diastolic) and calculating regression lines and correlation coefficients for each rest period in the whole material. An example of such a plot for the relationship between diastolic blood pressure and burst amplitude is shown in Fig. 4. Although at each pressure, individual burst amplitudes varied markedly (standard deviations of 50 % of the mean were not uncommon), the mean values regularly showed a fairly good inverse correlation to diastolic blood pressure (mean correlation coefficient for the whole material = -0 72). The degree of correlation to systolic pressure was always lower with a mean correlation coefficient of - 0*16. Since absolute burst amplitudes are highly dependent on the position of the electrode tip in relation to the active fibres and since this factor cannot be controlled with the present recording technique no attempt was made to compare burst amplitudes between different subjects. The direction of the blood pressure changes In some recordings with pronounced regular blood pressure fluctuations it was apparent that the sympathetic bursts were more frequent during periods when blood pressure was falling than when it was in a rising phase. This is illustrated in Fig. 5,

627 SYMPATHETIC ACTIVITY AND BLOOD PRESSURE in which the dotted areas mark the heart beats that correspond to the sympathetic bursts (compensation made for a reflex delay of 1*3 sec between blood pressure and neural events). However, in most cases the blood pressure fluctuations were smaller and more irregular than in Fig. 5 and then the dependency upon the direction of an ongoing blood pressure change was more difficult to detect. Therefore, to test whether the directional dependency was systematic or not, rest periods were divided into two 1200

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fractions, one consisting of heart beats preceded by beats with lower diastolic pressure and one of beats preceded by beats with higher diastolic pressure. For each fraction burst incidences and mean diastolic blood pressures were compared:

628 6. SUNDLOF AND B. G. WALLIN 132 rest periods from fifteen subjects were analysed in this way. Eighteen periods from one subject were excluded because of supraventricular extra systoles which distorted the pressure differences between the fractions and six other periods from different subjects had to be excluded for technical reasons. In 131 rest periods burst incidence was higher during decreasing than during increasing blood pressure, the mean difference being 30-8 bursts/100 heart beats (range 4.0-56.2). However, since mean diastolic blood pressure always was lower during the fraction of decreasing pressure the question arose whether this could explain the difference in burst 40

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Fig. 6. Expected versus observed differences in burst incidence between fractions of decreasing and increasing blood pressure for 132 rest periods in fifteen subjects. Line at 450 denotes line of identity. Threshold variability diagram shown in upper right corner illustrates method of calculating expected difference in burst incidence (b) from observed difference in mean diastolic blood pressures (a) between fractions of decreasing and increasing blood pressure.

incidence. This was tested for each rest period by using the threshold variability diagram of the period as illustrated in the insert in the upper right corner of Fig. 6. From the observed difference in mean diastolic pressures between the fractions (a) the 'expected' difference in burst incidence (b) was determined, and 'expected' and 'observed' differences in burst incidence were then plotted against each other. As shown in Fig. 6 the observed differences were greater than the expected in virtually every rest period confirming that for a given diastolic blood pressure bursts were more likely to occur if pressure was falling than if it was rising. To express the directional dependency in pressure terms the process was reversed and for each rest period the observed difference in burst incidence between rising and falling pressure was used to calculate an 'expected' difference in diastolic blood pressure. The magnitude of the difference was then determined by subtracting the ' observed' pressure difference from the 'expected'. For the whole material the mean difference was 5 mmHg, i.e. burst incidences would be equal if mean rising blood pressure were 5 mmHg lower than mean falling pressure.

SYMPATHETIC ACTIVITY AND BLOOD PRESSURE 629 Burst amplitudes were also compared between fractions of decreasing and increasing pressure and in 129 of the 132 rest periods mean burst amplitude was higher when pressure was decreasing. The simultaneous difference in diastolic blood pressure between the fractions was compensated for by a procedure similar to that used for burst incidence. Utilizing the regression line for the relationship between diastolic blood pressure and burst amplitude calculated for each rest period (see insert in Fig. 7) the 'expected' difference in mean burst amplitude was determined and then plotted against the 'observed' difference. As shown in Fig. 7 the observed differences were greater in almost all instances and consequently for a given diastolic blood pressure both burst incidence and burst amplitude were greater when pressure was decreasing than when it was increasing. I

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Comparisons were also made between the regression lines for the relationship between diastolic blood pressure and burst amplitude for decreasing and increasing pressures. Due to the low number of bursts (especially in the 'increasing fraction') and the large amplitude variability significant regression lines (slope of line tested with Student's t test, P < 0-01) for both fractions were obtained only in thirty-five rest periods from eleven subjects. Fig. 8A shows an example of the comparison of the lines from one period in which the slope of the line from the 'decreasing fraction' was steeper than that from the 'increasing fraction'. As illustrated in Fig. 8B, the

6. SUNDLOF AND B. G. WALLIN 630 results were similar in most of the thirty-five periods suggesting that for a given blood pressure change, sympathetic activity changes more if pressure is falling that if it is rising. Differences in slope of the regression lines were statistically significant (P < 0-001, Student's t test). X 1000

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-20 -40 -60 -80 -100 60 70 80 90 Decreasing pressure (slope) Diastolic blood pressure (mmHg) Fig. 8. The differences in slope of the regression lines for the relationship between diastolic pressure and burst amplitude between fractions of decreasing and increasing *) and blood pressure. A, example from a 3 min rest period with decreasing (@ increasing (O---0) pressure fractions analysed separately. B, comparison of the slopes in 35 rest periods from eleven subjects. Continuous line denotes line of identity.

The relationship between mean burst incidence and the static blood pressure level During continuous recording in a given subject burst incidence was fairly constant in all rest periods, confirming previous findings by Sundl6f & Wallin (1977). For each subject on whom simultaneous recordings of MSA and blood pressure were made, mean burst incidence and mean values of diastolic, mean and systolic blood pressure were calculated for the whole experiment. If two recordings were made on the same subject mean values were calculated from all rest periods during both recordings. There were marked differences both in burst incidence and blood pressure levels between subjects but there was no correlation between the parameters. This is illustrated in Fig. 9 which shows the relationship between the mean values of diastolic blood pressure and burst incidence for each subject. If the amount of sympathetic activity was expressed as bursts/min to account for interindividual differences in heart rate the correlation to diastolic blood pressure was equally poor. The burst incidence was also correlated to the variability of different pressure parameters (expressed as the standard deviation) but no relationship was found. The reflex delay between blood pressure and neural events As shown by Delius et al. (1972) and Wallin et al. (1974) each sympathetic burst corresponds to a given diastole occurring slightly more than one second before the burst is recorded in the peroneal nerve at the fibular head. For a few subjects the exact reflex latency was determined by Delius et al. (1972) by feeding the neurogram into an averager which was triggered by the R-wave of the e.c.g. The latency was measured from the e.c.g., to the start of the appropriate systolic inhibition. The same

SYMPATHETIC ACTIVITY AND BLOOD PRESSURE 631 method was used in the present study and Fig. 10 shows the reflex latencies from twenty-seven healthy subjects plotted against subject height. The figure shows a clear trend towards increasing latencies with increasing height. (r = + 0*71 for the linear regression. Slope of line significant, P < 0.001, Student's t test.) 100 r

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Fig. 10. Reflex latencies between the QRS-complexes in the e.c.g. and the start of appropriate systolic inhibitions in the integrated neurogram (time constant 0.1 see) plotted against subject height. Each latency determined by averaging 128 oscilloscope sweeps triggered on the R wave. Fig. 11. Relationship between subject age and mean amount of MSA expressed as bursts/100 heart beats for thirty-three subjects. Correlation coefficient for linear regression + 0-40.

The relationship between mean burst incidence and age Fig. 11 shows the relationship between the 'level' of MSA (expressed as mean number of bursts per 100 heart beats) and age for all subjects. If more than one recording was made on the same subject the mean value of both recordings was used.

G. SUNDLOF AND B. G. WALLIN 632 The dominant finding was the wide scatter of the experimental values implying that, regardless of age, some subjects have a high and some a low 'level' of MSA at rest. In linear regression the correlation coefficient was low (r = + 0.40) but as illustrated in Fig. 11 there was a positive slope of the calculated line (significantly different from zero, P < 0-01, Student's t test) implying an increasing MSA with increasing age. As shown in Fig. 11 two subjects had a very low burst incidence, one close to 0 and the other 10 bursts/100 heart beats. In neither case was the scarcity of bursts due to a poor recording site since high amplitude bursts could be elicited in one subject by the Valsalva manoeuvre and in the other by low diastolic pressures following occasional supraventricular extrasystoles. Consequently, in the recumbent position some subjects may have virtually no sympathetic outflow in their muscle nerves at rest. DISCUSSION

In confirmation of previous findings (Delius et al. 1972; Wallin et al. 1973, 1974) the pulse synchrony, the inverse relationship between temporary blood pressure variations and the occurrence of sympathetic bursts and the individually constant reflex delay between blood pressure (e.c.g.) and neural events, all agree with the notion of arterial baroreflex modulation of the sympathetic outflow to the vascular bed of the skeletal muscle. Since each systolic pressure wave seems to cause a complete sympathetic inhibition whereas the bursts correspond to the diastoles it is not surprising that the strength of the activity (i.e. both the occurrence of bursts and their amplitudes) always correlated better to variations in diastolic than in systolic blood pressure. Neither is the intermediary correlation to mean blood pressure variations surprising, the mean pressure being a function of both systolic and diastolic pressures. Pulse pressure is also a function of both systolic and diastolic pressures and since the outflow of sympathetic impulses is completely inhibited by the systolic pressure waves one would expect change in pulse pressure to affect the MSA only when associated with changes in diastolic blood pressure. The positive correlation between pulse pressure variations and the occurrence of bursts should therefore probably be regarded as secondary to the inverse correlation to diastolic blood pressure variations. Previous studies of the relationship between blood pressure and sympathetic activity in renal, splanchnic, intestinal, splenic, and cardiac nerves (Green & Heffron, 1968; Kezdi & Geller, 1968; Ninomiya, Nisimaru & Irisawa, 1971) were made on anaesthetized animals on which pressure variations were applied by perfusing the carotid sinus with sinusoidally varying pressures, by clamping the aorta or by changing the blood volume. In agreement with the present findings and in agreement with other studies in which conclusions about the sympathetic outflow were drawn from effector organ responses (for references see Korner, 1971; Sleight, 1974; Oberg, 1976; Kirchheim, 1976) an inverse relationship was found between mean blood pressure variations in baroreceptor regions and the level of sympathetic activity. In previous direct recordings of sympathetic activity the relative importance of different pressure parameters (systolic, diastolic and pulse pressure) was not evaluated. However, concerning pulse pressure variations there are many previous

633 SYMPATHETIC ACTIVITY AND BLOOD PRESSURE studies in which the effect on the systemic arterial blood pressure was investigated (Scher & Young, 1963; Levison, Barnett & Jackson, 1966; Gero & Gerova, 1967; Stegemann & Tibes, 1969; Angell James & Daly, 1970; Schmidt, Kumada & Sagawa, 1972). In these studies an increase in pulse pressure in the isolated carotid sinus or aortic arch with constant mean pressure (i.e. an increase in systolic and decrease in diastolic pressure) gave a decrease in systemic blood pressure. In view of this, the present results showing an increase in MSA with increasing pulse pressure are somewhat surprising. Methodological differences may, however, contribute to the discrepancy. In the present study the baroreceptors were stimulated by physiological pressure waves with systoles of considerably shorter durations than diastoles. In previous studies, on the other hand, sinusoidal pressure changes were used as baroreceptor stimuli and since in that situation systoles and diastoles were of the same duration the effects of the pressure changes on the vasomotor centres may well have been different from those of the present study. In addition, since there are established differences in the extent of baroreflex control over different vascular beds (Resnicoff, Harris, Hampsey & Schwartz, 1969; Ninomiya et al. 1971; Kendrick, Oberg & Wennergren, 1972; Wallin et al. 1974; Wallin et al. 1975) it is possible. that the sympathetic outflow to the vascular bed of skeletal muscle is controlled differently from the outflow to other regions participating in blood pressure homoeostasis. For example, if the systolic pressure waves only caused a partial inhibition of the sympathetic activity one would expect a different relationship between pulse pressure variations and the strength of the activity than that found in the present study.

The relationship between mean burst incidence and the static blood pressure level No relationship was found between the static blood pressure level and the mean burst incidence. This cannot be explained as an artifact due to imperfect recording technique or due to large individual variations in MSA since Sundl6f & Wallin (1977) showed that in a given subject the mean burst incidence was remarkably constant in different muscle nerves, not only in one recording but also when recordings were repeated with intervals of weeks or months. This lack of correlation between the static blood pressure level and the 'level' of MSA in face of an intimate relationship between transient variations in blood pressure and sympathetic activity suggests that the sympathetic outflow to the vascular bed of skeletal muscle is of importance for buffering acute blood pressure changes but has little influence on the long term blood pressure level. This may be of relevance in arterial hypertension. It has previously been shown in experimental animals that although the baroreceptors initially increase their firing when blood pressure is elevated, the activity soon decreases again and returns to the initial level (McCubbin, Green & Page, 1956; Kezdi, 1962; Aars, 1968; Krieger, 1970). This, together with the present results, suggest that when a human subject develops hypertension there may be an initial reduction in MSA (corresponding to the phase of increased baroreceptor firing) but in established hypertension the MSA will probably have returned to the 'prehypertension' level. For most subjects mean burst incidence was 40-60 bursts/100 heart beats and consequently their mean diastolic blood pressure fell close to the blood pressure threshold for sympathetic outflow. As arterial baroreceptors are known to adapt

634 6. SUNDLOF AND B. a. WALLIN their working range to the prevailing blood pressure (McCubbin et al. 1956; Kezdi, 1962; Aars, 1968; Krieger, 1970; Korner, 1975), this relationship between the sympathetic threshold and the blood pressure would seem natural, and in terms of blood pressure regulation it would also be the optimal working point with opportunities both for increasing and decreasing the MSA. However, the full range of burst incidences was from less than 10 to more than 90 bursts/100 heart beats and for subjects towards the ends of the range the situation was different. For those subjects with high burst incidence the mean value of the diastolic blood pressure was in general lower than the threshold and for those with low burst incidence the relationship was the reverse. The reason for these interindividual differences is not known. One possibility is that since sitting and standing rather than lying, are the 'physiological resting postures' in man (cf. Gauer & Thron, 1965) burst incidence in lying could be fairly unimportant and the MSA instead optimally adjusted to compensate for blood pressure changes in sitting and standing. Some support for this notion comes from Burke, Sundl6f & Wallin (1977) who showed that subjects with low burst incidence in lying increased, and some subjects with high burst incidence in lying decreased burst incidence when going from lying to sitting, the net results being smaller interindividual differences in the sitting than in the lying

posture. The directional sensitivity The finding that the same diastolic blood pressure was associated with more sympathetic activity during falling than during rising pressure further illustrates the dynamic characteristics of the baroreflex regulatory system. This may be due to the dynamic properties of the baroreceptors themselves (Spickler & Kezdi, 1967; Ninomiya & Irisawa, 1967; Katona & Barnett, 1969; Angell James, 1971; Pickering, Gribbin & Sleight, 1972; Pelletier, Clement & Shepherd, 1972) but central mechanisms may also contribute. At any rate it implies that the reflex variations in sympathetic outflow tend to occur with a phase lead in relation to the blood pressure changes from which they arise. This phase lead may help not only to compensate for the slow conduction velocities in the sympathetic fibres and the sluggishness in the responses of the vascular smooth muscle, but also to reduce oscillatory tendencies in the baroreflex loop. The finding that the directional sensitivity of the system was higher for decreasing than for increasing pressures is consistent with previous data showing stronger blood pressure and heart rate responses during falling than during rising intracarotid pressure (Scher & Young, 1963; Levison et al. 1966; Katona, Barnett & Jackson, 1967; Thron, Brechmann, Wagner & Keller, 1967; Pickering et al; Stegemann, Busert & Brock, 1974; Bjurstedt, Rosenhammer & Tyden, 1975). Whatever the mechanism behind this 'asymmetry' in the directional sensitivity may be, it indicates a more potent protection against acute blood pressure falls than against acute blood pressure rises. Baroreflex latency It is not surprising to find a close correlation between the reflex latency and the height of the subject. Although there are different contributing factors (like the time delay between the R-deflexion in the e.c.g. and the time when the blood pressure

SYMPATHETIC ACTIVITY AND BLOOD PRESSURE 635 wave reaches the arterial baroreceptors, the time for afferent transmission, central transmission) the main part of the reflex latency must be considered to derive from the efferent transmission in the sympathetic fibres which have a conduction velocity of about 1 m/sec. Therefore it seems likely, that this technique of measuring reflex latency could be used in clinical work to investigate transmission in sympathetic C-fibres. The relationship between mean burst incidence and age A tendency for increasing nerve activity with increasing age was found in the present study. However, although the slope of the regression line in Fig. 11 was statistically significant, the wide scatter of the experimental points indicates that age is not a major determinant of sympathetic activity in human muscle nerves. It should also be added that the number of subjects with very low levels of activity may well be underestimated in the present study since it is always difficult to decide whether an absence of bursts is due to true 'sympathetic silence' or poor recording site. Since the strength of the MSA depends on the strength of the baroreceptor inhibition a correlation between MSA and age (if confirmed in a large material) could be due to a reduction of baroreceptor activity with increasing age. This may occur both because of baroreceptor degeneration (Muratori, 1967; Abrah6m, 1967) or because of reduced distensibility of the vessel walls in the baroreceptor areas (Bader, 1967) in higher ages. There is also evidence of a decrease in skeletal muscle blood flow in elderly people (Allwood, 1958; Amery, Bossaert & Verstraete, 1969) which at least partly could reflect a higher level of MSA. The investigation was supported by the Swedish Medical Research Council grant no. B7604X-3546-05C. We thank Peter Hellstrom and Eva BAth for valuable technical assistance. REFERENCES AARS, H. (1968). Aortic baroreceptor activity in normal and hypertensive rabbits. Acta phy8iol.

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