A Quantitative Study of Muscle Nerve Sympathetic Activity in Resting Normotensive and Hypertensive Subjects

Transcription

1 Original Articles A Quantitative Study f Muscle Nerve Sympathetic Activity in Resting Nrmtensive and Hypertensive Subjects B. GUNNAR WALLIN, M.D., AND GORAN SUNDLOF, M.D. Dwnladed frm by n September 7, 218 SUMMARY Recrdings f multi-unit sympathetic activity were made frm muscle branches f the perneal r median nerves in 33 healthy and 12 hypertensive subjects resting in tbe recumbent psitin. Simultaneus recrdings f intra-arterial bld pressure were made n 17 nnntensive and all hypertensive subjects. The neural activity, quantified by cunting the number f sympathetic pulse-synchrnus impulse bursts in the mean vltage neurgram (burst incidence) was pltted against the age and the arterial bld pressure level f the subjects. Between different subjects there were marked differences in mean burst incidence, frm less than 1 t mre than 9 bursts/1 heart beats and there was a tendency fr increasing values with increasing age. Taking the age differences int accunt there was n significant crrelatin between the amunt f activity and the bld pressure level. The effect f spntaneus temprary bld pressure fluctuatins was studied by crrelating different pressure parameters f individual heart beats t the prbability f ccurrence f a sympathetic burst and t the mean vltage amplitude f tbe ccurring burst. Irrespective f the mean burst incidence, the ccurrence f the bursts and their mean vltage amplitudes were determined mainly by fluctuatins f the diastllc bld pressure. The diastlic bld pressure threshld fr sympathetic utflw was fund t be reset t higher bld pressure values in the hypertensive subjects and the variability f their threshlds was als greater than fr the nrmtensive cntrls. At a given diastlic bld pressure, mre sympathetic activity ccurred if diastlic bld pressure was falling than if it was rising, and this directinal dependence was mre prnunced in the hypertensive subjects. We suggest that the increased directinal dependence accunts fr the greater variability f the bld pressure threshld fr sympathetic utflw in the hypertensive subjects. The differences can be explained n the basis f findings in animals with experimental hypertensin, and it appears that they are secndary t the hypertensin. Hypertensin 1:67-77,1979) KEY WORDS pathphysilgy f hypertensin micreurgraphy vascnstrictr activity muscle nerves barreflex cntrl ALTHOUGH vcractivity in the sympathetic nervus system ften has been cnsidered an imprtant factr in the pathgenesis f arterial hypertensin in man, the supprting evidence is still incmplete. In early (r labile) hypertensin there are signs f a net increase f adrenergic influence n the heart 1 but at least in established hypertensin this seems t be due mre t a withdrawal f parasympathetic rather than t an increase f sympathetic tne. 1 In early hypertensin ttal peripheral resistance is t high in relatin t the elevated cardiac utput,' and in established essential hypertensin there is an abslute increase in ttal peripheral resistance. In neither case, hwever, is it clear whether this is due Frm the Departments f Clinical Neurphysilgy and Internal Medicine, University Hspital, Uppsala, Sweden. Supprted in part by the Swedish Medical Research Cuncil, Grant B78-14X-O3546-O7. Address fr reprints: B. Gunnar Wallin, M.D., Department f Clinical Neurphysilgy, University Hspital, S Uppsala, Sweden. 67 nly t structural alteratins f the bld vessel walls* r if there is als an increased sympathetic drive.' The cncentratin f nradrcnaline in plasma has been used as an index f ttal sympathetic activity and there are several reprts f increased nradrenaline levels in essential hypertensin. 6 " 1 Recently, hwever, these results have been cntested by Lake et al. 11 wh, in a large series, fund n differences between nrmal and hypertensive subjects when differences in age between the grups were taken int accunt. With the intrductin f the micrneurgraphic technique, it became pssible t make direct recrdings f sympathetic actin ptentials in human peripheral nerves, 11 and in a study f sympathetic utflw in skin and muscle nerves n qualitative differences were fund between nrmal and hypertensive subjects. 18 Recently, we devised methds fr quantitating muscle nerve sympathetic activity (MSA) and shwed that there are large reprducible differences in the amunt f activity between different nrmal subjects resting in the recumbent psture."- "

2 68 HYPERTENSION VOL 1, N 2, MARCH-APRIL 1979 Dwnladed frm by n September 7, 218 In each individual transient variatins in the strength f the MSA crrelated intimately t transient diasthc bld pressure fluctuatins but there was n crrelatin between the average amunt f activity and the average bld pressure level. In the present study resting MSA has been recrded in a grup f subjects with arterial hypertensin and the results are cmpared with thse f nrmal cntrls. The aim has been t search fr pssible differences either in the relatinship between bld pressure and sympathetic activity r in the average amunt f sympathetic activity. Subjects Nrmtensive Subjects Material and Methds Recrdings f MSA were made in 33 healthy subjects, 25 men and eight wmen aged (mean 32.1) years. The recrdings were made either in the perneal nerve at the fibular head (28 subjects) r in the median nerve at the elbw level (five subjects). Intra-arterial bld pressure was recrded tgether with the sympathetic activity in 17 subjects aged (mean 29.6) years. Hypertensive Patients Simultaneus recrdings f MSA (recrded in the perneal nerve at the fibular head) and intra-arterial bld pressure were made in 12 subjects (nine men and TABLE 1. Clinical and Experimental Data n It Subjects with Arterial Hypertensin Case n Sex/ Age (yrs) M/18 M/24* F/31* F/35 M/36 M/43 M/43 M/44f M/44f M/48 M/49 F/58 Resting BP befre experiment (mm Hg) 15/9-16/11 14/8-16/15 12/8-16/115 15/11-22/13 13/8-19/13 15/95-18/115 14/9-185/12 15/1-19/115 18/12-21/145 15/95-16/115 18/12-22/15 21/13-22/14 Clinical Knwn duratin f hypertensin 2ma 3wkB 6 ms 2wks 6yre 2 ma 8 yrs 3 ms lyr 7 yrs 5 yrs 1 m Subject with brderline hypertensin. fsubject with renal hypertensin. Abbreviatin: BP - bld pressure. data Degree f hypertensive retinal changes I-II I-II I I I-II three wmen) with arterial hypertensin, aged (mean 39.4) years. The mst imprtant clinical and experimental data n these subjects are presented in table 1. Based n rutine clinical investigatin fr hypertensin, 1 patients were classified as hypertensive and tw as brderline. Althugh clinically classified as hypertensive, ne patient (Case 5, table 1) had nrmal bld pressure during the experiment. The rutine examinatin included ECGs, which shwed suspected left ventricular hypertrphy in fur subjects (Cases 8, 9, 1 and 11) and was nrmal in all thers. The heart vlume, determined by chest x-ray, was mderately increased in tw subjects (Cases 11 and 12) and nrmal in all thers. Renal arterigraphy was carried ut in eight patients. One patient (Case 8) had a hypplastic left kidney withfivetimes higher plasma renin activity (PRA) in venus bld frm that kidney cmpared with bld frm the ther kidney. This subject became nrmtensive after nephrectmy and was classified as having renvascular hypertensin. Anther patient (Case 5) had a hypplastic right kidney but n side-difference in renin activity. Signs f renal artery stensis were fund in fur ther patients (Cases 6, 7, 9 and 11). One patient (Case 9) had twice as high PRA in venus bld frm the affected kidney and was als cnsidered having renvascular hypertensin. In three patients (Cases 6, 7 and 11) the arterial stensis was cnsidered f n clinical significance. Seven subjects had taken antihypertensive drugs at sme previus time. At the time f the investigatin three had been ff medicatin fr 5 weeks Renal arterigraphy Hypplastic rt kidney Stensis rt renal artery Bilateral renal artery stensis Hypplastic It kidney Stensis It renal artery, Stensis rt renal artery Resting BP during experiment (mm Hg) 162/11 138/91 152/92 188/122 13/88 189/118 18/16 18/15 175/16 167/ / /12 Experimental data Heart rate/min Sympathetic bursts/1 heart beats Sympathetic burste/min

3 MSA IN HUMAN HYPERTENSION/ Wallin and Sundlbf 69 Dwnladed frm by n September 7, 218 r mre, tw (Cases 6 and 9) had been withut drugs (hydralazine and a thiazide diuretic) fr 16 and 1 days, respectively, anther patient (Case 8) fr 14 days (prpranll) and the last patient (Case 9) fr 5 days (methyldpa). Prcedures Nerve electrdes, recrding technique and display system have been described in detail previusly. 14 -" Neural recrdings were made with insulated tungsten micrelectrdes that were manually inserted thrugh intact skin int a muscle nerve fascicle. The electrde was adjusted until a psitin was fund in which sympathetic impulses culd be recrded. After amplificatin the neural activity was fed thrugh a RC-integrating netwrk (time cnstant.1 sec) t btain a mean vltage neurgram. Bth the riginal neural recrd and mean vltage neurgram were stred n an 8- channel FM tape recrder (PI 62, Precisin Instruments, Pal Alt, CA). Arterial bld pressure was mnitred thrugh a catheter in the brachial artery cnnected t a pressure transducer EMT 35 and electrmanmeter EMT 31 (Siemens-Elema Ltd., Stckhlm, Sweden) and stred n the tape recrder. Electrcardigrams were recrded by surface chest electrdes. Respiratry mvements were recrded by a strain gauge strapped arund the chest with a rubber band. Analyses The mean vltage neurgram tgether with ECG, arterial bld pressure and respiratry mvements were displayed frm the tape n an inkjet recrder (Minggraph 8, Siemens-Elema Ltd, Sweden) with a paper speed f 3-5 mm/sec. The recrds were divided int analysis perids f apprximately 3 minutes (range 2-4 minutes) duratin and all the pulse synchrnus sympathetic bursts that culd be identified by inspectin were marked. The analg signals f the mean vltage neurgram and the bld pressure were then cnverted int digital frm (sampling frequency 1 Hz) and fed int a cmputer (PDP 11/4, Digital Equipment, Maynard, MA). In previus recrdings f MSA a reflex delay was demnstrated between bld pressure and neural events and apprpriate cmpensatin fr this delay was made by the cmputer, using a standard value f 1.45 secnds fr all subjects. 16 Fr each heart beat the cmputer determined systlic, diastlic, mean and pulse pressure, and marked which beats were assciated with a pulse synchrnus burst. As a quantitative measure f the strength f the sympathetic bursts, the cmputer als calculated the peak amplitudes f the bursts in the mean vltage neurgtam. T summarize the results frm each 3-minute perid, pressures were gruped in 2-mm Hg intervals and burst incidence (in bursts/1 heart beats) and mean burst amplitude (in arbitrary units) were calculated fr each interval. The relatinship was pltted graphically in pressure threshld diagrams as described previusly." Since heart rate varied between subjects, the ttal amunt f activity during a rest perid was als expressed as bursts/min. T cmpare the amunt f MSA in perids f falling and rising bld pressure, the cmputer divided each rest perid in tw parts, ne cmprised f heart beats preceded by beats with higher bld pressure, and ne f heart beats preceded by lwer pressure. Beat-t-beat analyses were then perfrmed separately fr each ppulatin f heart beats. Experimental Prcedure. Subjects were in a cmfrtable recumbent psitin. The micrelectrde was manually inserted int the nerve and small electrde adjustments were then made until a recrding site with ptimal signal-t-nise rati fr sympathetic impulses was fund. Details f the identificatin prcedure and evidence that the impulses derived frm sympathetic vascnstrictr fibers have been described previusly." The spntaneus multiunit sympathetic activity was then recrded during a number f 3-minute rest perids. On the average seven rest perids (range 2-14) were recrded in each subject and the different perids ften were separated by maneuvers such as deep breathing, fist clenchings, and mental arithmetic. The effects f these maneuvers will be described separately. The first 2 secnds after a maneuver were excluded frm the quantitative analyses. Results Relatinship Between Transient Bld Pressure Variatins and Sympathetic Bursts In agreement with previus results 18 the general character f the MSA was similar in nrmal and hypertensive subjects. The sympathetic impulses were gruped in pulse synchrnus bursts, which usually ccurred in irregular sequences separated by perids f mre r less ttal neural silence. This is illustrated in figure 1, which shws examples f the MSA at rest in ne nrmal and ne hypertensive subject. The figure als illustrates that in bth types f subjects there was an inverse relatinship between the ccurrence f bursts and spntaneus bld pressure fluctuatins. The bursts ccurred mst frequently during temprary bld pressure reductins and disappeared during peaks in the bld pressure curve. This type f relatinship suggests that fr each individual there is a characteristic bld pressure threshld belw which the bursts ccur and abve which they disappear. The threshld can be expressed quantitatively by means f "threshld variability diagrams" as we described earlier Figure 2A shws examples f such diagrams fr diastlic and systlic pressures frm a single rest perid in ne nrmal and ne hypertensive subject. Fr bth subjects there is a clse negative crrelatin t diastlic bld pressure," but there is n apparent crrelatin t systlic pressures fr any f the subjects. The results were similar in all recrdings, i.e. the ccurrence f bursts regularly crrelated

4 7 HYPERTENSION VOL 1, N 2, MARCH-APRIL 1979 NORMOTENSIVE HYPERTENSIVE 5s FIGURE 1. Examples f the relatinship between arterial bld pressure and muscle nerve sympathetic activity at rest in ne nrmtensive and ne hypertensive subject. Tracings frm abve: Mean vltage neurgram (time cnstant.1 sec), bld pressure, instantaneus heart rate. t! LU c 1 8 Diastlic Systlic Dwnladed frm by n September 7, 218 B t O LU t Z O 4 t 2 Diastlic mmhg BLOOD PRESSURE Systlic ml -1, -,5-1, -,5,5 RRELATION EFFICIENT (r) FIGURE 2. The ccurrence f sympathetic bursts in relatin t diastlic and systlic bld pressures. A: Examples f relatinship during a 3-minute rest perid frm ne nrmtensive (slid circle) and ne hypertensive (pen circle) subject. Crrelatin cefficients fr linear regressin are: -.95 and +.21 fr the nrmtensive subject and.93 and.7 fr the hypertensive subject. B: Distributin f crrelatin cefficients fr 17 rest perids in 17 nrmtensive subjects (pen clumns} and 85 perids in 12 hypertensive subjects (hatched clumns).

5 MSA IN HUMAN HYPERTENSION/Wallin and Sundldf 71 Dwnladed frm by n September 7, 218 better t diastlic than t systlic pressures and there was n difference in the degree f crrelatin between nrmal and hypertensive subjects. This is illustrated in figure 2B which summarizes the crrelatin cefficients frm the threshld variability diagrams frm 17 rest perids in 17 nrmtensive subjects and 85 rest perids in 12 hypertensive and brderline patients. Similar analyses were als made fr mean and pulse pressures and pulse interval. In mst cases there, was a negative crrelatin t mean bld pressure with the crrelatin cefficients falling between thse f diastlic and systlic pressures. T pulse pressure and pulse interval, n the ther hand, the crrelatin was usually psitive, that is, the higher the pulse pressure and the lnger the pulse interval the higher the prbability fr the ccurrence f a burst. When cmparing the results frm the nrmal and hypertensive grups, crrelatin cefficients fr mean bld pressure and pulse interval were similar in bth grups, whereas crrelatin cefficients fr pulse pressure were ften lwer in the hypertensive grup. Table 2 summarizes mean crrelatin cefficients in the tw grups fr all pressure parameters and the pulse intervals during all rest perids. The threshld variability diagrams are cnveniently characterized by the bld pressure value at which 5% f the heart beats were assciated with a burst (T M ) and by the slpe f the regressin line which gives a measure f the variability f the threshld. In the patients with established hypertensin, T M was ± 1.2 (mean ± SD); in thse with brderline hypertensin, 89.9; and in the nrmal subjects, 78. ± 8.1 mm Hg. These figures indicate that the bld pressure threshld fr sympathetic utflw f the hypertensive subjects was psitined higher up n the bld pressure axis than in nrmal subjects (fig. 2A). The steepness f the slpe fr the threshld variability diagrams varied cnsiderably between different rest perids and between different subjects, but as illustrated in figure 3 there was a systematic difference between nrmtensive and hypertensive subjects, mean values being -4.7 in the nrmtensive and 3.48 in the hypertensive (including brderline) grup (p <.1, Student's t test). Fr bth the nrm- and hypertensive subjects a crrelatin was fund between the steepness f the slpe (the degree f threshld variability) and the amunt f variatin f the diastlic bld pressure. As illustrated 2 1 a O 16 I 12 SLOPE OF REGRESSION LINE FIGURE 3. Distributin f slpes f the regressin lines fr all threshld variability diagrams in nrmtensive (pen clumns, n = 17), hypertensive (hatched clumns, n = 76) and brderline (filled clumns, n = 9) subjects. in figure 4, the smaller the threshld variability the smaller the bld pressure variatins. In view f this finding the questin arse whether the greater threshld variability in the hypertensive subjects was assciated with a greater instability f their diastlic bld pressure as cmpared t the cntrl subjects. When cmparing the variatins in diastlic pressure between the tw grups there was, hwever, nly a small and insignificant difference (mean bserved standard deviatin f diastlic bld pressure/rest perid, 3.7 ± 1.6 mm Hg in nrmtensive subjects and 4 ± 2.3 in hypertensive subjects; p >.1). c Uj Of a. SI < i a: TABLE 2. Mean Crrelatin Cefficients fr the Relatinship Between Burst Incidence and Different Bld Pressure (BP) Parameters Patient grup Nrmtensive Hypertensive Diastlic BP Mean crrelatin cefficient Mean Systlic Pulse BP BP BP Pulse interval SLOPE OF REGRESSION LINE FIGURE 4. Relatinship between slpe f regressin line fr threshld variability diagram and diastlic bld pressure variability (expressed as the standard deviatin) during the same rest perid. Each pint represents the mean diastlic pressure variability fr all rest perids within a slpe interval f.5. The figure is based n all rest perids in bth nrmtensive and hypertensive subjects (n = 255). -14

6 72 HYPERTENSION VOL 1, N 2, MARCH-APRIL 1979 Relatinship Between Transient Bld Pressure Variatins and Burst Amplitude In additin t burst incidence, burst amplitude als increased during temprary bld pressure reductins bth in nrm- and hypertensive subjects. This was shwn by pltting burst amplitudes against crrespnding bld pressure values and calculating regressin lines and crrelatin cefficients fr each rest perid in bth grups f subjects. Figure 5A shws examples f such plts fr diastlic and systlic pressures frm a single rest perid in ne nrmtensive and ne hypertensive subject. Fr bth subjects there is a clse negative crrelatin t diastlic and n crrelatin t systlic pressures. The results were similar in all recrdings and as illustrated in Figure 5B and table 3 there was n appreciable difference in the degree f crrelatin between the nrm- and the hypertensive grups. Since the abslute burst amplitude depends n the psitin f the electrde tip in relatin t the active fibers, a factr which cannt be cntrlled with the present recrding technique, n attempt was made t cmpare abslute burst amplitudes between different subjects. TABLE 3. Mean Crrelatin Cefficients fr the Relatinship Between Burst Amplitude and Bld Pressure (BP) Patient grup Nrmtensive Hypertensive Mean crrelatin cefficient Diastlic BP Systlic BP Directin f Bld Pressure Changes Burst Incidence In nrmal subjects, Sundlflf and Wallin 18 shwed that at a given diastlic bld pressure, sympathetic bursts were mre likely t ccur if pressure was falling than if it was rising. T test whether this was true als fr hypertensive subjects, the rest perids were divided int tw fractins, ne cnsisting f heart beats preceded by beats with lwer diastlic pressure and ne cnsisting f beats preceded by beats with higher pressure. Fr each fractin burst incidence and mean diastlic bld pressure were cmpared. The 132 rest perids frm nrmtensive subjects and 83 perids Dwnladed frm by n September 7, 218 B J LU a Z>~ 8 Q. > s 6 < 4 (X. 2 Z QC LU z \ \ \\ V mmhg K> mmhg DIASTOLIC BLOOD PRESSURE SYSTOLIC BLOOD PRESSURE -U *Q5 +1J RRELATION EFFICIENT FIGURE 5. A: Relatinship between amplitudes f sympathetic bursts in integrated neurgram and diastlic (left) and systlic (right) bld pressures in a 3-minute rest perid in ne nrmtensive (slid circle) and ne hypertensive (pen circle) subject. Each pint represents mean amplitude f all bursts at a given bld pressure interval. Crrelatin cefficients fr linear regressin are:.99 and +.4 fr the nrmtensive subject and.92 and -.41 fr the hypertensive subject, respectively. B: Distributin f crrelatin cefficients fr the whle material. Open clumns = nrmtensive subjects; hatched clumns = hypertensive subjects.

7 MSA IN HUMAN HYPERTENSION/Wallin and Sundldf 73 frm hypertensive subjects were analyzed in this way (4 perids had t be excluded fr technical reasns). In bth grups burst incidence was virtually always higher during decreasing than during increasing bld pressure, the mean difference being 3.8 bursts/1 heart beats in the nrmtensive and 27.2 bursts/1 heart beats in the hypertensive grup. Hwever, in bth grups mean diastlic bld pressure was always lwer during the fractin f decreasing pressure and therefre it was questined whether this culd explain the difference in burst incidence. This was tested fr each rest perid by using the threshld variability diagram as illustrated in the upper right crner f figure 6. Frm the bserved difference in mean diastlic bld pressures between the fractins (a), the "expected" difference in burst incidence (b) was determined, and "expected" and "bserved" differences were then pltted against each ther. As shwn in figure 6 the bserved differences were greater than the expected in almst all rest perids, indicating that bth in nrm- and hypertensive subjects a given diastlic bld pressure is mre likely t be assciated with a sympathetic burst if pressure is falling than if it is rising. The directinal dependence was als expressed in pressure terms. This was dne by using the difference in burst incidence between rising and falling pressure and the slpe f the threshld variability diagram t calculate an "expected" difference in diastlic bld pressure. The "directinal dependence" was then determined by subtracting the bserved pressure difference frm the expected. Fr the nrmal subjects the difference was 4.8 ±3.5 mm Hg (mean ± SD), i.e. burst incidences wuld be equal if mean rising diastlic bld pressure was 4.8 mm lwer than mean falling diastlic bld pressure. Fr the hypertensive grup crrespnding figures were 6.5 ± 5.5 mm Hg (difference between grups was significant at the p <.1 level). The questin arse whether this difference in directinal dependence was assciated with the difference in threshld variability between nrm- and hypertensive subjects demnstrated in figure 4. Fr this reasn the slpe f the threshld variability diagram fr each rest perid was related t the directinal dependence f the same perid. The results were similar in bth the nrm- and hypertensive grup and therefre data frm all subjects are summarized in figure 7. The diagram shws that there Dwnladed frm by n September 7, 218 U Z a: Q B Q X in i i IU mm Hg CHASTOUC BIOOO PRESSURE OT OBSERVED DIFFERENCE (Bursts/lOO heart beats) FIGURE 6. Expected versus bserved differences in burst incidence between fractins f decreasing and increasing bld pressure in nrmtensive (clsed circles) and hypertensive (pen circles) subjects. Line at 45 dentes line f identity. Threshld variability diagram shwn in upper right crner illustrates methd f calculating expected difference in burst incidence (b) frm bserved difference in mean diastlic bld pressure (a) between fractins f decreasing and increasing bld pressure.

8 74 HYPERTENSION VOL 1, N 2, MARCH-APRIL 1979 Dwnladed frm by n September 7, 218 u z Hi a z z mmhg ' SLOPE OF REGRESSION LINE FIGURE 7. Relatinship between slpe f threshld variability diagram and directinal dependence f sympathetic activity during the same rest perid. Directinal dependence = "bserved"-"expected" difference in diastlic bld pressure between fractins f increasing and decreasing bld pressure. Calculatins were based n difference in burst incidence between fractins and slpe f threshld variability diagram. See text fr details. Each pint represents the mean directinal dependence fr all rest perids within a slpe interval f.5. Pled data frm 215 rest perids in nrm- and hypertensive subjects. was an apprximately expnential relatinship between the variables s that the steeper the slpe the smaller the directinal dependence. Burst Amplitudes Burst amplitudes were als cmpared between fractins f decreasing and increasing pressure. In each rest perid the difference in mean diastlic bld pressure between the fractins were cmpensated fr by a prcedure similar t that used fr burst incidence. The result was that the "bserved" difference in burst amplitude between the fractins was greater than the "expected" in apprximately 93% f the rest perids in bth grups. When the directinal dependence was expressed in bld pressure terms it was 4.9 ± 5.4 mm Hg (mean ± SD) in the nrmtensive and 8.5 ± 9.1 mm Hg in the hypertensive grup (significant difference p <.1, Student's t test). In nrmal subjects we cmpared the regressin lines fr the relatinship between diastlic bld pressure and burst amplitude fr decreasing and increasing pressures. 1 ' We fund that the slpe f the line frm the "decreasing fractin" in general was steeper than that frm the "increasing fractin," suggesting that fr a given bld pressure change, sympathetic activity changes mre if pressure is falling than if it is rising. A similar cmparisn was made fr the hypertensive subjects. Due t the lw number f bursts (especially in the "increasing fractin") and the large amplitude variability, significant regressin lines (slpe f line tested with Student's t test,/> <.1) fr bth fractins were btained nly in 35 rest perids in 11 nrmtensive and 28 perids in 11 hypertensive subjects. Figure 8A shws individual examples f the cmparisns f the lines frm ne perid in each grup in which the lines frm the "decreasing fractin" were steeper than thse frm the "increasing fractin." In figure 8B the results frm the tw grups are summarized. In bth grups the "decreasing slpes" were steeper than the "increasing" nes (p <.1 in the nrmtensive, and p <.5 in the hypertensive grup, Student's t test). There was, n the ther hand, n significant difference in the degree f asymmetry between nrm- and hypertensive subjects (tested by cmparing the ratis f the slpes in the tw grups,/? >.1, Student's t test). Relatinship Between the Mean Amunt f Sympathetic Activity and the Static Bld Pressure Lerel In agreement with ur earlier findings"- " burst incidence usually shwed nly small variatins between different rest perids in the same individual. Fr each subject in the tw grups n whm simultaneus recrdings f MSA and bld pressure were made, mean burst incidence and mean diastlic bld pressure fr all rest perids were calculated. As illustrated in figure 9, there were marked differences between individuals in bth bld pressure and sympathetic activity. When the amunt f activity was expressed as bth bursts/1 heart beats (fig. 9A) and bursts/ min (fig. 9B) there was a slight tendency fr increasing activity at higher bld pressure levels (slpe f regressin line different frm at the/? <.1 level in A, and at the p <.5 in B). Relatinship Between Mean Amunt f Sympathetic Activity and Age Figure 1 shws the relatinship between the mean amunt f sympathetic activity (expressed as mean number f sympathetic bursts/1 heart beats) and age fr all subjects. In bth the nrmtensive and hypertensive grup there was a wide scatter f the experimental pints and in bth grups there was a tendency fr increasing amunt f activity with increasing age. (Slpe f regressin line different frm at the p <.5 level fr nrmtensive and at the p <.1 level fr hypertensive subjects, respectively, Student's t test. If all subjects are treated as ne grup the significance increases t p <.1). When the amunt f sympathetic activity was expressed as bursts/min t accunt fr differences in heart rate, the result was similar and in neither case was there a significant difference between the slpes f the regressin lines fr the nrm- and hypertensive grups.

9 MSA IN HUMAN HYPERTENSION/Wallin and Sundlbf 75 UJ Q _ 8 Nrmtensive Hypertensive B 6 A % "P DIASTOLIC BLOOD PRESSURE 14 mmhg -1 Nrmtensive -1 Hypertensive ct B Z> cc U Z -2-2 Dwnladed frm by n September 7, DECREASING PRESSURE (slpe) FIGURE 8. The differences in slpe f the regressin lines fr the relatinship between diastlic bld pressure and burst amplitude between fractins f decreasing and increasing bld pressure. A: Example frm a 3-minute rest perid in ne nrmtensive and ne hypertensive subject with decreasing (slid circles and line) and increasing (pen circles, dtted line) pressure fractins analyzed separately. B: Cmparisn f the slpes in 35 rest perids frm 11 nrmtensive and 28 rest perids frm 11 hypertensive subjects. Lines at 45 dente lines f identity B 8 6 * mmha mmhfl D1ASTCX.IC BLOOD PRESSURE FIGURE 9. Relatinship between mean diastlic bld pressure and amunt f muscle nerve sympathetic activity expressed as bursts/1 heart beats (A) and bursts/min (B). Each pint represents mean values frm all rest perids in ne subject. Slid circle = nrmtensive subjects; pen circle = hypertensive subjects. Crrelatin cefficients fr linear regressin:.34 in A, and.41 in B.

10 76 HYPERTENSION VOL 1, N 2, MARCH-APRIL 1979 Dwnladed frm by n September 7, 218 t i LU H- c x -C years AGE FIGURE 1. Relatinship between subject age and mean amunt f muscle nerve sympathetic activity expressed as bursts 11 heart beats fr 33 nrmtensive subjects (slid circles and line) and 12 hypertensive (pen circles and dtted line) subjects. Crrelatin cefficients fr linear regressin:.4 fr nrmtensive, and.57 fr hypertensive subjects, respectively. Discussin The hypertensive patients in the present study d nt cmprise a hmgeneus grup with regard t the type and severity f hypertensin. In the majrity, the clinical diagnsis was essential hypertensin but tw patients were thught t have brderline and tw renal hypertensin. An additinal three subjects had abnrmal renal arterigrams but the changes were nt cnsidered as clinically significant. Despite this inhmgeneity the material has been treated as ne grup, the aim being t investigate whether hypertensin as such is assciated with an abnrmal sympathetic utflw, rather than separating between different types f hypertensin. The results d nt, hwever, give any hint f differences between subjects with hypertensin f different etilgies. Static Bld Pressure Level Althugh the material is t small fr a definite cnclusin, the present study des nt prvide evidence fr an increased "level" f MSA in hypertensin. It is true that there was a weak tendency fr higher "levels" f MSA at higher bld pressures but this was prbably due t the hypertensive subjects being lder than the nrmtensive cntrls. Thus, t the extent that the strength f the MSA is reflected in the plasma level f nradrenaline, the present results agree with thse f Lake et al. 11 wh fund n significant difference in plasma nradrenaline levels between age-matched nrm- and hypertensive subjects at rest. In this cntext it shuld be remembered, hwever, that the sympathetic utflw is cntrlled reginally 1 " and therefre the present results must nt be generalized t ther vascular beds. We recently shwed that in nrmtensive subjects there was a tendency fr increasing amunts f MSA with increasing age." Fr hypertensive subjects the data shw a similar trend. Althugh the exact reasn fr the age dependency is unknwn it may be related t a reductin f barreceptr activity. This may ccur bth because f barreceptr degeneratin 18-1 r because f reduced distensabuity f the vessel walls in the barreceptr regins in higher ages. 2 Bld Pressure Variatins As discussed by Wallin et al. 1 ' the pulse synchrny and the inverse relatinship between variatins in bld pressure and MSA indicate that barreflex mdulatin f the sympathetic utflw still ccurs in hypertensive subjects. The elevated bld pressure threshld fr sympathetic utflw, fund in the present investigatin, in all prbability reflects the wellknwn static resetting f the perating range f the barreflex, secndary t the hypertensin.* 1 "" In additin, the present study shws that qualitatively the dynamic characteristics f the reflex are preserved. The variatins in strength f the MSA were determined mainly by diastlic bld pressure fluctuatins and, at a given bld pressure, mre sympathetic activity ccurred if pressure was falling than if it was rising (directinal dependence). Cnsequently, in hypertensive subjects the barreflex defends the elevated bld pressure level in a way similar t that fund in nrmal subjects. Hwever, quantitatively there were tw differences between nrm- and hypertensive subjects: 1) the slpes f the threshld variability diagrams were less steep, and 2) when determined frm bth burst incidence and burst amplitude the directinal dependence was greater in the hypertensive than in the nrmtensive grup. The tw differences are prbably related t each ther. The less steep slpes in the threshld variability diagrams indicate that the bld pressure threshld fr sympathetic utflw varies mre in hypertensive than in nrmtensive subjects. In view f the findings shwn in figure 7 it seems likely that there is a causal relatinship between the degree f directinal dependence and the variability f the threshld. Therefre, the reasn fr hypertensive subjects having a higher variability f the threshld may be the greater directinal dependence. Culd this finding be f imprtance fr the pathgenesis f the hypertensin? Prbably nt. In animal experiments it has repeatedly been shwn that fr a given bld pressure, barreceptr firing is strnger when pressure is increasing than when it is decreasing. 14 "* 7 Althugh central mechanisms cannt be excluded,* 8 it seems likely that this barreceptr hysteresis, is an imprtant reasn fr the directinal dependence f the MSA fund in the present study. In animals with experimental hypertensin, the wrking range f the barreceptrs becmes reset and their sensitivity t bld pressure changes becmes reduced " M In additin, Angell-James 8 fund that the barreceptr hysteresis t rising and falling pressures was mre prnunced in

11 MSA IN HUMAN HYPERTENSION/ Wallin and Sundl&f 77 Dwnladed frm by n September 7, 218 hypertensive than in cntrl animals. If the hysteresis is increased als in hypertensive man it wuld prvide a pssible explanatin fr the increased directinal dependence in hypertensive subjects fund in the present study. In view f these cnsideratins, there seems t be n need t suspect that any f the bserved differences in MSA between nrm- and hypertensive subjects are f primary imprtance fr the pathgenesis f the hypertensin. On the cntrary, the differences can be explained by such changes f arterial barreceptr functin that are knwn t ccur secndary t the bld pressure elevatin. Acknwledgment We thank Eva Bath fr valuable technical assistance. References 1. Julius S, Pascual AV, Lndn R: Rle f parasympathetic inhibitin in the hyperkinetic type f brderline hypertensin. Circulatin 44: 413, Krner PI, Shaw J, Uther JB, West MJ, McRitchie RJ, Richards JG: Autnmic and nn-autnmic circulatry cmpnents in essential hypertensin in man. Circulatin 48: 17, Julius S, Cnway J: Hemdynamic studies in patients with brderline bld pressure elevatin. Circulatin 38: 282, Flkw B, Hallback M, Lundgren Y, Sivertssn R, Weiss L: Imprtance f adaptive changes in vascular design fr establishment f primary hypertensin studied in man and in spntaneusly hypertensive rats. Circ Res 32 and 33 (suppl I): 1-2, Engelman K, Prtny B, Sjerdsma A: Plasma catechlamine cncentratins in patients with hypertensin. Circ Res 27 (suppl I): 1-141, De Quattr V, Chan S: Raised plasma-catechlamines in sme patients with primary hypertensin. Lancet 1: 86, Geffen LB, Rush RA, Luis WJ, Dyle AE: Plasma dpamine -hydrxylase and nradenaline amunts in essential hypertensin. Clin Sci 44: 617, Luis WJ, Dyle AE, Anavekar S: Plasma nrepinephrine levels in essential hypertensin. N Engl J Med 288: 599, De Quattr V, Miura Y, Lurvey A, Csgrve M, Mendez R: Increased plasma catechlamine cncentratins and vas deferens nrepinephrine bisynthesis in men with elevated bld pressure. Circ Res 36: 118, Dc Champlain JD, Farley L, Cusineau D, Van Ameringen M-R: Circulating catechlamine levels in human and experimental hypertensin. Circ Res 38: 19, Lake CR, Ziegler MG, Cleman MD, Kpin IJ: Age-adjusted plasma nrepinephrine levels are similar in nrmtensive and hypertensive subjects. N Engl J Med 296: 28, Hagbarth K-E, Vallb AB: Pulse and respiratry gruping f sympathetic impulses in human muscle nerves. Acta Physil Scand 74: 96, Wallin BG, Delius W, Hagbarth K-E: Cmparisn f sympathetic nerve activity in nrmtensive and hypertensive subjects. Circ Res 33: 9, SundlGf G, Wallin BG: The variability f muscle nerve sympathetic activity in resting recumbent man. J Physil 272: 383, SundlBf G, Wallin BG: Human muscle nerve sympathetic activity at rest. Relatinship t bld pressure and age. J Physil 274: 621, Wallin BG, Delius W, Hagbarth K-E: Reginal cntrl f sympathetic utflw in human skin and muscle nerves. In Central- Rhythmic and Regulatin, edited by Umbach W, Kepchen HP. Stuttgart, Hippkrates-Verlag, 1974, p Wallin BG, Delius W, SundlBf G: Human muscle nerve sympathetic activity in cardiac arrhythmias. Scand J Clin Lab Invest 34: 293, Abraham A: The structure f barreceptrs in pathlgical cnditins in man. In Barreceptrs and Hypertensin, edited by Kezdi P. Oxfrd, Pergamn Press, 1967, p Muratri G: Histlgical bservatins n the structure f the cartid sinus in man and mammals. In Barreceptrs and Hypertensin, edited by Kezdi P. Oxfrd, Pergamn Press, 1967, p Bader H: Dependence f wall stress in the human thracic arta n age and pressure. Circ Res 2: 354, McCubbin JW, Green JH, Page IH: Barreceptr functin in chrnic renal hypertensin. Circ Res 4: 25, Kezdi P: Resetting f the cartid sinus in experimental renal hypertensin. In Barreceptrs and Hypertensin, edited by Kezdi P. Oxfrd, Pergamn Press, 1967, p Aars H: Artic barreceptr activity in nrmal and hypertensive rabbits. Acta Physil Scand 72: 298, Spickler JW, Kezdi P: Dynamic respnse characteristics f cartid sinus barreceptrs. Am J Physil 212: 472, Angell-James JE: The respnses f artic and right subclavian barreceptrs t changes f nnpulsatile pressure and their mdificatin by hypthermia. J Physil 26: 21, Pelletier CL, Clement DL, Shepherd JT: Cmparisn f afferent activity f canine artic and sinus nerves. Circ Res 26: 557, Ninmiya I, Irisawa H: Artic nervus activities in respnse t pulsatile and nnpulsatile pressure. Am J Physil 213: 154, Katna PG, Barnett GO: Central rigin f asymmetry in the cartid sinus reflex. Ann NY Acad Sci 156: 779, Brwn AM, Saum WR, Tuley FH: A cmparisn f artic barreceptr discharge in nrmtensive and spntaneusly hypertensive rats. Circ Res 39: 488, Angell-James JE: Characteristics f single artic and right subclavian barreceptr fiber activity in rabbits with chrnic renal hypertensin. Circ Res 32: 149, 1973