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Inability to deactivate sympathetic nervous system in brainstem infarct patients
,lmtrnal ql the Neurologieal Sciences. 1983, 58:223 234
223
Elsevier Biomedical Press
INABILITY TO DEACTIVATE SYMPATHETIC NERVOUS SYSTEM IN BRAINSTEM INFARCT PATIENTS
EMILIAN STOICA and OLIMPIA ENULESCU
Institute oi' Neuroh~Kv and Ps)'ehiat13'. Bucharest (Romania) (Received 21 April, 1982) (Revised, received 26 July, 1982) (Accepted 4 August, 1982)
SUMMARY
Catecholamine urinary excretion under basal conditions and after head down tilting (4 °) was studied in normo- and hypertensive controls and in patients with hemisphere and brainstem infarction, respectively. Both the normo- and hypertensive controls and patients with hemisphere infarction displayed a conspicuous decrease (about 400,,) in noradrenaline (NA) urinary excretion after head down tilting. In contrast the patients with brainstem infarction increased NA urinary excretion after the manoeuvre, suggesting activation instead of deactivation of the sympathetic nervous system (SNS). In normo- and hypertensive controls the values of night NA excretion were lower than those of day NA excretion, whereas in brainstem infarct patients the night NA excretion was close to the day NA excretion. This finding also supports the view that the brainstem infarct patients are not able to deactivate their SNS during night recumbency. The SNS reactivity disorder of such patients if associated with impairment of autoregulation of cerebral circulation might generate an abnormal increase in cerebral circulation during night recumbency.
INTRODUCTION
Although the sympathetic outflow stems from the intermedio-lateral column of the thoraco-lumbar spinal cord, the higher structures of the CNS seem to play
Reprint requests to Dr. Emilian Stoica, Institute of Neurology and Psychiatry, Sos. Berceni 10-12, C.P.61-80, R-75622 Bucharest, Romania. 0022-510X/83/0000-0000/$03.00 c,c) 1983 Elsevier Biomedical Press
224
an important part in the modulation of sympathetic activity. Thus, it has been reported that patients with cervical spinal cord transection have particularly low values of noradrenaline (NA) plasma concentration and display an enhanced pressor response to the infusion of this mediator (Mathias et al. 1976). An overreactivity to NA infusion was also noticed in parkinsonian patients, which, together with their low blood pressure values, were ascribed to reduced sympathetic tonus due to lesions of the basal ganglia or brainstem structures (Aminoff and Wilcox 1971). A deficit of sympathetic nervous system (SNS) was reported in patients with orthostatic hypotension in whom the cerebellar and extrapyramidal signs and the cranial nerve defects indicated that the major lesions were located in the brainstem (Ziegler et al. 1977). In such patients NA plasma levels failed to increase normally after standing or exercising. Taking into consideration the above clinical data it seemed reasonable to assume that a reactivity disorder of SNS may also exist in patients with ischemic lesions of brainstem structures. The hypothesis was partly checked in one of our previous works showing that, unlike control subjects, brainstem infarction patients failed to increase their NA urinary excretion after head up tilting at 8 ° (Stoica and Enulescu 1981). As a continuation of our investigations we were laced with the problem of whether SNS reactivity disorders are not more complex in patients with brainstem infarction, involving also the SNS capacity to reduce its activity under certain conditions. It has been shown that blood shifting to the thoracic vascular bed by passively raising the legs of a recumbent subject brings about a dilatation of the forearm vessels (Roddie et al. 1957). The alteration seems to be a consequence of SNS deactivation resulting in a release of vasoconstrictor tone in muscle vessels. Body immersion in water, producing an increase in atrial pressure due to increased thoracic blood volume (Korz et al. 1969), results in a depression in NA urinary excretion (McCally and Graveline 1963). In the present study we investigated the effect of head down tilting on catecholamine (CA) urinary excretion. The investigation was made in patients with brainstem infarction and patients with hemisphere infarction as well as in normoand hypertensive controls. According to the above-quoted data such a manoeuvre, increasing the central blood volume and then stimulating the baroreceptors in high and low pressure systems, should result in a depression of sympathetic tonus, expressed by a decrement of NA urinary excretion. In some patients with brainstem infarction and in some normo- and hypertensive controls the day and night CA urinary excretion were also determined. Normally a depression in NA urinary excretion must occur during night recumbency (Elmadjian et al. 1957; Serrano et al. 1964); the absence of this alteration and of a depressed NA excretion alter head down tilting in patients with brainstem infarction would point to the lack of SNS deactivation.
225 MATERIALS AND METHODS The investigations were made in the lbllowing categories of subjects who were all hospitalized: (a) 19 patients with lumbar disc disease and with normal blood pressure (mean age 56.7 years). (b) 21 patients with uncomplicated essential hypertension (mean age 60.7 years). In almost all of them history showed hypertension in other family members. Blood urea and urine analysis were normal in all patients. The ocular fundus examination showed spastic retinal arteries with an exaggerated arterial reflex in all and in many the presence of Salus Gunn's sign, but no other more severe alterations (i.e. hemorrhage, exudative lesions, papilloedema). (c) 12 patients with hemisphere infarction (mean age 55.3 years), 8 of them being hypertensive. In all patients the diagnosis was based on clinical findings, CSF analysis (colourless fluid, without erythrocytes in the sediment) and, in 8 cases, on carotid angiography which showed occlusion of the internal carotid or middle cerebral artery. The infarction was probably cortical in most of the patients, 10 of them displaying dysphasia. The investigation was made within the first month alter stroke in 5 patients, and after a longer interval in the remaining 7. (d) 31 patients with brainstem infarction (mean age 57.8 years); 19 of them were hypertensive and 12 normotensive. Diagnosis was based on clinical data (neurologic picture with sudden onset characterized by cranial nerve nuclei dysfunction, cerebellar or/and bilateral pyramidal signs). In all patients lumbar puncture showed a colourless fluid without erythrocytes in the sediment. According to the clinical picture the infarction affected the superior part of the brainstem in 20 patients and the bulbo-pontine region in the remaining 11. The tests were made within the first month after stroke in 18 patients, and later in the remaining 13. In patients with cerebral infarction the medication consisted in dipyridamole, xanthinol nicotinate, papaverine and vitamins. In hypertensive patients the medication included antihypertensive drugs (diuretics and reserpine 0.5 mg daily). The hypertensive controls received only the antihypertensive medication. The normotensive subjects with lumbar disc disease received analgesics and muscle relaxing drugs. In patients and controls the medication was withdrawn 2 days before CA determination. Their diet was free of CA tbr 3 days before investigation. The investigation followed this schedule: At 7 a.m. the lasting subject emptied his bladder, then drank 200 ml of water and lay in bed until 9 a.m. The urine collected at the end of this period was measured and 25 ml were transferred in a bottle containing 1 ml of 1"~i,sodium metabisulfite and 1 ml of 4 N perchloric acid. The bottle was then stored at - 2 0 °C until required for analysis of CA which was performed within the first week alter collection. In this urine sample the basal urinary excretion of CA was assayed. At 9 a.m. blood pressure and heart rate were measured, the subject being in the supine position. Then, the subject was head down tilted to an angle of 4 °, by changing the position of the bed. The tilting down of the subject was maintained for 10 min, blood
226
pressure and heart rate were measured during tilting down (in min 3 and 10). The bed was restored to the horizontal position and blood pressure and heart rate were again measured 2 min after cessation of the manoeuvre. The subject remained in bed until ll a.m. when the urine was collected again and treated in the same manner as shown before. In this sample of urine the CA excretion alter head down tilting was determined. In brainstem infarct patients and control subjects in whom the day and night CA urinary excretion was measured the urine was collected from 7 a.m. to 7 p.m. for the day CA excretion, and from 7 p.m. to 7 a.m. for the night CA excretion. As the "basilar" patients displayed no motor deficit it may be admitted that their daily motor activity was similar to that of control subjects. Measurement of CA urinary excretion was made with McCullough's (1968) method as modified by us (Stoica and Enulescu 1978). RESULTS
CA urinary excretion after head down tilting In most of the control subjects both normo- and hypertensive the slight tilting down of the body (4 °) for a short interval of time (10 rain) induced a conspicuous decrease in N A urinary excretion (Figs. 1A and B). On average the reduction in N A excretion was 3 8 ~ in normotensives and 3 6 ~ in hypertensives, being highly significant in both categories (Table 1). So far as the medication of hypertensive A eg/h
D
B
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pg/h
100
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0~, 060 /
04
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/
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o.~
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o.o -0~
-0.~ O~
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120
120
o4o
-R20
0.40
-040
0.60
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0.~0t
-080~
=1
tOG 120
120
,ooi
- 120
NAB
NAH~
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f
NAB
t
NAHD
NAB
NAKD
Fig. 1. Individual variations in noradrenaline (NA) urinary excretion after head down tilting (4 °) in normotensive controls (A), hypertensive controls (B), patients with hemisphere infarction (C) and patients with brainstem infarction (D). Ordinate: values of NA urinary excretion expressed in #g/h. NAHD: alterations (increases or decreases) in NA urinary excretion after head down as compared to the basal value of NA (NAB) taken as 0.
227 TABL E 1 I N F L U E N C E OF H E A D D O W N (HD) T I L T I N G (4 °) ON N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN V A R I O U S C A T E G O R I E S OF SUBJECTS
Investigated group
Urine volume (ml/h) Before HD
N A urinary excretion (/1g/h)
A urinary excretion (#g/h)
Before HD
After HD
Difference
Before HD
After HD
Difference
After HD
Difference
Normotensive controls (N = 19) MV 128.0 142.7 SE 16.1 19.7 t P
14.7 13.0 1.13 >0.05
1.40 0.15
0.87 0.10
-0.53 0.14 3.79 <0.005
0.30 0.05
0.29 0.02
-0.01 0.05 0.20 >0.05
Hypertensive controls (N = 21) MV 145.0 147.7 SE 14.9 13.7 t P
2.7 10.4 0.26 >0.05
1.99 11.17
1.28 0.13
-0.71 0.15 4.73 <0.001
0.29 0.05
0.43 0.05
0.14 0.04 3.50 <0.005
1.66 0.22
1.08 0.20
-0.58 0.19 3.05 <0.02
0.26 0.07
0.41 0.06
0.15 0.08 1.86 >0.05
1.49 0.10
1.71 0.12
0.22 0.10 2.20 <0.05
0.27 0.03
0.27 0.04
0.0 0.05 0.0 >0.05
Patients with hemisphere infarction (N = 12) MV 91.2 92.9 1.7 SE 20.2 13.3 12.1 t 0.14 P >0.05 Patients with brainstem infarction (N = 3l) MV 101.8 112.8 ll.0 SE 15.2 13.4 12.4 t 0.89 P >0.05
MV = mean values, SE = standard error.
controls included reserpine the similarity of NA decrement in normo- and hypertensive controls suggests that reserpine medication, discontinued 2 days before testing, did not significantly influence the N A response to head down tilting. The patients with hemisphere infarction reacted to head down tilting in the same way as the controls, i.e. by a significant decrease in NA urinary excretion (Fig. 1C). In contrast with controls and patients with hemisphere infarction, the patients with brainstem infarction responded to head down tilting by an increase in NA urinary excretion (Fig. 1D, Table 1). The abnormal response to head down tilting in patients with brainstem infarction was noticed both in those investigated within the first month after stroke and in those studied later (Table 2). The blood pressure values of such patients seem to be not involved in the lack of a proper response either, as the disorder in NA excretion after head down tilting was found in brainstem infarction patients with hypertension as well as in those with normotension (Table 3). Finally, neither
228 TABLE 2 I N F L U E N C E OF H E A D D O W N (HD) T I L T I N G (4 °) ON N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN P A T I E N T S W I T H B R A I N S T E M I N F A R C T I O N IN T E R M S OF T H E I N V E S T I G A T I O N P E R I O D Patients with brainstem infarction
Urine volume NA urinary excretion A urinary excretion (ml/h) (#g/h) (#g/h) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Before After DifferBefore After DifferBefore After DifferHD HD ence HD HD ence HD HD ence
Investigated within the first m o n t h after stroke (N = 18) MV 75,0 106.4 31.4 1.38 SE 12.6 18.4 10.8 0.14 t 2.91 P <0.01 Investigated later ( N = 13) MV 138.9 SE 29,4 t P
121.5 19.7
- 17.4 24.0 0.73 >0.05
1.64 0.15
1.61 0.14
0.23 0.13 1.77 >0.05
0.25 0.04
0.35 0.05
0.10 0.05 2.00 >0.05
1.85 0.21
0.21 0.15 1.40 >0.05
0.29 0.06
0.16 0.04
-0.13 0.07 1.86 >0.05
TABLE 3 I N F L U E N C E O F H E A D D O W N (HD) T I L T I N G (4 °) O N N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN P A T I E N T S W I T H B R A I N S T E M I N F A R C T I O N IN TERMS OF BLOOD PRESSURE VALUES Patients with brainstem infarction
Urine volume (ml/h) Before HD
Normotensive (N = 12) MV 66.6 SE ll.6 t P Hypertensive (N = 19) MV 122.8 SE 22.6 t
P
N A urinary excretion (#g/h)
A urinary excretion (#g/h) Before HD
After HD
Difference
After HD
Difference
Before HD
After HD
Difference
95.0 19.1
26.4 9.9 2.67 <0.05
1.47 0.15
1.65 0.18
0.18 0.15 1.20 >0.05
0.26 0.06
0.31 0.06
0.05 0.07 0.71 >0.05
124.0 18.1
1.2 19,2 0.06 >0.05
1.51 0.14
1.75 0.17
0.24 0.13 1.85 >0.05
0.28 0.04
0.24 0.05
-0.04 0.06 0,67 >0.05
TABLE 4 I N F L U E N C E OF H E A D D O W N (HD) T I L T I N G (4 °) ON N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN PATIENTS W I T H BRAINSTEM I N F A R C T I O N IN TERMS OF LESION LOCATION
Patients with brainstem infarction
Urine volume (ml/h) Before HD
Upper brainstem (N - 20) MV 82.2 SE 13.3 t P Lower brainstem (N - 11) 137.4 SE 33.8 I P
NA urinary excretion (/~g/h)
A urinary excretion (/lg/h)
Before HD
After HD
Difference
Before HD
After HD
Difference
After HD
Differrence
104.9 14.1
22.7 11.9 1.91 >0.05
1.41 0.12
1.55 0.14
0.14 0.10 1.40 >0.05
0.27 0.05
0.26 0.04
-0.01 0.05 0.20 >0.05
127.1 28.3
-10.3 27.3 0.38 >0.05
1.63 0.19
1.99 0.22
0.36 0.20 1.80 >0.05
0.28 0.04
0.29 0.09
0.01 0.09 0.11 >0.05
TABLE 5 I N F L U E N C E OF HEAD D O W N (HD) T I L T I N G (4 °) ON MEAN A R T E R I A L BLOOD PRESSURE IN VARIOUS C A T E G O R I E S OF SUBJECTS
Investigated group
Mean arterial blood pressure (ram Hg) Initial value (IV)
At 3 min
Difference (IV 3 mini
At 10 min
Difference After (IV 10 mini 2 min
Difference (IV after 2 mini
Normotensive controls (N = 19) MV 96.9 96.3 SE 2.0 1.9 t P
-0.6 1.7 0.35 >0.05
96.4 2.3
-0.5 2.0 0.25 >0.05
96.5 2.2
-0.4 1.9 0.21 >0.05
Hypertensive controls (N = 21) MV 128.7 127.0 SE 3.5 3.7 t P
- 1.7 1.5 1.13 >0.05
124.4 3.7
-4.3 1.1 3.91 <0.001
127.8 3.4
-0.9 0.9 1.00 >0.05
101.9 3.7
-3.0 2.0 1.50 >0.05
103.9 3.8
- 1.0 1.3 0.77 >0.05
113.2 4.0
-0.9 1.3 0.69 >0.05
112.2 4.2
1.9 1.2 1.58 >0.05
Patients with hemisphere infarction (N = 12) MV 104.9 104.5 -0.4 SE 4.2 3.7 1.8 I 0.22 P >0.05 Patients with brainstern infarction (N = 31) MV 114.1 113.4 -0.7 SE 4.2 3.8 1.3 t 0.54 P >0.05
230 the patients with upper b r a in s te m infarction (mid-brain), n o r those with lower b r ai n s t em infarction ( b u l b o - p o n t i n e ) displayed a r e d u c t i o n in N A excretion after head d o w n tilting, which suggests no relation between the i n a d e q u a t e C A response seen in such patients and the site o f b rai n st em vascular lesion (Table 4). Th e m a n o e u v r e r e m a i n e d practically w i t h o u t influence on b l o o d pressure an d heart rate in all categories o f subjects except h y p e r t e n s i v e c o n t r o l s in w h o m a small but significant r e d u c t i o n in m e a n arterial b l o o d pressure an d heart rate was f o u n d d u r i n g the m a n o e u v r e (Tables 5 an d 6).
Day-night CA urinary excretion N o r m o t e n s i v e c o n t r o l s excreted higher a m o u n t s o f N A by d ay than by night, the m e a n v a lu e for day N A e x c r e ti o n being the d o u b l e o f the night m e a n value. T h e m e a n difference between those two values was highly significant (Table 7). In h y p e r t e n s i v e c o n t r o l s the s a m e p h e n o m e n o n was observed, i.e. the day N A excretion surpassed significantly the night N A excretion. In c o n t r a s t with c o n t r o l
TABLE 6 INFLUENCE OF HEAD DOWN (HD) TILTING (4°) ON HEART RATE IN VARIOUS CATEGORIES OF SUBJECTS Investigated group
Heart rate (beats/min) ............................................... Initial At 3 min Difference At 10 min Difference After value (IV-3 min) (IV-10 min). 2 min (IV)
Difference (IV-after 2 min)
Normotensive controls (N = 19) MV 65.5 63.5 SE 2.3 2.1 t P
-2.0 1.0 2.00 >0.05
63.2 1.9
-2.3 1.2 1,92 >0.05
64.2 2.1
- 1.3 0.9 1.44 >0.05
Hypertensive controls (N = 21) MV 67.2 66.4 SE 1.9 2.0 t P
- 0.8 0.6 1.33 >0.05
65.7 2.0
- 1.5 0.5 3.00 <0.01
66.2 1.8
- 1.0 0.7 1.43 >0.05
65.8 2.4
0.0 0.7 0.0 >0.05
66.2 2.1
0.4 0.8 0.50 >0.05
66.6 1.6
- 0.2 0.5 0.40 >0.05
67.2 1.6
0.4 0.5 0.80 >0.05
Patients with hemisphere infarction (N = 12) MV 65.8 65.3 -0.5 SE 2.1 2.3 0.7 t 0.71 P >0.05 Patients with brainstem infarction (N = 31) MV 66.8 66.8 0.0 SE 1.7 1.7 0.5 t 0.0 P >0.05
231 TABLE 7 DAY A N D N I G H T N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y EXCRETION IN VARIOUS C A T E G O R I E S OF SUBJECTS
Investigated
Urine volume
NA urinary excretion
A urinary excretion
group
(ml/12 h)
(/~g/12 h)
(#g/12 h)
Day
Night
Difference
Day
Night
Differ-
Day
Night
-171.3 116.7 1.47 >(/.05
22.23 1.81
11.36 1.19
10,87 1.16 9,35 <0.001
3.41 0.67
2.16 0.43
1.25 0.46 2.73 <0.02
52.2 80.5 0.65 >0.05
24.15 2.98
16.61 2.07
-7,54 2.79 2.70 <0.02
2.45 0.72
1.88 0.36
-0.57 0.48 1.18 >II.05
20.02 1.89
18.99 1.99
- 1.03 2.69 0.38 >0.05
2.74 0.32
1.92 0.34
-0.82 0.39 2.09 >0.05
Differ-
ence
ence
Normotensive controls (N = 12) MV SE t P
762.1 82.3
590.8 69.8
Hypertensive controls (N = 14) MV SE t P
688.2 51.7
740.4 93.5
Patients with brainstem infarction (N = 161 MV SE ! P
695.3 56.2
761.9 42.7
66.6 57.2 1.17 >0.05
subjects many patients with brainstem infarction excreted similar amounts of NA by day and by night and some of them excreted more NA by night than by day. The mean value for day N A excretion was close to the mean value for night NA excretion (Table 7). DISCUSSION
Admittedly most of the NA excreted in urine is extra-adrenal in origin, being released from sympathetic nerve endings (Elmadjian et al. 1957; von Euler 19661. Therefore, one may maintain that the marked reduction in NA excretion observed in controls and patients with hemisphere infarction after head down tilting reflects a depression in SNS tonus. Noteworthy is the long lasting effect of this postural change: a 10-min period of head down tilting was enough to depres NA excretion for the next 2 hours. The reduction in sympathetic activity found in controls and patients with hemisphere infarction after head down tilting seems to be due to the stimulation of baroreceptors in the high and low pressure systems. Nonetheless it is hard to specify clearly the part played by the arterial or venous receptors in the postural sympathetic depression observed in our model. Roddie et al. (1957) have reported forearm muscle vasodilatation induced by passively raising the legs of recumbent
232 subjects. The manoeuvre was accompanied by increases in central venous pressure and amplitude of venous pulsation. Absence of correlation between forearm vasodilatation and the mean arterial or pulse pressure suggested that the dilatation was not a consequence o f arterial baroreceptors stimulation. The authors therefore ascribed the peripheral vasodilatation to stimulation of receptors in low pressure area of the intrathoracic vascular bed. The above data, obtained in a clinical model relatively similar to ours, support the idea that the venous baroreceptors are playing the major part in sympathetic deactivation here reported. It seems all the more unlikely that stimulation of arterial baroreceptors is involved in the production of this phenomenon as initially the head down tilting at 4 ° had no significant effects on mean arterial blood pressure (Table 5). A reduction in heart rate and in mean arterial blood pressure were noted in our hypertensive controls 10 rain after head down tilting, but in all probability the alteration was secondary to sympathetic tonus depression. Most of our patients with brainstem infarction displayed an abnormal sympathetic response to head down tilting, which might be due to the disorder of baroreceptor apparatus itself. The supposition seems unlikely as in most patients a reverse response and not a lack of response was found. This paradoxical reaction is rather suggestive of an impairment of central mechanisms, an interpretation supported by a set of experimental investigations. It was demonstrated that midpontine section of the brainstem produced in the cat the disappearance ot" the pressor response to carotid occlusion and appearance of a paradoxical pressor response to sinus stretch (Reis and Cu6nod 1965). In rats with experimental lesions which disconnected the anterior hypothalamus from the middle hypothalamus, carotid occlusion made shortly after the lesion resulted in a fall of blood pressure instead of an increase (Lopes and Cipollaneto 1973). The modulating effect of the hypothalamus on the input from baroreceptors was also reported by Weiss and Crill (1969)who showed primary afferent depolarization in the carotid sinus nerve of the cat by stimulating the posterior hypothalamus. According to Zehr et al. (1969) the hypothalamus is also involved in the humoral reflex adjustments operated through baroreceptors in the low pressure system; they consider that the principal input into the supraoptic and paraventricular nuclei controlling A D H secretion arises from the left atrial baroreceptors. The abnormal response of SNS found in patients with brainstem infarction is then more probably due to the disorder of central mechanisms controlling the sympathetic activity. Admittedly large areas of CNS exert a control on SNS (Ziegler et al. 1977). However, as the inability to deactivate properly the SNS by head down tilting has been seen in patients with brainstem vascular lesions but not in those with hemisphere vascular lesions, it is conceivable that the central mechanisms involved in postural sympathetic deactivation are located in the brainstem and not in more rostrally situated areas. On the other hand the central mechanism controlling the postural sympathetic deactivation seems to be widespread within the brainstem as the sympathetic reactivity disorder was observed both in patients with upper and lower brainstem lesions.
233 It has been reported that in normals the day value for NA excretion is twice as high as the night value (Elmadjian et al. 1957). Lower values for night NA excretion compared to day NA excretion were also found by Serrano et al. (1964) in their normo- and hypertensive subjects, but the day/night difference was not so marked as that reported by Elmadjian et al. (1957). The results obtained by us in controls corroborate those of the latter, the day NA excretion being twice the night excretion. The day/night difference in NA excretion was less pronounced in our hypertensive subjects and practically no such difference was found in our patients with brainstem inl;arction. The high value of night NA excretion in patients with brainstem int'arction, a value very close to that of day NA excretion, also suggests the existence of a sympathetic reactivity disorder in such patients. Apparently they are not able to deactivate their sympathetic system during the night recumbency. It is most probable that the disorders of SNS in patients with brainstem inl;arction are subsequent to the vascular accident. On the other hand, one may hypothesize that the alteration precedes the stroke, at least in some cases, being ascribed to the hypertension, a morbid condition often observed in patients with brainstem int:arction. The assumption is suggested by the study of Frohlich et al. (1967) who reported decreased sympathetic nervous system responsiveness after postural stimulus in hypertensives with severe form of disease. In the present study the inability to deactivate the SNS was found both in hyper- and normotensive patients with brainstem infarction; moreover, our hypertensive subjects without stroke responded normally to head down tilting. Such results favour the view that the abnormality is secondary to brainstem accident rather than being linked with hypertension. It should be mentioned that our hypertensive subjects displayed a benign form of disease with moderate lesions of retinal vessels. It is possible that patients with a more severe form of hypertension are unable to deactivate their SNS, but this has not been investigated. Finally, another problem requiring special comments is that of pathophysiologic signification of the abnormality observed in patients with brainstem infarction. Gauer and Thron (1965) consider that in the supine position, which is associated with an increase in thoracopulmonary blood volume, the effort of the cardiovascular system is higher than when upright. SNS deactivation must play an important part in the body adaptation to recumbency as the depression of sympathetic tonus will increase the blood flow in skeletal muscle by the dilatation of resistance vessels, precapillary sphincters and capacitance vessels (Mellander 1978). The blood will be diverted from the central to the peripheral vascular bed. Moreover, by decreasing the pre/postcapillary resistance ratio, sympathetic deactivation will result in an augmentation of transcapillary fluid filtration (Oberg 1963), a phenomenon decreasing the circulatory blood volume. The patients with brainstem infarction were not able to deactivate their SNS during recumbency or head down tilting. In fact in many of them an activation of SNS occurred during this postural challenge stimulating the baroreceptors in the high and low pressure systems. The activation of SNS produced by the supine position may have as a hemodynamic component vasoconstriction instead of vasodilatation of the muscular vascular bed,
234
an alteration which can generate an increase in central blood volume and subsequently, in cardiac output. If the autoregulation of cerebral circulation is intact this systemic change may remain without consequence on cerebral blood flow. If autoregulation is impaired, and this seems to be so in patients with brainstem vascular disorders (Naritomi et al. 1979), then the supine increase of thoracopulmonar circulation may bring about excessive filling of the cerebral vascular bed. By capillary overdistension, plasma ultrafiltration and nerve cell oedema the supine overfilling of the cerebral circulation might aggravate the clinical picture in hypertensive patients with brainstem infarction. REFERENCES Aminoff, M. J. and C. S. Wilcox (1971) Assessment of autonomic function in patients with a parkinsonian syndrome, Brit. reed. J., IV: 80-84. Elmadjian, F., M.J. Hope and E.T. Lamson (1957) Excretion of epinephrine and norepinephrine in various emotional states, J. clin. EndocrinoL, 17: 608-620. Frohlich, E. D., R.C. Tarazi, M. Ulrych, H.P. Dustan and I.H. Page (1967) Tilt test for investigating a neural component in hypertension --- Its correlation with clinical characteristics, Circulation, 36: 387-393. Gauer, O.H. and H.L. Thron (1965) Postural changes in the circulation. In: W.F. Hamilton (Ed,), Handbook o f Physiology, Section 2 (Circulation), Vol. III, American Physiological Society, Washington, DC, pp. 2409-2439. Korz, R.F., R. Fischer and C. Behn (1969) Renin-angiotensin System bei stimulierter Hypervol/imie durch Immersion, Klin. Wschr., 47: 1263-1268. Lopes, O.U. and J. Cipollaneto (1973) The effect of hypothalamic lesions on the carotid occlusion reflex, J. Physiol. (Lond.), 232: 37P. McCally, M. and D.E. Graveline (1963) Sympathoadrenal response to water immersion, Aerospace Med., 34: 1007-1011. McCullough, H. (1968) Semi-automated method for the differential determination of plasma catecholamines, J. clin. Path., 21 : 759--763. Mathias, C. J,, H. L. Frankel, N.J. Christensen and J. M. K. Spalding (1976) Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection, Brain, 99: 757-770. Mellander, S. (1978) Influence of control systems and vasoactive agents on resistance, exchange and capacitance functions in the skeletal muscle vascular bed. In: A. M. Chernukh, B.I. Tkatchenko, A. G. B. Kowich and S. Bir6 (Eds.), Regulation o f Capacitance Vessels, Akad6miai Kiad6, Budapest, pp. 593-617. Naritomi, H., F. Sakai and J.S. Meyer (1979) Pathogenesis of transient ischemic attacks within the vertebrobasilar arterial system, Arch. Neurol. (Chic.), 36: 131-138. Oberg, B. (1963) Aspects on the reflex control of capillary filtration transfer between blood and interstitial fluid, Med. Exp., 9: 4%61. Reis, D.J. and M. Cu6nod (1965) Central neural regulation of carotid baroreceptor reflexes in cat, Amer. J. Physiol., 209: 1267- 1279. Roddie, 1. C.. J. T. Shepherd and R. F. Whelan (1957) Reflex changes in vasoconstrictor tone in human skeletal muscle in response to stimulation of receptors in a low-pressure area of the intrathoracic vascular bed, J. Physiol. (Lond.), 139: 369-376. Serrano, E A,, G. Figueroa, M. Torres and A. Ramirez del Angel (1964) Adrenaline, noradrenaline and dopamine excretion in patients with essential hypertension, Amer. J. Cardiol., t 3: 484-488. Stoica, E. and O. Enulescu (1978) Abnormal epinephrine urinary excretion in parkinsonians ..... Correction of the disorder by levodopa administration, J. neurol. Sci., 38: 215-227. Stoica, E. and O. Enulescu (1981) Reactivity disorders of sympathetic nervous system in patients with brainstem infarction, Rev. Roum. M~d. - Neurol. Psychiat., 19: 205-218. Von Euler, U.S. (1966) Twenty years of noradrenaline, Pharmacol. Rev., 18: 29-38. Weiss, G. K. and W.E. Crill (1969) Carotid sinus nerve - - Primary afferent depolarization evoked by hypothalamic stimulation, Brain Res. , 16: 269-272. Zehr, J.E., J.A. Johnson and W.W. Moore (1969) Left atrial pressure, plasma osmolality and ADH levels, Amer. J. Physiol., 217: 1672-1680. Ziegler, M.G., R. Lake and 1. J. Kopin (1977) The sympathetic nervous system defect in primary orthostatic hypotension, N. Engl. J. Med., 296: 293-297.
223
Elsevier Biomedical Press
INABILITY TO DEACTIVATE SYMPATHETIC NERVOUS SYSTEM IN BRAINSTEM INFARCT PATIENTS
EMILIAN STOICA and OLIMPIA ENULESCU
Institute oi' Neuroh~Kv and Ps)'ehiat13'. Bucharest (Romania) (Received 21 April, 1982) (Revised, received 26 July, 1982) (Accepted 4 August, 1982)
SUMMARY
Catecholamine urinary excretion under basal conditions and after head down tilting (4 °) was studied in normo- and hypertensive controls and in patients with hemisphere and brainstem infarction, respectively. Both the normo- and hypertensive controls and patients with hemisphere infarction displayed a conspicuous decrease (about 400,,) in noradrenaline (NA) urinary excretion after head down tilting. In contrast the patients with brainstem infarction increased NA urinary excretion after the manoeuvre, suggesting activation instead of deactivation of the sympathetic nervous system (SNS). In normo- and hypertensive controls the values of night NA excretion were lower than those of day NA excretion, whereas in brainstem infarct patients the night NA excretion was close to the day NA excretion. This finding also supports the view that the brainstem infarct patients are not able to deactivate their SNS during night recumbency. The SNS reactivity disorder of such patients if associated with impairment of autoregulation of cerebral circulation might generate an abnormal increase in cerebral circulation during night recumbency.
INTRODUCTION
Although the sympathetic outflow stems from the intermedio-lateral column of the thoraco-lumbar spinal cord, the higher structures of the CNS seem to play
Reprint requests to Dr. Emilian Stoica, Institute of Neurology and Psychiatry, Sos. Berceni 10-12, C.P.61-80, R-75622 Bucharest, Romania. 0022-510X/83/0000-0000/$03.00 c,c) 1983 Elsevier Biomedical Press
224
an important part in the modulation of sympathetic activity. Thus, it has been reported that patients with cervical spinal cord transection have particularly low values of noradrenaline (NA) plasma concentration and display an enhanced pressor response to the infusion of this mediator (Mathias et al. 1976). An overreactivity to NA infusion was also noticed in parkinsonian patients, which, together with their low blood pressure values, were ascribed to reduced sympathetic tonus due to lesions of the basal ganglia or brainstem structures (Aminoff and Wilcox 1971). A deficit of sympathetic nervous system (SNS) was reported in patients with orthostatic hypotension in whom the cerebellar and extrapyramidal signs and the cranial nerve defects indicated that the major lesions were located in the brainstem (Ziegler et al. 1977). In such patients NA plasma levels failed to increase normally after standing or exercising. Taking into consideration the above clinical data it seemed reasonable to assume that a reactivity disorder of SNS may also exist in patients with ischemic lesions of brainstem structures. The hypothesis was partly checked in one of our previous works showing that, unlike control subjects, brainstem infarction patients failed to increase their NA urinary excretion after head up tilting at 8 ° (Stoica and Enulescu 1981). As a continuation of our investigations we were laced with the problem of whether SNS reactivity disorders are not more complex in patients with brainstem infarction, involving also the SNS capacity to reduce its activity under certain conditions. It has been shown that blood shifting to the thoracic vascular bed by passively raising the legs of a recumbent subject brings about a dilatation of the forearm vessels (Roddie et al. 1957). The alteration seems to be a consequence of SNS deactivation resulting in a release of vasoconstrictor tone in muscle vessels. Body immersion in water, producing an increase in atrial pressure due to increased thoracic blood volume (Korz et al. 1969), results in a depression in NA urinary excretion (McCally and Graveline 1963). In the present study we investigated the effect of head down tilting on catecholamine (CA) urinary excretion. The investigation was made in patients with brainstem infarction and patients with hemisphere infarction as well as in normoand hypertensive controls. According to the above-quoted data such a manoeuvre, increasing the central blood volume and then stimulating the baroreceptors in high and low pressure systems, should result in a depression of sympathetic tonus, expressed by a decrement of NA urinary excretion. In some patients with brainstem infarction and in some normo- and hypertensive controls the day and night CA urinary excretion were also determined. Normally a depression in NA urinary excretion must occur during night recumbency (Elmadjian et al. 1957; Serrano et al. 1964); the absence of this alteration and of a depressed NA excretion alter head down tilting in patients with brainstem infarction would point to the lack of SNS deactivation.
225 MATERIALS AND METHODS The investigations were made in the lbllowing categories of subjects who were all hospitalized: (a) 19 patients with lumbar disc disease and with normal blood pressure (mean age 56.7 years). (b) 21 patients with uncomplicated essential hypertension (mean age 60.7 years). In almost all of them history showed hypertension in other family members. Blood urea and urine analysis were normal in all patients. The ocular fundus examination showed spastic retinal arteries with an exaggerated arterial reflex in all and in many the presence of Salus Gunn's sign, but no other more severe alterations (i.e. hemorrhage, exudative lesions, papilloedema). (c) 12 patients with hemisphere infarction (mean age 55.3 years), 8 of them being hypertensive. In all patients the diagnosis was based on clinical findings, CSF analysis (colourless fluid, without erythrocytes in the sediment) and, in 8 cases, on carotid angiography which showed occlusion of the internal carotid or middle cerebral artery. The infarction was probably cortical in most of the patients, 10 of them displaying dysphasia. The investigation was made within the first month alter stroke in 5 patients, and after a longer interval in the remaining 7. (d) 31 patients with brainstem infarction (mean age 57.8 years); 19 of them were hypertensive and 12 normotensive. Diagnosis was based on clinical data (neurologic picture with sudden onset characterized by cranial nerve nuclei dysfunction, cerebellar or/and bilateral pyramidal signs). In all patients lumbar puncture showed a colourless fluid without erythrocytes in the sediment. According to the clinical picture the infarction affected the superior part of the brainstem in 20 patients and the bulbo-pontine region in the remaining 11. The tests were made within the first month after stroke in 18 patients, and later in the remaining 13. In patients with cerebral infarction the medication consisted in dipyridamole, xanthinol nicotinate, papaverine and vitamins. In hypertensive patients the medication included antihypertensive drugs (diuretics and reserpine 0.5 mg daily). The hypertensive controls received only the antihypertensive medication. The normotensive subjects with lumbar disc disease received analgesics and muscle relaxing drugs. In patients and controls the medication was withdrawn 2 days before CA determination. Their diet was free of CA tbr 3 days before investigation. The investigation followed this schedule: At 7 a.m. the lasting subject emptied his bladder, then drank 200 ml of water and lay in bed until 9 a.m. The urine collected at the end of this period was measured and 25 ml were transferred in a bottle containing 1 ml of 1"~i,sodium metabisulfite and 1 ml of 4 N perchloric acid. The bottle was then stored at - 2 0 °C until required for analysis of CA which was performed within the first week alter collection. In this urine sample the basal urinary excretion of CA was assayed. At 9 a.m. blood pressure and heart rate were measured, the subject being in the supine position. Then, the subject was head down tilted to an angle of 4 °, by changing the position of the bed. The tilting down of the subject was maintained for 10 min, blood
226
pressure and heart rate were measured during tilting down (in min 3 and 10). The bed was restored to the horizontal position and blood pressure and heart rate were again measured 2 min after cessation of the manoeuvre. The subject remained in bed until ll a.m. when the urine was collected again and treated in the same manner as shown before. In this sample of urine the CA excretion alter head down tilting was determined. In brainstem infarct patients and control subjects in whom the day and night CA urinary excretion was measured the urine was collected from 7 a.m. to 7 p.m. for the day CA excretion, and from 7 p.m. to 7 a.m. for the night CA excretion. As the "basilar" patients displayed no motor deficit it may be admitted that their daily motor activity was similar to that of control subjects. Measurement of CA urinary excretion was made with McCullough's (1968) method as modified by us (Stoica and Enulescu 1978). RESULTS
CA urinary excretion after head down tilting In most of the control subjects both normo- and hypertensive the slight tilting down of the body (4 °) for a short interval of time (10 rain) induced a conspicuous decrease in N A urinary excretion (Figs. 1A and B). On average the reduction in N A excretion was 3 8 ~ in normotensives and 3 6 ~ in hypertensives, being highly significant in both categories (Table 1). So far as the medication of hypertensive A eg/h
D
B
~,~i h
pg/h
100
/ 2t
t.00
0~, 060 /
04
//
o 2o aO
/
,oo
o.~
/
/
o.o -0~
-0.~ O~
t~ ]
120
120
o4o
-R20
0.40
-040
0.60
°.6°i O~
0.~0t
-080~
=1
tOG 120
120
,ooi
- 120
NAB
NAH~
12O
f
NAB
t
NAHD
NAB
NAKD
Fig. 1. Individual variations in noradrenaline (NA) urinary excretion after head down tilting (4 °) in normotensive controls (A), hypertensive controls (B), patients with hemisphere infarction (C) and patients with brainstem infarction (D). Ordinate: values of NA urinary excretion expressed in #g/h. NAHD: alterations (increases or decreases) in NA urinary excretion after head down as compared to the basal value of NA (NAB) taken as 0.
227 TABL E 1 I N F L U E N C E OF H E A D D O W N (HD) T I L T I N G (4 °) ON N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN V A R I O U S C A T E G O R I E S OF SUBJECTS
Investigated group
Urine volume (ml/h) Before HD
N A urinary excretion (/1g/h)
A urinary excretion (#g/h)
Before HD
After HD
Difference
Before HD
After HD
Difference
After HD
Difference
Normotensive controls (N = 19) MV 128.0 142.7 SE 16.1 19.7 t P
14.7 13.0 1.13 >0.05
1.40 0.15
0.87 0.10
-0.53 0.14 3.79 <0.005
0.30 0.05
0.29 0.02
-0.01 0.05 0.20 >0.05
Hypertensive controls (N = 21) MV 145.0 147.7 SE 14.9 13.7 t P
2.7 10.4 0.26 >0.05
1.99 11.17
1.28 0.13
-0.71 0.15 4.73 <0.001
0.29 0.05
0.43 0.05
0.14 0.04 3.50 <0.005
1.66 0.22
1.08 0.20
-0.58 0.19 3.05 <0.02
0.26 0.07
0.41 0.06
0.15 0.08 1.86 >0.05
1.49 0.10
1.71 0.12
0.22 0.10 2.20 <0.05
0.27 0.03
0.27 0.04
0.0 0.05 0.0 >0.05
Patients with hemisphere infarction (N = 12) MV 91.2 92.9 1.7 SE 20.2 13.3 12.1 t 0.14 P >0.05 Patients with brainstem infarction (N = 3l) MV 101.8 112.8 ll.0 SE 15.2 13.4 12.4 t 0.89 P >0.05
MV = mean values, SE = standard error.
controls included reserpine the similarity of NA decrement in normo- and hypertensive controls suggests that reserpine medication, discontinued 2 days before testing, did not significantly influence the N A response to head down tilting. The patients with hemisphere infarction reacted to head down tilting in the same way as the controls, i.e. by a significant decrease in NA urinary excretion (Fig. 1C). In contrast with controls and patients with hemisphere infarction, the patients with brainstem infarction responded to head down tilting by an increase in NA urinary excretion (Fig. 1D, Table 1). The abnormal response to head down tilting in patients with brainstem infarction was noticed both in those investigated within the first month after stroke and in those studied later (Table 2). The blood pressure values of such patients seem to be not involved in the lack of a proper response either, as the disorder in NA excretion after head down tilting was found in brainstem infarction patients with hypertension as well as in those with normotension (Table 3). Finally, neither
228 TABLE 2 I N F L U E N C E OF H E A D D O W N (HD) T I L T I N G (4 °) ON N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN P A T I E N T S W I T H B R A I N S T E M I N F A R C T I O N IN T E R M S OF T H E I N V E S T I G A T I O N P E R I O D Patients with brainstem infarction
Urine volume NA urinary excretion A urinary excretion (ml/h) (#g/h) (#g/h) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Before After DifferBefore After DifferBefore After DifferHD HD ence HD HD ence HD HD ence
Investigated within the first m o n t h after stroke (N = 18) MV 75,0 106.4 31.4 1.38 SE 12.6 18.4 10.8 0.14 t 2.91 P <0.01 Investigated later ( N = 13) MV 138.9 SE 29,4 t P
121.5 19.7
- 17.4 24.0 0.73 >0.05
1.64 0.15
1.61 0.14
0.23 0.13 1.77 >0.05
0.25 0.04
0.35 0.05
0.10 0.05 2.00 >0.05
1.85 0.21
0.21 0.15 1.40 >0.05
0.29 0.06
0.16 0.04
-0.13 0.07 1.86 >0.05
TABLE 3 I N F L U E N C E O F H E A D D O W N (HD) T I L T I N G (4 °) O N N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN P A T I E N T S W I T H B R A I N S T E M I N F A R C T I O N IN TERMS OF BLOOD PRESSURE VALUES Patients with brainstem infarction
Urine volume (ml/h) Before HD
Normotensive (N = 12) MV 66.6 SE ll.6 t P Hypertensive (N = 19) MV 122.8 SE 22.6 t
P
N A urinary excretion (#g/h)
A urinary excretion (#g/h) Before HD
After HD
Difference
After HD
Difference
Before HD
After HD
Difference
95.0 19.1
26.4 9.9 2.67 <0.05
1.47 0.15
1.65 0.18
0.18 0.15 1.20 >0.05
0.26 0.06
0.31 0.06
0.05 0.07 0.71 >0.05
124.0 18.1
1.2 19,2 0.06 >0.05
1.51 0.14
1.75 0.17
0.24 0.13 1.85 >0.05
0.28 0.04
0.24 0.05
-0.04 0.06 0,67 >0.05
TABLE 4 I N F L U E N C E OF H E A D D O W N (HD) T I L T I N G (4 °) ON N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y E X C R E T I O N IN PATIENTS W I T H BRAINSTEM I N F A R C T I O N IN TERMS OF LESION LOCATION
Patients with brainstem infarction
Urine volume (ml/h) Before HD
Upper brainstem (N - 20) MV 82.2 SE 13.3 t P Lower brainstem (N - 11) 137.4 SE 33.8 I P
NA urinary excretion (/~g/h)
A urinary excretion (/lg/h)
Before HD
After HD
Difference
Before HD
After HD
Difference
After HD
Differrence
104.9 14.1
22.7 11.9 1.91 >0.05
1.41 0.12
1.55 0.14
0.14 0.10 1.40 >0.05
0.27 0.05
0.26 0.04
-0.01 0.05 0.20 >0.05
127.1 28.3
-10.3 27.3 0.38 >0.05
1.63 0.19
1.99 0.22
0.36 0.20 1.80 >0.05
0.28 0.04
0.29 0.09
0.01 0.09 0.11 >0.05
TABLE 5 I N F L U E N C E OF HEAD D O W N (HD) T I L T I N G (4 °) ON MEAN A R T E R I A L BLOOD PRESSURE IN VARIOUS C A T E G O R I E S OF SUBJECTS
Investigated group
Mean arterial blood pressure (ram Hg) Initial value (IV)
At 3 min
Difference (IV 3 mini
At 10 min
Difference After (IV 10 mini 2 min
Difference (IV after 2 mini
Normotensive controls (N = 19) MV 96.9 96.3 SE 2.0 1.9 t P
-0.6 1.7 0.35 >0.05
96.4 2.3
-0.5 2.0 0.25 >0.05
96.5 2.2
-0.4 1.9 0.21 >0.05
Hypertensive controls (N = 21) MV 128.7 127.0 SE 3.5 3.7 t P
- 1.7 1.5 1.13 >0.05
124.4 3.7
-4.3 1.1 3.91 <0.001
127.8 3.4
-0.9 0.9 1.00 >0.05
101.9 3.7
-3.0 2.0 1.50 >0.05
103.9 3.8
- 1.0 1.3 0.77 >0.05
113.2 4.0
-0.9 1.3 0.69 >0.05
112.2 4.2
1.9 1.2 1.58 >0.05
Patients with hemisphere infarction (N = 12) MV 104.9 104.5 -0.4 SE 4.2 3.7 1.8 I 0.22 P >0.05 Patients with brainstern infarction (N = 31) MV 114.1 113.4 -0.7 SE 4.2 3.8 1.3 t 0.54 P >0.05
230 the patients with upper b r a in s te m infarction (mid-brain), n o r those with lower b r ai n s t em infarction ( b u l b o - p o n t i n e ) displayed a r e d u c t i o n in N A excretion after head d o w n tilting, which suggests no relation between the i n a d e q u a t e C A response seen in such patients and the site o f b rai n st em vascular lesion (Table 4). Th e m a n o e u v r e r e m a i n e d practically w i t h o u t influence on b l o o d pressure an d heart rate in all categories o f subjects except h y p e r t e n s i v e c o n t r o l s in w h o m a small but significant r e d u c t i o n in m e a n arterial b l o o d pressure an d heart rate was f o u n d d u r i n g the m a n o e u v r e (Tables 5 an d 6).
Day-night CA urinary excretion N o r m o t e n s i v e c o n t r o l s excreted higher a m o u n t s o f N A by d ay than by night, the m e a n v a lu e for day N A e x c r e ti o n being the d o u b l e o f the night m e a n value. T h e m e a n difference between those two values was highly significant (Table 7). In h y p e r t e n s i v e c o n t r o l s the s a m e p h e n o m e n o n was observed, i.e. the day N A excretion surpassed significantly the night N A excretion. In c o n t r a s t with c o n t r o l
TABLE 6 INFLUENCE OF HEAD DOWN (HD) TILTING (4°) ON HEART RATE IN VARIOUS CATEGORIES OF SUBJECTS Investigated group
Heart rate (beats/min) ............................................... Initial At 3 min Difference At 10 min Difference After value (IV-3 min) (IV-10 min). 2 min (IV)
Difference (IV-after 2 min)
Normotensive controls (N = 19) MV 65.5 63.5 SE 2.3 2.1 t P
-2.0 1.0 2.00 >0.05
63.2 1.9
-2.3 1.2 1,92 >0.05
64.2 2.1
- 1.3 0.9 1.44 >0.05
Hypertensive controls (N = 21) MV 67.2 66.4 SE 1.9 2.0 t P
- 0.8 0.6 1.33 >0.05
65.7 2.0
- 1.5 0.5 3.00 <0.01
66.2 1.8
- 1.0 0.7 1.43 >0.05
65.8 2.4
0.0 0.7 0.0 >0.05
66.2 2.1
0.4 0.8 0.50 >0.05
66.6 1.6
- 0.2 0.5 0.40 >0.05
67.2 1.6
0.4 0.5 0.80 >0.05
Patients with hemisphere infarction (N = 12) MV 65.8 65.3 -0.5 SE 2.1 2.3 0.7 t 0.71 P >0.05 Patients with brainstem infarction (N = 31) MV 66.8 66.8 0.0 SE 1.7 1.7 0.5 t 0.0 P >0.05
231 TABLE 7 DAY A N D N I G H T N O R A D R E N A L I N E (NA) A N D A D R E N A L I N E (A) U R I N A R Y EXCRETION IN VARIOUS C A T E G O R I E S OF SUBJECTS
Investigated
Urine volume
NA urinary excretion
A urinary excretion
group
(ml/12 h)
(/~g/12 h)
(#g/12 h)
Day
Night
Difference
Day
Night
Differ-
Day
Night
-171.3 116.7 1.47 >(/.05
22.23 1.81
11.36 1.19
10,87 1.16 9,35 <0.001
3.41 0.67
2.16 0.43
1.25 0.46 2.73 <0.02
52.2 80.5 0.65 >0.05
24.15 2.98
16.61 2.07
-7,54 2.79 2.70 <0.02
2.45 0.72
1.88 0.36
-0.57 0.48 1.18 >II.05
20.02 1.89
18.99 1.99
- 1.03 2.69 0.38 >0.05
2.74 0.32
1.92 0.34
-0.82 0.39 2.09 >0.05
Differ-
ence
ence
Normotensive controls (N = 12) MV SE t P
762.1 82.3
590.8 69.8
Hypertensive controls (N = 14) MV SE t P
688.2 51.7
740.4 93.5
Patients with brainstem infarction (N = 161 MV SE ! P
695.3 56.2
761.9 42.7
66.6 57.2 1.17 >0.05
subjects many patients with brainstem infarction excreted similar amounts of NA by day and by night and some of them excreted more NA by night than by day. The mean value for day N A excretion was close to the mean value for night NA excretion (Table 7). DISCUSSION
Admittedly most of the NA excreted in urine is extra-adrenal in origin, being released from sympathetic nerve endings (Elmadjian et al. 1957; von Euler 19661. Therefore, one may maintain that the marked reduction in NA excretion observed in controls and patients with hemisphere infarction after head down tilting reflects a depression in SNS tonus. Noteworthy is the long lasting effect of this postural change: a 10-min period of head down tilting was enough to depres NA excretion for the next 2 hours. The reduction in sympathetic activity found in controls and patients with hemisphere infarction after head down tilting seems to be due to the stimulation of baroreceptors in the high and low pressure systems. Nonetheless it is hard to specify clearly the part played by the arterial or venous receptors in the postural sympathetic depression observed in our model. Roddie et al. (1957) have reported forearm muscle vasodilatation induced by passively raising the legs of recumbent
232 subjects. The manoeuvre was accompanied by increases in central venous pressure and amplitude of venous pulsation. Absence of correlation between forearm vasodilatation and the mean arterial or pulse pressure suggested that the dilatation was not a consequence o f arterial baroreceptors stimulation. The authors therefore ascribed the peripheral vasodilatation to stimulation of receptors in low pressure area of the intrathoracic vascular bed. The above data, obtained in a clinical model relatively similar to ours, support the idea that the venous baroreceptors are playing the major part in sympathetic deactivation here reported. It seems all the more unlikely that stimulation of arterial baroreceptors is involved in the production of this phenomenon as initially the head down tilting at 4 ° had no significant effects on mean arterial blood pressure (Table 5). A reduction in heart rate and in mean arterial blood pressure were noted in our hypertensive controls 10 rain after head down tilting, but in all probability the alteration was secondary to sympathetic tonus depression. Most of our patients with brainstem infarction displayed an abnormal sympathetic response to head down tilting, which might be due to the disorder of baroreceptor apparatus itself. The supposition seems unlikely as in most patients a reverse response and not a lack of response was found. This paradoxical reaction is rather suggestive of an impairment of central mechanisms, an interpretation supported by a set of experimental investigations. It was demonstrated that midpontine section of the brainstem produced in the cat the disappearance ot" the pressor response to carotid occlusion and appearance of a paradoxical pressor response to sinus stretch (Reis and Cu6nod 1965). In rats with experimental lesions which disconnected the anterior hypothalamus from the middle hypothalamus, carotid occlusion made shortly after the lesion resulted in a fall of blood pressure instead of an increase (Lopes and Cipollaneto 1973). The modulating effect of the hypothalamus on the input from baroreceptors was also reported by Weiss and Crill (1969)who showed primary afferent depolarization in the carotid sinus nerve of the cat by stimulating the posterior hypothalamus. According to Zehr et al. (1969) the hypothalamus is also involved in the humoral reflex adjustments operated through baroreceptors in the low pressure system; they consider that the principal input into the supraoptic and paraventricular nuclei controlling A D H secretion arises from the left atrial baroreceptors. The abnormal response of SNS found in patients with brainstem infarction is then more probably due to the disorder of central mechanisms controlling the sympathetic activity. Admittedly large areas of CNS exert a control on SNS (Ziegler et al. 1977). However, as the inability to deactivate properly the SNS by head down tilting has been seen in patients with brainstem vascular lesions but not in those with hemisphere vascular lesions, it is conceivable that the central mechanisms involved in postural sympathetic deactivation are located in the brainstem and not in more rostrally situated areas. On the other hand the central mechanism controlling the postural sympathetic deactivation seems to be widespread within the brainstem as the sympathetic reactivity disorder was observed both in patients with upper and lower brainstem lesions.
233 It has been reported that in normals the day value for NA excretion is twice as high as the night value (Elmadjian et al. 1957). Lower values for night NA excretion compared to day NA excretion were also found by Serrano et al. (1964) in their normo- and hypertensive subjects, but the day/night difference was not so marked as that reported by Elmadjian et al. (1957). The results obtained by us in controls corroborate those of the latter, the day NA excretion being twice the night excretion. The day/night difference in NA excretion was less pronounced in our hypertensive subjects and practically no such difference was found in our patients with brainstem inl;arction. The high value of night NA excretion in patients with brainstem int'arction, a value very close to that of day NA excretion, also suggests the existence of a sympathetic reactivity disorder in such patients. Apparently they are not able to deactivate their sympathetic system during the night recumbency. It is most probable that the disorders of SNS in patients with brainstem inl;arction are subsequent to the vascular accident. On the other hand, one may hypothesize that the alteration precedes the stroke, at least in some cases, being ascribed to the hypertension, a morbid condition often observed in patients with brainstem int:arction. The assumption is suggested by the study of Frohlich et al. (1967) who reported decreased sympathetic nervous system responsiveness after postural stimulus in hypertensives with severe form of disease. In the present study the inability to deactivate the SNS was found both in hyper- and normotensive patients with brainstem infarction; moreover, our hypertensive subjects without stroke responded normally to head down tilting. Such results favour the view that the abnormality is secondary to brainstem accident rather than being linked with hypertension. It should be mentioned that our hypertensive subjects displayed a benign form of disease with moderate lesions of retinal vessels. It is possible that patients with a more severe form of hypertension are unable to deactivate their SNS, but this has not been investigated. Finally, another problem requiring special comments is that of pathophysiologic signification of the abnormality observed in patients with brainstem infarction. Gauer and Thron (1965) consider that in the supine position, which is associated with an increase in thoracopulmonary blood volume, the effort of the cardiovascular system is higher than when upright. SNS deactivation must play an important part in the body adaptation to recumbency as the depression of sympathetic tonus will increase the blood flow in skeletal muscle by the dilatation of resistance vessels, precapillary sphincters and capacitance vessels (Mellander 1978). The blood will be diverted from the central to the peripheral vascular bed. Moreover, by decreasing the pre/postcapillary resistance ratio, sympathetic deactivation will result in an augmentation of transcapillary fluid filtration (Oberg 1963), a phenomenon decreasing the circulatory blood volume. The patients with brainstem infarction were not able to deactivate their SNS during recumbency or head down tilting. In fact in many of them an activation of SNS occurred during this postural challenge stimulating the baroreceptors in the high and low pressure systems. The activation of SNS produced by the supine position may have as a hemodynamic component vasoconstriction instead of vasodilatation of the muscular vascular bed,
234
an alteration which can generate an increase in central blood volume and subsequently, in cardiac output. If the autoregulation of cerebral circulation is intact this systemic change may remain without consequence on cerebral blood flow. If autoregulation is impaired, and this seems to be so in patients with brainstem vascular disorders (Naritomi et al. 1979), then the supine increase of thoracopulmonar circulation may bring about excessive filling of the cerebral vascular bed. By capillary overdistension, plasma ultrafiltration and nerve cell oedema the supine overfilling of the cerebral circulation might aggravate the clinical picture in hypertensive patients with brainstem infarction. REFERENCES Aminoff, M. J. and C. S. Wilcox (1971) Assessment of autonomic function in patients with a parkinsonian syndrome, Brit. reed. J., IV: 80-84. Elmadjian, F., M.J. Hope and E.T. Lamson (1957) Excretion of epinephrine and norepinephrine in various emotional states, J. clin. EndocrinoL, 17: 608-620. Frohlich, E. D., R.C. Tarazi, M. Ulrych, H.P. Dustan and I.H. Page (1967) Tilt test for investigating a neural component in hypertension --- Its correlation with clinical characteristics, Circulation, 36: 387-393. Gauer, O.H. and H.L. Thron (1965) Postural changes in the circulation. In: W.F. Hamilton (Ed,), Handbook o f Physiology, Section 2 (Circulation), Vol. III, American Physiological Society, Washington, DC, pp. 2409-2439. Korz, R.F., R. Fischer and C. Behn (1969) Renin-angiotensin System bei stimulierter Hypervol/imie durch Immersion, Klin. Wschr., 47: 1263-1268. Lopes, O.U. and J. Cipollaneto (1973) The effect of hypothalamic lesions on the carotid occlusion reflex, J. Physiol. (Lond.), 232: 37P. McCally, M. and D.E. Graveline (1963) Sympathoadrenal response to water immersion, Aerospace Med., 34: 1007-1011. McCullough, H. (1968) Semi-automated method for the differential determination of plasma catecholamines, J. clin. Path., 21 : 759--763. Mathias, C. J,, H. L. Frankel, N.J. Christensen and J. M. K. Spalding (1976) Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection, Brain, 99: 757-770. Mellander, S. (1978) Influence of control systems and vasoactive agents on resistance, exchange and capacitance functions in the skeletal muscle vascular bed. In: A. M. Chernukh, B.I. Tkatchenko, A. G. B. Kowich and S. Bir6 (Eds.), Regulation o f Capacitance Vessels, Akad6miai Kiad6, Budapest, pp. 593-617. Naritomi, H., F. Sakai and J.S. Meyer (1979) Pathogenesis of transient ischemic attacks within the vertebrobasilar arterial system, Arch. Neurol. (Chic.), 36: 131-138. Oberg, B. (1963) Aspects on the reflex control of capillary filtration transfer between blood and interstitial fluid, Med. Exp., 9: 4%61. Reis, D.J. and M. Cu6nod (1965) Central neural regulation of carotid baroreceptor reflexes in cat, Amer. J. Physiol., 209: 1267- 1279. Roddie, 1. C.. J. T. Shepherd and R. F. Whelan (1957) Reflex changes in vasoconstrictor tone in human skeletal muscle in response to stimulation of receptors in a low-pressure area of the intrathoracic vascular bed, J. Physiol. (Lond.), 139: 369-376. Serrano, E A,, G. Figueroa, M. Torres and A. Ramirez del Angel (1964) Adrenaline, noradrenaline and dopamine excretion in patients with essential hypertension, Amer. J. Cardiol., t 3: 484-488. Stoica, E. and O. Enulescu (1978) Abnormal epinephrine urinary excretion in parkinsonians ..... Correction of the disorder by levodopa administration, J. neurol. Sci., 38: 215-227. Stoica, E. and O. Enulescu (1981) Reactivity disorders of sympathetic nervous system in patients with brainstem infarction, Rev. Roum. M~d. - Neurol. Psychiat., 19: 205-218. Von Euler, U.S. (1966) Twenty years of noradrenaline, Pharmacol. Rev., 18: 29-38. Weiss, G. K. and W.E. Crill (1969) Carotid sinus nerve - - Primary afferent depolarization evoked by hypothalamic stimulation, Brain Res. , 16: 269-272. Zehr, J.E., J.A. Johnson and W.W. Moore (1969) Left atrial pressure, plasma osmolality and ADH levels, Amer. J. Physiol., 217: 1672-1680. Ziegler, M.G., R. Lake and 1. J. Kopin (1977) The sympathetic nervous system defect in primary orthostatic hypotension, N. Engl. J. Med., 296: 293-297.