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Idiopathic orthostatic hypotension: Circulatory dynamics in chronic autonomic insufficiency
Idiopathic Orthostatic Hypotension: Circulatory Dynamics in Chronic Autonomic Insufficiency
M. MOHSEN IBRAHIM, MD* ROBERT C. TARAZf, MD, FACC HARRIET P. DUSTAN, MD, FACC EMMANUEL L. BRAVO, MD Cleveland, Ohio
From the Research Division, The Cleveland Clinic Foundation and The Cleveland Clinic Educational Foundation, Cleveland, Ohio. This study was supported in part by Grants 70 960 from the American Heart Association, New York, N. Y. and HL 6635 from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Manuscript accepted January 2, 1974. *Present address: Lecturer in Cardiology, Facufty of Medicine, University of Cairo, Cairo,
Idiopathic orthostatic hypotension offers a unique opportunity to study the effect of chronic autonomic insufficiency on circulatory dynamics in man. Evidence of abnormal cardiac performance was found in eight patients with idiopathic orthostatic hypotension secondary to efferent adrenergic dysfunction. Compared with normal subjects these patients had a lower cardiac output (2.37 liters/min per m*, P
Idiopathic orthostatic hypotension is a relatively rare disease that runs a progressive but fluctuant course leading to disability because of severe postural symptoms. The clinical features are well defined and have been described in detail.1-4 Various tests of autonomic function have suggested impairment in different portions of the baroceptor reflex arc in different patients. 3-5 Failure of reflex arteriolar constriction and defective venous return have been demonstrated to be the hemodynamic end result responsible for the reduction in arterial pressure with upright posture. s-g However, except for isolated case reports dealing mainly with postural adjustments,s,g there has been no reported investigation of blood volume or supine hemodynamics in this disease. Since our initial studies suggested alterations in these functions, the question was raised whether impaired cardiac performance might participate in the postural maladjustment in some patients. This report is based on a study of eight patients with idiopathic orthostatic hypotension due to efferent adrenergic dysfunction. Variations in cardiac output both at rest and during head-up tilt were correlated with changes in intravascular and cardiopulmonary volumes to assess cardiac performance in the presence of chronic autonomic insufficiency. Methods
Egypt.
Patients investigated
Address for reprints: Robert C. Tarazi, MD, Research Divisiin, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44106.
(five men and three women) whose ages ranged from
288
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The study included eight patients with idiopathic orthostatic
CARMOLOOY Vofume 34
hypotension
53 to 76 years (median
IDIOPATHIC ORTHOSTATIC
HYPOTENSION-IBRAHIM
ET AL.
TABLE I Summary
Case no. __--___--
of Clinical Data
Age (yr) & Sex
Duration of Symptoms (mo) Anhidrosis
Impotence
Sphincteric Disturbances
1 2 3
54M 68F 68M
7 60 24
+ + +
+ +
+ -
4 5
53F 63F
24 24
-
-
-
6 7 8
76M 62M 62M
2 48 36
+ + +
+ + +
+ -t
-f- = present;
-
+
Neuropsychiatric
Other Findings --.
Symptoms
None Shy-Drager ? Depression; early Parkinsonism Depression Depression; brain stem vascular disease Depression None None
None Renal arterial None
disease
Urinary tract infection Hiatus hernia
Chronic obstructive emphysema Impaired carbohydrate tolerance None
= absent.
62 years). All complained of loss of consciousness associated with a documented decrease in arterial pressure when upright; the fainting spells occurred only on standing, often with dramatic suddenness, and were preceded by symptoms of autonomic dysfunction, such as nausea, pallor or sweating. There was no demonstrable cause for the postural hypotension in any patient; one had abnormal results of a glucose tolerance test on one occasion, but he presented no evidence of somatic peripheral neuropathy. The duration of postural symptoms ranged from 2 months to 5 years (median 24 months); more uniform and quite impressive was the history given by each patient of marked variability, sometimes from day to day, in the frequency and severity of symptoms. In spite of these fluctuations, progressive deterioration occurred in most. The other clinical features of the disease are summarized in Table I; one patient was the subject of a previous case report.10 Impotence preceded the onset of orthostatic hypotension in men; failure to maintain erection was noted first, followed later by complete impotence. Of interest was the 20 year interval by which anhidrosis antedated the postural symptoms in Case 1. A psychiatric depressive illness was diagnosed in four cases; Shy-Drager disease was suggested as a possibility in one. One patient (Case 6) had severe chronic obstructive emphysema and mild respiratory insufficiency. All patients were hospitalized but were encouraged to be as active as possible; neither their activity nor diet was restricted. All medications were discontinued for at least a week before the studies. A careful history ensured that none of them had had vasoactive, antidepressant or sedative medication for at least the preceding 6 months. Brachial arterial pressure was recorded in the hospital four times daily with patients in both the supine and standing positions, and weekly averages were compared with daily fluctuations and with pressures obtained during the hemodynamic studies.
Tests for Autonomic Function and Localization of the Lesion Responses to passive head-up tilt,” and to the Valsalva maneuver12 were used to test the integrity of the baroreflex arc. Stimulation of efferent sympathetic fibers from other routes was investigated by the cold pressor test and stress-
ful mental arithmetic; in addition, a reflex sweat test was performed in four patients. Responsiveness of the vasomotor center was tested by hyperventilation for 15 seconds.1” Phenylephrine (25 and 50 rg intravenously) was given to evaluate receptor responsiveness of arteriolar smooth muscle. To investigate vagal participation in the disease, heart rate responses to intravenously administered atropine (0.03 and 0.04 mg/kg body weight) were compared with those to head-up tilt. All tests were performed with continuous monit,oring of the electrocardiogram and intraarterial pressure.
Hemodynamic Studies Plasma volume was determined in seven patients with Risaa (1311 or 1251) in the morning after an overnight fast and at least 30 to 45 minutes of supine rest. A 10 minute equilibration period was used and blood volume was calculated from the plasma volume and simultaneously determined corrected hematocrit as described previously.14 Results were expressed in milliliters per centimeter of height to minimize differences due to agel or obesity.14 In calculations of data from both men and women, results were expressed as percent of the expected normal value for our laboratory.i4 Cardiac output was determined by the dye-dilution technique, using indocyanine green dye as previously described in detail.lsJ” Patients were studied without premedication in the morning after an overnight fast. Polyethylene catheters (70 cm long, inner diameter 1.1 mm) were passed percutaneously into the right antecubital vein and brachial artery and advanced at least to the subclavian vein and artery, respectively. In three patients (Cases 1,4 and 7) the two catheters were carefully positioned under fluoroscopic guidance, one at the junction of the superior vena cava and right atrium and the other in the ascending aorta above the aortic valve. Arterial and venous pressures were measured using Statham P23Db transducers, with the zero reference set at the mid-chest level. An electrocardiogram (lead II) was continously recorded throughout each study. Cardiac output, ejection time and derived variables were determined by standard methods.16J7 Cardiopulmonary volume was calculated only in those three patients with carefully positioned central catheters.‘& The
September 1974
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Journal of CARDIOLOGY
Volume 34
289
IDIOPATHIC ORTHOSTATIC
HYPOTENSION-IBRAHIM
ET AL.
VALSALVA
MANEUVER
NORMAL RESPONSE
(15 set)
IDIOPATHIC ORTHOSTATIC
HYPOlTENSlON
140 120 IO0 80
FIGURE 1. Arterial pressure response to a Valsalva maneuver in a normal subject (A) and a patient with idiopathic orthostatic hypotension (B) illustrating the absence of pressure overshoot after release of straining (phase 4).
delay time of the system was determined in each case separately and the cardiopulmonary volume calculated as the product of the corrected mean transit time and blood flow per second.l* Contiol values were derived from results of similar studies of normotensive volunteers, many of which have been previously reported.11J6J7 Standard statistical methodsI were used to calculate averages, standard devia-
tions, standard errors and correlation coefficients as well as the statistical significance of the results. Results are expressed as averages f 1 standard error.
Results Localization of the Defect Interruption of the baroreceptor reflex arc was demonstrated in all eight patients by the absence of diastolic pressure overshoot after a Valsalva maneuver (Fig. 1) and by the inability to maintain arterial pressure in the upright position (Table II). That the afferent and central parts of the reflex arc were intact was shown by the occurrence of cardiac slowing with an increase in blood pressure induced by phenylephrine and by a depressor response to hyperventilation.13 The lesion was therefore localized to the efferent sympathetic system; this finding was also supported by lack of blood pressure response to cold or to stressful mental arithmetic and by the loss of reflex sweating; Two patients (Cases 3 and 8) did respond to cold with an increase in blood pressure but were still thought to have efferent sympathetic dysfunction because of (1) the documented integrity in both the afferent and central parts of the barocepko;;eflex, and (2) the absence of reflex sweating in In all patients,
299
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administered
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The American Journal of CARDIOLOGY
ephrine evoked a pressor response of varying magnitude indicating intact receptor sites in arteriolar smooth muscle. With the increase in blood pressure, heart rate slowed in all by 8 to 14 beats/min, thereby indicating adequate baroceptor sensor and central connections and at least a partially functioning efferent vagal mechanism. Changes in Heart Rate All patients but one had a rapid resting heart rate (average 83 beats/min); the single exception (Case 3) has sinus bradycardia and his findings will be discussed separately. Various degrees of cardiac acceleration developed in all during head-up tilt (Fig. 2); the average increase in heart rate (14 percent) was not different from the normal response (16 percent). Intravenously administered atropine accelerated the heart rate (11 percent) to about the same degree as head-up tilt, but significantly less than the normal 49 percent reported by Heimbach and Crout2’l or the 54 percent determined in hypertensive patients in our laboratory (Tarazi et al, unpublished observations). Plasma and Total Blood Volumes All but one of the eight patients had contracted plasma (90.4 percent f 3.0, standard error) and total blood volumes (89.9. percent f 3.0) (Table III). The reduction in total blood volume correlated significantly with the severity of hypotension on head-up tilt (r = -0.805, P <0.05); this correlation, however, did not include Patient 3 referred to earlier (Fig. 3). Intravascular volume also appeared to be correlated
Volume 34
IDIOPATHIC ORTHOSTATIC
HYPOTENSION-IBRAHIM
ET AL.
TABLE II Tests of Autonomic
Function Case no. ____
Changes in systolic blood pressure Phenylephrine, intravenously
1
2
+20 +63 0 -4 -22 0 Impaired
+42
3
4
5
6
7
8
+31 ... +8 0
...
...
+22 +4
+10 0
+30 i-57 0 -15 -16 0 Impaired
$40 +44 +30 -20 -30 0 Impaired
:::
...
...
0 Impaired
...
(mm Hg)
25 pg 50 Icg Cold pressor test Mental arithmetic Hyperventilation Valsalva (overshoot) Reflex sweat test
... +46
... 0 0 -55 0
+30
...
0
+4
0
...
0
0
...
...
l30-
.
s 5
12O-
FfWRE 2 (left). Response rate to head-up tilt and to nously admlnistereft atropine patients, showing remarkable ity in degree of response stimuli.
of heart intravein seven simllarto both
z f > 2
I IO-
t
IOO-
. .
.
5
FfGURE 3 (right). Reduction of mean arterial pressure (MAP) with head-up tilt. (percent.of supine value) correlat* significantly with total intravascular volurns (TEV) (percent of normal) in seven patients with idiopathic orthostatic hypotension. Patient 3 (x) was excluded from’statlstical analysis because he had ?o postural hypbtension at time of study.
z i t
sox
r = -0.805 p > 0.05
I
80-
I
70
+ II% ATROPINE
sb
+ 14%
I
,
SUPINE
TILT
TBV
110 PERCENT
OF
NORMAL
TABLE Ill Supine Hemodynamics
and Blood Volume Measurements Blood Pressure
Case no. 1 2 3 4 5 6 7 8 Mean SE
BSA (mB)
(mm W (week’s average)
2.05 1.62 2.06 1.64 1.70 1.83 2.04 1.96 1.86 0.07
107175 124182 120177 116/79 125177 132/71 94175 122f 79 118176 4.211.8
BSA = body surface = percent of normaPr; resistance index.
PV
TBV
(ml/cm)
%N
(Wcm)
17.1 13 16.1 14.9 12.6 ... 16.9 19.4
91 83 86 97 82 ... 90 104 90.4 3.0
27.8 20.9 26.1 ?3.4 20.4 ... 24.7 32 ... ...
... ...
%N 90 87 84 98 a5
... 82 103 89.9 3.0
Cl MAP (liters/min (mm Hg) per me) 85 120 98 108 109 109 65 115 101 6.4
2.00 2.94 1.72 2.97 3.34 2.05 1.65 2.29 2.37 0.22
SI
TPR
MRLVE (ml/se4
(ml/m*>
(units)
per n?)
21 34 37 31 46 21 22 29 30 3.1
43 39 57 36 33 53 39 50 44 3.1
87 121 115 112 144 93 75 103 106 7.7
area; Cl = cardiac index; MAP = mean arterial pressure; MRLVE = mean rate of left ventricular ejection; SN PV = plasma volume; SE = standard error; SI = stroke index; TBV = total blood volume; TPR = total peripheral
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Vefums 34
231
N = NORMAL CONTROLS (29) IOH = IDIOPATHIC ORTHOSTATIC
HYPOTENSION
(8)
I
1 = SE
I
FIGURE 4. Lefl. Supine hemodynamic indexes in 29 normal subjects and 8 patients with idiopathic otthostatic hypotension. Cl = cardiac index HR = heart rate; MAP = mean arterial pressure; MRLVE = mean rate of left ventriculai ejection; SI = stroke volume index; TPR = total peripheral resistance. FIGURE 5. Rlaht. Variations in mean arterial pressure (MAP), cardiac index (Cl) and total peripheral resistance (TPR) produced by head-up tilt in patients with idiopathic orthostatic hypotension and nor&al sbbjects.
directly with the average weekly diastolic pressure (r = O-529), hut the correlation was not statistically significant. There was no correlation between blood volume and cardiac output (r = 0.219). Hemodynamic Studies
Supine (Table III; Fig. 4): Cardiac index was lower (2.37 liters/min per m2) than our normal values (P
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contrasted with the rapid heart rate of others. These differences might have been related to the variability in the course of his disease; whereas he had marked postural hypotension when seen initially, his symptoms and hypotension lessened considerably without treatment during his hospital stay. With exclusion of this patient, the change in peripheral resistance with tilt averaged +2.4 percent.
Cardiopulmonary
blood
volume:
(Table
IV):
This volume in three patients averaged 498 f 86 ml/ m2, which was significantly lower (P <0.05) than average for eight normal volunteers (657 ml/m2). As expected, cardiopulmonary blood volume was reduced during head-up tilt both in patients and in normal subjects (341 f 18 and 515 f 18 ml/m2, respectively, P <0.005); stroke index was reduced by 47 percent to 13 ml/m2. However, more significant for this study than changes in absolute values was the correlation between cardiopulmonary blood volume and stroke volume; the two were correlated both in patients (r = 0.937) and in normal subjects (r = 0.873) at a high level of significance despite the small number investigated. This relation, which has been reported also for other conditions,1s,22,23 helped evaluate cardiac function, a low ratio of stroke to cardiopulmonary volume indicating diminished cardiac performance. Patients had a significantly lower ratio (0.050 f 0.004) than normal subjects (0.061 f 0.002, P
Volume 34
IDIOPATHIC ORTHOSTATIC
HYPOTENSION-IBRAHIM
ET AL.
TABLE IV Cardiopulmonary
Blood Volume Measurements
Supine
__~
Tilt -__
Caseno.
CPV
CPVI
CI/CPVI
SI/CPVI
CPV
CPVI
CI/CPVI
SI/CPVI
1 2 7 Mean
815 1089 799 901
454 664 376 498
4.41 4.77 3.31 4.16
0.046 0.047 0.059 0.050
648 708 565 640
316 432 276 341
4.219 3.73 3.31 3.750
0.041 0.0288 0.047 0.039
Cl = cardiac index; CPV = cardiopulmonary blood volume (ml); CPVI = cardiopulmonary face area; A % CPVI = change of CPVI with head-up tilt in percent; SI = stroke index. decrease was associated with a rapid heart rate (P
September
A % CPVI -30 -35 -27 -31
blood volume per square meter body sur-
output. Taylor et al. 27 found that cardiac output did not change after 3 to 4 weeks of almost complete rest in bed. Two important physiologic mechanisms regulating cardiac output could be compromised in patients with idiopathic orthostatic hypotension: venous filling and myocardial contractility. Contraction of total blood volume could contribute to reduction in stroke output by diminished filling of the heart. Our patients had reduced blood and plasma volume (89.9 and 90.4 percent of normal, respectively) and showed a significant correlation (r = -0.805, P <0.05)between intravascular volume and the reduction of mean arterial pressure with head-up tilt (Fig. 3). However, the degree of hypovolemia did not correlate with cardiac output, thus indicating that factors other than contraction of intravascular volume may be involved in the reduction of output. Impaired cardiac performance might be such a factor; favoring this assumption were not only the small stroke volume and very low rate of left ventricular ejection, but also the reduced ratio of stroke output to cardiopulmonary volume. This ratio was shown to be a reliable index of cardiac performances”; increase of cardiac contractility by isoproterenol resulted in a significant rise of this ratio, whereas administration of propran0101led to the opposite effect. Impaired myocardial contractility: Like other investigators,16~18~22we found a close relation between stroke index and cardiopulmonary volume; in this context, an increase in the latter without a corresponding rise in stroke index would imply diminished myocardial performance since it would indicate that more blood is retained in the heart and lungs.s:+ This was the case in patients with idiopathic orthostatic hypotension who had a significantly lower ratio of stroke to cardiopulmonary volume at rest than normal subjects. Further, this ratio was reduced by 33 percent with head-up tilt, whereas it scarcely changed in normal subjects. Diminished venoconstriction2s could explain in part the impressive reduction in cardiopulmonary volume and cardiac output during tilt in patients with idiopathic orthostatic hypotension (36 vs. 13 percent in normal subjects, P
1974
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293
IDIOPATHIC ORTHOSTATIC
HYPOTENSION-IBRAHIM
ET AL.
ated with a proportionate reduction in output and stroke volume in normal subjects so that ratios did not change appreciably. In contrast, among our patients the reduction in stroke volume (47 percent) was much greater than that of cardiopulmonary volume (31 percent). Defective myocardial contractility apparently limited the ability of the heart to compensate for the diminished venous return and thus further exaggerated the reduction of cardiac output.31 This myocardial factor may not necessarily be due to a structural alteration of the muscle but may result from defective sympathetic cardiac innervation.32 Reduced blood volume: The small plasma volume in our patients contrasted with the volume expansion
that occurs in patients receiving adrenergic blocking agents33; the cause of that contraction is not clear. Prolonged immobilization in bed is associated with reduction in plasma volume,34 but none of our patients was confined to bed, either at home or in the hospital. Some patients with idiopathic orthostatic hypotension were found to have low levels of plasma renin activity and urinary aldosterone excretion at rest35*36 that did not rise with sodium depletion.“6 Gill et a1.37 presented some evidence for impaired sodium conservation during guanethidine therapy. However, study of that aspect in our patients (Bravo et al., unpublished ‘observations) did not reveal any impairment in aldosterone response to, or sodium conservation during, a period of low sodium intake.
References 1. Bradbury S, Egglesfon C: Postural hypotension: a report of three cases. Amer Heart J 1:73-86, 1926 2. Verel D: Postural hypotension: the focalization of the lesion. Br Heart J 13:61-67, 1951 3. Wagner HN Jr: Otthostatic hypotension. Bull Johns Hopkins 105:322-359, 1959 4. Lewis HD Jr, Dunn M: Orthostatic hypotension syndrome. A case report. Am Heart J 74:396-401,1967 5. Love DR, Brown JJ, Chinn RH, el al: Plasma renin in idiopathic orthostatic hypotension: differential response in subjects with probable afferent and efferent autonomic failure. Clin Sci 41: 289-299, 1971 6. Stead EA, Ebert RV: Postural hypotension; a disease of sympathetic nervous system. Arch Intern Med 67:546-562, 1941 7. Mac Clean AR, Allen EV: Orthostatic hypotension and orthostatic tachycardii. JAMA 155:2162-2167, 1940 8. Hlckan JB, Pryor WW: Card&c output in postural hypotension. J Clin Invest 30:401-405, 1951 9. Rickefmann AG, Lippschutz EJ, Branjes CF: Hemodynamics of idiopathic orthostatic hypotension. Am J Med 30:26-38, 196 1 10. Shafer WH, Frohllch ED, Wallace TW, et al: fdiopathic orthostatic hypotension: a report of a case. Cleve Clin 0 36:137141, 1969 11. Frohlich ED, Tarazl RC, Ulrych M, et al: Tilt test for investigating a neural component in hypertension. Its correlation with clinical characteristics. Circulation 36:387-393, 1967 EP: Effects of Valsalva’s maneuver on the 12. Sharpey-Schafer normal and falling circulation. Br Med J 1:693-695, 1955 13. Sharpey-Schafer EP, Taylor PJ: Absent circulatory reflexes in diabetic neuritis. Lancet 1:559-562, 1960 14. Tarazl RC, Diwfan HP, Frohlkh ED, et al: Plasma volume and chronic hypertension. Relationship to arterial pressure levels in different hypertensive diseases. Arch Intern Med 125:835-842, 1970 15. Chien S, Nasmi S, Sfmmons RL, et al: Blood volume and age: repeated measurements of normal men after 17 years. J Appl Physiol21:583-588, 1966 16. Ulrych M, Frohllch ED, Tarazl RC, et al: Cardiac output and distribution of blood volume in central and peripheral circulations in hypertensive and normotensive man. Br Heart J 31:570-574, 1969 17. Frohllch ED, Tarazi RC, Dustan HP: Re-examination of the hemodynamics of hypertension. Am J Med Sci 257:9-23, 1969 18. Mllnor WR, Jose AD, McGaff CJ: Pulmonary vascubr volume, resistance and compliance in man. Circulation 22:130-137, 1960 19. Croxlon RE, Cowden DJ: Applied General Statistics. New York,
294
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1974
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Prentice-Hall, 1941, p 40 20. Heimbach DY. Crout JR: Effect of atrooine on the tachvcardia of hyperthyroidfsm. Arch Intern Med 1291430-432, 1972 * 21. Brandfonbrener M, Landowne M, Shock NW: Changes in cardiac output with age. Circulation 12:557-566, 1955 22. Levlnson GE, Pacffko AD, Frank MJ: Studies of the cardiopulmonary blood volume. Circulation 33:347-356, 1966 23. Yu PN: Pulmonary Blood Volume in Health and Disease. Philadelphia, Lea 8 Febiger, 1969, p 96, 110 24. Jose AD, Collinson 0: The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 4: 180-187, 1970 25. Leon DF, Shaver JA, Leonard JJ: Reflex heart rate control in man. Am Heart J 80:729-739, 1970 26. Same1 P, Frltts HW Jr, Flshman AP, et al: The blood volume in heart disease. Medicine 36:21 l-235, 1957 27. Taylor HL, Henschel A, Brozek J, et al: Effects of bed rest on cardiovascular function and work performance. J Appl Physiol 2:223-239, 1949 28. Tarazi RC, lbrahfm MM, Dustan HP, et al: Cardiac factors in hypertension. Presented to Council for High Blood Pressure Research, Cleveland, 1973 29. Folkow B, Mellander S: Veins and venous tone. Am Heart J 88:397-408, 1964 30. Shepherd JT: Role of the veins in the circulation. Circulation 33:484-491, 1966 31. Wefssler AM, Roehll WH, Peek RG: Effect of posture on the cardiac response to increased peripheral demands. J Lab Clin Med 59:1000-1007, 1962 32. Braunwald E: The control of ventricular function in man. Br Heart J 27:1-16, 1965 33. Well JV, ChkJsey CA: Plasma volume expansion resulting from interference with adrenergic function in man. Circulation 37: 54-61, 1968 34. Vogt FB, Johnson PC: Plasma volume and extracellular fluid volume change associated with 10 days bed recumbency. Aerosp Med 38:21-25, 1967 35. Hedeland H, Dymberg JF, Hokfelt B: Catecholamines. renin and aidosterone in postural hypotension. Acta Endocrinol (Kbh) 62:399-410, 1969 36. Gordon RD, Kiichel 0, Llddle GM, et al: Role of sympathetic nervous system in regulating renin and aldosterone production in man. J Clin Invest 46:599-605. 1967 37. Gill JR Jr, Mason DT, Bartter FC: Adrenergic nervous system in sodium metabolism: effects of guanethidine and sodium retaining steroids in normal man. J Clin Invest 43: 177- 184, 1984
Vdume 34
M. MOHSEN IBRAHIM, MD* ROBERT C. TARAZf, MD, FACC HARRIET P. DUSTAN, MD, FACC EMMANUEL L. BRAVO, MD Cleveland, Ohio
From the Research Division, The Cleveland Clinic Foundation and The Cleveland Clinic Educational Foundation, Cleveland, Ohio. This study was supported in part by Grants 70 960 from the American Heart Association, New York, N. Y. and HL 6635 from the National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Manuscript accepted January 2, 1974. *Present address: Lecturer in Cardiology, Facufty of Medicine, University of Cairo, Cairo,
Idiopathic orthostatic hypotension offers a unique opportunity to study the effect of chronic autonomic insufficiency on circulatory dynamics in man. Evidence of abnormal cardiac performance was found in eight patients with idiopathic orthostatic hypotension secondary to efferent adrenergic dysfunction. Compared with normal subjects these patients had a lower cardiac output (2.37 liters/min per m*, P
Idiopathic orthostatic hypotension is a relatively rare disease that runs a progressive but fluctuant course leading to disability because of severe postural symptoms. The clinical features are well defined and have been described in detail.1-4 Various tests of autonomic function have suggested impairment in different portions of the baroceptor reflex arc in different patients. 3-5 Failure of reflex arteriolar constriction and defective venous return have been demonstrated to be the hemodynamic end result responsible for the reduction in arterial pressure with upright posture. s-g However, except for isolated case reports dealing mainly with postural adjustments,s,g there has been no reported investigation of blood volume or supine hemodynamics in this disease. Since our initial studies suggested alterations in these functions, the question was raised whether impaired cardiac performance might participate in the postural maladjustment in some patients. This report is based on a study of eight patients with idiopathic orthostatic hypotension due to efferent adrenergic dysfunction. Variations in cardiac output both at rest and during head-up tilt were correlated with changes in intravascular and cardiopulmonary volumes to assess cardiac performance in the presence of chronic autonomic insufficiency. Methods
Egypt.
Patients investigated
Address for reprints: Robert C. Tarazi, MD, Research Divisiin, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio 44106.
(five men and three women) whose ages ranged from
288
September 1874
The AmerkanJournal of
The study included eight patients with idiopathic orthostatic
CARMOLOOY Vofume 34
hypotension
53 to 76 years (median
IDIOPATHIC ORTHOSTATIC
HYPOTENSION-IBRAHIM
ET AL.
TABLE I Summary
Case no. __--___--
of Clinical Data
Age (yr) & Sex
Duration of Symptoms (mo) Anhidrosis
Impotence
Sphincteric Disturbances
1 2 3
54M 68F 68M
7 60 24
+ + +
+ +
+ -
4 5
53F 63F
24 24
-
-
-
6 7 8
76M 62M 62M
2 48 36
+ + +
+ + +
+ -t
-f- = present;
-
+
Neuropsychiatric
Other Findings --.
Symptoms
None Shy-Drager ? Depression; early Parkinsonism Depression Depression; brain stem vascular disease Depression None None
None Renal arterial None
disease
Urinary tract infection Hiatus hernia
Chronic obstructive emphysema Impaired carbohydrate tolerance None
= absent.
62 years). All complained of loss of consciousness associated with a documented decrease in arterial pressure when upright; the fainting spells occurred only on standing, often with dramatic suddenness, and were preceded by symptoms of autonomic dysfunction, such as nausea, pallor or sweating. There was no demonstrable cause for the postural hypotension in any patient; one had abnormal results of a glucose tolerance test on one occasion, but he presented no evidence of somatic peripheral neuropathy. The duration of postural symptoms ranged from 2 months to 5 years (median 24 months); more uniform and quite impressive was the history given by each patient of marked variability, sometimes from day to day, in the frequency and severity of symptoms. In spite of these fluctuations, progressive deterioration occurred in most. The other clinical features of the disease are summarized in Table I; one patient was the subject of a previous case report.10 Impotence preceded the onset of orthostatic hypotension in men; failure to maintain erection was noted first, followed later by complete impotence. Of interest was the 20 year interval by which anhidrosis antedated the postural symptoms in Case 1. A psychiatric depressive illness was diagnosed in four cases; Shy-Drager disease was suggested as a possibility in one. One patient (Case 6) had severe chronic obstructive emphysema and mild respiratory insufficiency. All patients were hospitalized but were encouraged to be as active as possible; neither their activity nor diet was restricted. All medications were discontinued for at least a week before the studies. A careful history ensured that none of them had had vasoactive, antidepressant or sedative medication for at least the preceding 6 months. Brachial arterial pressure was recorded in the hospital four times daily with patients in both the supine and standing positions, and weekly averages were compared with daily fluctuations and with pressures obtained during the hemodynamic studies.
Tests for Autonomic Function and Localization of the Lesion Responses to passive head-up tilt,” and to the Valsalva maneuver12 were used to test the integrity of the baroreflex arc. Stimulation of efferent sympathetic fibers from other routes was investigated by the cold pressor test and stress-
ful mental arithmetic; in addition, a reflex sweat test was performed in four patients. Responsiveness of the vasomotor center was tested by hyperventilation for 15 seconds.1” Phenylephrine (25 and 50 rg intravenously) was given to evaluate receptor responsiveness of arteriolar smooth muscle. To investigate vagal participation in the disease, heart rate responses to intravenously administered atropine (0.03 and 0.04 mg/kg body weight) were compared with those to head-up tilt. All tests were performed with continuous monit,oring of the electrocardiogram and intraarterial pressure.
Hemodynamic Studies Plasma volume was determined in seven patients with Risaa (1311 or 1251) in the morning after an overnight fast and at least 30 to 45 minutes of supine rest. A 10 minute equilibration period was used and blood volume was calculated from the plasma volume and simultaneously determined corrected hematocrit as described previously.14 Results were expressed in milliliters per centimeter of height to minimize differences due to agel or obesity.14 In calculations of data from both men and women, results were expressed as percent of the expected normal value for our laboratory.i4 Cardiac output was determined by the dye-dilution technique, using indocyanine green dye as previously described in detail.lsJ” Patients were studied without premedication in the morning after an overnight fast. Polyethylene catheters (70 cm long, inner diameter 1.1 mm) were passed percutaneously into the right antecubital vein and brachial artery and advanced at least to the subclavian vein and artery, respectively. In three patients (Cases 1,4 and 7) the two catheters were carefully positioned under fluoroscopic guidance, one at the junction of the superior vena cava and right atrium and the other in the ascending aorta above the aortic valve. Arterial and venous pressures were measured using Statham P23Db transducers, with the zero reference set at the mid-chest level. An electrocardiogram (lead II) was continously recorded throughout each study. Cardiac output, ejection time and derived variables were determined by standard methods.16J7 Cardiopulmonary volume was calculated only in those three patients with carefully positioned central catheters.‘& The
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IDIOPATHIC ORTHOSTATIC
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ET AL.
VALSALVA
MANEUVER
NORMAL RESPONSE
(15 set)
IDIOPATHIC ORTHOSTATIC
HYPOlTENSlON
140 120 IO0 80
FIGURE 1. Arterial pressure response to a Valsalva maneuver in a normal subject (A) and a patient with idiopathic orthostatic hypotension (B) illustrating the absence of pressure overshoot after release of straining (phase 4).
delay time of the system was determined in each case separately and the cardiopulmonary volume calculated as the product of the corrected mean transit time and blood flow per second.l* Contiol values were derived from results of similar studies of normotensive volunteers, many of which have been previously reported.11J6J7 Standard statistical methodsI were used to calculate averages, standard devia-
tions, standard errors and correlation coefficients as well as the statistical significance of the results. Results are expressed as averages f 1 standard error.
Results Localization of the Defect Interruption of the baroreceptor reflex arc was demonstrated in all eight patients by the absence of diastolic pressure overshoot after a Valsalva maneuver (Fig. 1) and by the inability to maintain arterial pressure in the upright position (Table II). That the afferent and central parts of the reflex arc were intact was shown by the occurrence of cardiac slowing with an increase in blood pressure induced by phenylephrine and by a depressor response to hyperventilation.13 The lesion was therefore localized to the efferent sympathetic system; this finding was also supported by lack of blood pressure response to cold or to stressful mental arithmetic and by the loss of reflex sweating; Two patients (Cases 3 and 8) did respond to cold with an increase in blood pressure but were still thought to have efferent sympathetic dysfunction because of (1) the documented integrity in both the afferent and central parts of the barocepko;;eflex, and (2) the absence of reflex sweating in In all patients,
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The American Journal of CARDIOLOGY
ephrine evoked a pressor response of varying magnitude indicating intact receptor sites in arteriolar smooth muscle. With the increase in blood pressure, heart rate slowed in all by 8 to 14 beats/min, thereby indicating adequate baroceptor sensor and central connections and at least a partially functioning efferent vagal mechanism. Changes in Heart Rate All patients but one had a rapid resting heart rate (average 83 beats/min); the single exception (Case 3) has sinus bradycardia and his findings will be discussed separately. Various degrees of cardiac acceleration developed in all during head-up tilt (Fig. 2); the average increase in heart rate (14 percent) was not different from the normal response (16 percent). Intravenously administered atropine accelerated the heart rate (11 percent) to about the same degree as head-up tilt, but significantly less than the normal 49 percent reported by Heimbach and Crout2’l or the 54 percent determined in hypertensive patients in our laboratory (Tarazi et al, unpublished observations). Plasma and Total Blood Volumes All but one of the eight patients had contracted plasma (90.4 percent f 3.0, standard error) and total blood volumes (89.9. percent f 3.0) (Table III). The reduction in total blood volume correlated significantly with the severity of hypotension on head-up tilt (r = -0.805, P <0.05); this correlation, however, did not include Patient 3 referred to earlier (Fig. 3). Intravascular volume also appeared to be correlated
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TABLE II Tests of Autonomic
Function Case no. ____
Changes in systolic blood pressure Phenylephrine, intravenously
1
2
+20 +63 0 -4 -22 0 Impaired
+42
3
4
5
6
7
8
+31 ... +8 0
...
...
+22 +4
+10 0
+30 i-57 0 -15 -16 0 Impaired
$40 +44 +30 -20 -30 0 Impaired
:::
...
...
0 Impaired
...
(mm Hg)
25 pg 50 Icg Cold pressor test Mental arithmetic Hyperventilation Valsalva (overshoot) Reflex sweat test
... +46
... 0 0 -55 0
+30
...
0
+4
0
...
0
0
...
...
l30-
.
s 5
12O-
FfWRE 2 (left). Response rate to head-up tilt and to nously admlnistereft atropine patients, showing remarkable ity in degree of response stimuli.
of heart intravein seven simllarto both
z f > 2
I IO-
t
IOO-
. .
.
5
FfGURE 3 (right). Reduction of mean arterial pressure (MAP) with head-up tilt. (percent.of supine value) correlat* significantly with total intravascular volurns (TEV) (percent of normal) in seven patients with idiopathic orthostatic hypotension. Patient 3 (x) was excluded from’statlstical analysis because he had ?o postural hypbtension at time of study.
z i t
sox
r = -0.805 p > 0.05
I
80-
I
70
+ II% ATROPINE
sb
+ 14%
I
,
SUPINE
TILT
TBV
110 PERCENT
OF
NORMAL
TABLE Ill Supine Hemodynamics
and Blood Volume Measurements Blood Pressure
Case no. 1 2 3 4 5 6 7 8 Mean SE
BSA (mB)
(mm W (week’s average)
2.05 1.62 2.06 1.64 1.70 1.83 2.04 1.96 1.86 0.07
107175 124182 120177 116/79 125177 132/71 94175 122f 79 118176 4.211.8
BSA = body surface = percent of normaPr; resistance index.
PV
TBV
(ml/cm)
%N
(Wcm)
17.1 13 16.1 14.9 12.6 ... 16.9 19.4
91 83 86 97 82 ... 90 104 90.4 3.0
27.8 20.9 26.1 ?3.4 20.4 ... 24.7 32 ... ...
... ...
%N 90 87 84 98 a5
... 82 103 89.9 3.0
Cl MAP (liters/min (mm Hg) per me) 85 120 98 108 109 109 65 115 101 6.4
2.00 2.94 1.72 2.97 3.34 2.05 1.65 2.29 2.37 0.22
SI
TPR
MRLVE (ml/se4
(ml/m*>
(units)
per n?)
21 34 37 31 46 21 22 29 30 3.1
43 39 57 36 33 53 39 50 44 3.1
87 121 115 112 144 93 75 103 106 7.7
area; Cl = cardiac index; MAP = mean arterial pressure; MRLVE = mean rate of left ventricular ejection; SN PV = plasma volume; SE = standard error; SI = stroke index; TBV = total blood volume; TPR = total peripheral
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231
N = NORMAL CONTROLS (29) IOH = IDIOPATHIC ORTHOSTATIC
HYPOTENSION
(8)
I
1 = SE
I
FIGURE 4. Lefl. Supine hemodynamic indexes in 29 normal subjects and 8 patients with idiopathic otthostatic hypotension. Cl = cardiac index HR = heart rate; MAP = mean arterial pressure; MRLVE = mean rate of left ventriculai ejection; SI = stroke volume index; TPR = total peripheral resistance. FIGURE 5. Rlaht. Variations in mean arterial pressure (MAP), cardiac index (Cl) and total peripheral resistance (TPR) produced by head-up tilt in patients with idiopathic orthostatic hypotension and nor&al sbbjects.
directly with the average weekly diastolic pressure (r = O-529), hut the correlation was not statistically significant. There was no correlation between blood volume and cardiac output (r = 0.219). Hemodynamic Studies
Supine (Table III; Fig. 4): Cardiac index was lower (2.37 liters/min per m2) than our normal values (P
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contrasted with the rapid heart rate of others. These differences might have been related to the variability in the course of his disease; whereas he had marked postural hypotension when seen initially, his symptoms and hypotension lessened considerably without treatment during his hospital stay. With exclusion of this patient, the change in peripheral resistance with tilt averaged +2.4 percent.
Cardiopulmonary
blood
volume:
(Table
IV):
This volume in three patients averaged 498 f 86 ml/ m2, which was significantly lower (P <0.05) than average for eight normal volunteers (657 ml/m2). As expected, cardiopulmonary blood volume was reduced during head-up tilt both in patients and in normal subjects (341 f 18 and 515 f 18 ml/m2, respectively, P <0.005); stroke index was reduced by 47 percent to 13 ml/m2. However, more significant for this study than changes in absolute values was the correlation between cardiopulmonary blood volume and stroke volume; the two were correlated both in patients (r = 0.937) and in normal subjects (r = 0.873) at a high level of significance despite the small number investigated. This relation, which has been reported also for other conditions,1s,22,23 helped evaluate cardiac function, a low ratio of stroke to cardiopulmonary volume indicating diminished cardiac performance. Patients had a significantly lower ratio (0.050 f 0.004) than normal subjects (0.061 f 0.002, P
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TABLE IV Cardiopulmonary
Blood Volume Measurements
Supine
__~
Tilt -__
Caseno.
CPV
CPVI
CI/CPVI
SI/CPVI
CPV
CPVI
CI/CPVI
SI/CPVI
1 2 7 Mean
815 1089 799 901
454 664 376 498
4.41 4.77 3.31 4.16
0.046 0.047 0.059 0.050
648 708 565 640
316 432 276 341
4.219 3.73 3.31 3.750
0.041 0.0288 0.047 0.039
Cl = cardiac index; CPV = cardiopulmonary blood volume (ml); CPVI = cardiopulmonary face area; A % CPVI = change of CPVI with head-up tilt in percent; SI = stroke index. decrease was associated with a rapid heart rate (P
September
A % CPVI -30 -35 -27 -31
blood volume per square meter body sur-
output. Taylor et al. 27 found that cardiac output did not change after 3 to 4 weeks of almost complete rest in bed. Two important physiologic mechanisms regulating cardiac output could be compromised in patients with idiopathic orthostatic hypotension: venous filling and myocardial contractility. Contraction of total blood volume could contribute to reduction in stroke output by diminished filling of the heart. Our patients had reduced blood and plasma volume (89.9 and 90.4 percent of normal, respectively) and showed a significant correlation (r = -0.805, P <0.05)between intravascular volume and the reduction of mean arterial pressure with head-up tilt (Fig. 3). However, the degree of hypovolemia did not correlate with cardiac output, thus indicating that factors other than contraction of intravascular volume may be involved in the reduction of output. Impaired cardiac performance might be such a factor; favoring this assumption were not only the small stroke volume and very low rate of left ventricular ejection, but also the reduced ratio of stroke output to cardiopulmonary volume. This ratio was shown to be a reliable index of cardiac performances”; increase of cardiac contractility by isoproterenol resulted in a significant rise of this ratio, whereas administration of propran0101led to the opposite effect. Impaired myocardial contractility: Like other investigators,16~18~22we found a close relation between stroke index and cardiopulmonary volume; in this context, an increase in the latter without a corresponding rise in stroke index would imply diminished myocardial performance since it would indicate that more blood is retained in the heart and lungs.s:+ This was the case in patients with idiopathic orthostatic hypotension who had a significantly lower ratio of stroke to cardiopulmonary volume at rest than normal subjects. Further, this ratio was reduced by 33 percent with head-up tilt, whereas it scarcely changed in normal subjects. Diminished venoconstriction2s could explain in part the impressive reduction in cardiopulmonary volume and cardiac output during tilt in patients with idiopathic orthostatic hypotension (36 vs. 13 percent in normal subjects, P
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IDIOPATHIC ORTHOSTATIC
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ET AL.
ated with a proportionate reduction in output and stroke volume in normal subjects so that ratios did not change appreciably. In contrast, among our patients the reduction in stroke volume (47 percent) was much greater than that of cardiopulmonary volume (31 percent). Defective myocardial contractility apparently limited the ability of the heart to compensate for the diminished venous return and thus further exaggerated the reduction of cardiac output.31 This myocardial factor may not necessarily be due to a structural alteration of the muscle but may result from defective sympathetic cardiac innervation.32 Reduced blood volume: The small plasma volume in our patients contrasted with the volume expansion
that occurs in patients receiving adrenergic blocking agents33; the cause of that contraction is not clear. Prolonged immobilization in bed is associated with reduction in plasma volume,34 but none of our patients was confined to bed, either at home or in the hospital. Some patients with idiopathic orthostatic hypotension were found to have low levels of plasma renin activity and urinary aldosterone excretion at rest35*36 that did not rise with sodium depletion.“6 Gill et a1.37 presented some evidence for impaired sodium conservation during guanethidine therapy. However, study of that aspect in our patients (Bravo et al., unpublished ‘observations) did not reveal any impairment in aldosterone response to, or sodium conservation during, a period of low sodium intake.
References 1. Bradbury S, Egglesfon C: Postural hypotension: a report of three cases. Amer Heart J 1:73-86, 1926 2. Verel D: Postural hypotension: the focalization of the lesion. Br Heart J 13:61-67, 1951 3. Wagner HN Jr: Otthostatic hypotension. Bull Johns Hopkins 105:322-359, 1959 4. Lewis HD Jr, Dunn M: Orthostatic hypotension syndrome. A case report. Am Heart J 74:396-401,1967 5. Love DR, Brown JJ, Chinn RH, el al: Plasma renin in idiopathic orthostatic hypotension: differential response in subjects with probable afferent and efferent autonomic failure. Clin Sci 41: 289-299, 1971 6. Stead EA, Ebert RV: Postural hypotension; a disease of sympathetic nervous system. Arch Intern Med 67:546-562, 1941 7. Mac Clean AR, Allen EV: Orthostatic hypotension and orthostatic tachycardii. JAMA 155:2162-2167, 1940 8. Hlckan JB, Pryor WW: Card&c output in postural hypotension. J Clin Invest 30:401-405, 1951 9. Rickefmann AG, Lippschutz EJ, Branjes CF: Hemodynamics of idiopathic orthostatic hypotension. Am J Med 30:26-38, 196 1 10. Shafer WH, Frohllch ED, Wallace TW, et al: fdiopathic orthostatic hypotension: a report of a case. Cleve Clin 0 36:137141, 1969 11. Frohlich ED, Tarazl RC, Ulrych M, et al: Tilt test for investigating a neural component in hypertension. Its correlation with clinical characteristics. Circulation 36:387-393, 1967 EP: Effects of Valsalva’s maneuver on the 12. Sharpey-Schafer normal and falling circulation. Br Med J 1:693-695, 1955 13. Sharpey-Schafer EP, Taylor PJ: Absent circulatory reflexes in diabetic neuritis. Lancet 1:559-562, 1960 14. Tarazl RC, Diwfan HP, Frohlkh ED, et al: Plasma volume and chronic hypertension. Relationship to arterial pressure levels in different hypertensive diseases. Arch Intern Med 125:835-842, 1970 15. Chien S, Nasmi S, Sfmmons RL, et al: Blood volume and age: repeated measurements of normal men after 17 years. J Appl Physiol21:583-588, 1966 16. Ulrych M, Frohllch ED, Tarazl RC, et al: Cardiac output and distribution of blood volume in central and peripheral circulations in hypertensive and normotensive man. Br Heart J 31:570-574, 1969 17. Frohllch ED, Tarazi RC, Dustan HP: Re-examination of the hemodynamics of hypertension. Am J Med Sci 257:9-23, 1969 18. Mllnor WR, Jose AD, McGaff CJ: Pulmonary vascubr volume, resistance and compliance in man. Circulation 22:130-137, 1960 19. Croxlon RE, Cowden DJ: Applied General Statistics. New York,
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Prentice-Hall, 1941, p 40 20. Heimbach DY. Crout JR: Effect of atrooine on the tachvcardia of hyperthyroidfsm. Arch Intern Med 1291430-432, 1972 * 21. Brandfonbrener M, Landowne M, Shock NW: Changes in cardiac output with age. Circulation 12:557-566, 1955 22. Levlnson GE, Pacffko AD, Frank MJ: Studies of the cardiopulmonary blood volume. Circulation 33:347-356, 1966 23. Yu PN: Pulmonary Blood Volume in Health and Disease. Philadelphia, Lea 8 Febiger, 1969, p 96, 110 24. Jose AD, Collinson 0: The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 4: 180-187, 1970 25. Leon DF, Shaver JA, Leonard JJ: Reflex heart rate control in man. Am Heart J 80:729-739, 1970 26. Same1 P, Frltts HW Jr, Flshman AP, et al: The blood volume in heart disease. Medicine 36:21 l-235, 1957 27. Taylor HL, Henschel A, Brozek J, et al: Effects of bed rest on cardiovascular function and work performance. J Appl Physiol 2:223-239, 1949 28. Tarazi RC, lbrahfm MM, Dustan HP, et al: Cardiac factors in hypertension. Presented to Council for High Blood Pressure Research, Cleveland, 1973 29. Folkow B, Mellander S: Veins and venous tone. Am Heart J 88:397-408, 1964 30. Shepherd JT: Role of the veins in the circulation. Circulation 33:484-491, 1966 31. Wefssler AM, Roehll WH, Peek RG: Effect of posture on the cardiac response to increased peripheral demands. J Lab Clin Med 59:1000-1007, 1962 32. Braunwald E: The control of ventricular function in man. Br Heart J 27:1-16, 1965 33. Well JV, ChkJsey CA: Plasma volume expansion resulting from interference with adrenergic function in man. Circulation 37: 54-61, 1968 34. Vogt FB, Johnson PC: Plasma volume and extracellular fluid volume change associated with 10 days bed recumbency. Aerosp Med 38:21-25, 1967 35. Hedeland H, Dymberg JF, Hokfelt B: Catecholamines. renin and aidosterone in postural hypotension. Acta Endocrinol (Kbh) 62:399-410, 1969 36. Gordon RD, Kiichel 0, Llddle GM, et al: Role of sympathetic nervous system in regulating renin and aldosterone production in man. J Clin Invest 46:599-605. 1967 37. Gill JR Jr, Mason DT, Bartter FC: Adrenergic nervous system in sodium metabolism: effects of guanethidine and sodium retaining steroids in normal man. J Clin Invest 43: 177- 184, 1984
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