A Kinetic Study of Plasma Renin and Aldosterone During Changes of Posture in Man JEAN SASSARD, MADELEINE VINCENT, GUY ANNAT, AND CHARLES A. BIZOLLON Departments of Physiology and Biophysics, University Lyon I, UER Grange Blanche—69373 — Lyon Cedex 2—France. significantly at the 15th min and exhibited a plateau 4.5 times its basal values after 90 min of upright posture. When subjects returned to the supine position all the parameters, except PAC decreased. During active orthostatism, a significant correlation was found between PAC and plasma potassium, but correlation was closer between PAC and PRA and between PAC and PRA + potassium. It can be concluded that the renin-angiotensin system is a more potent stimulus for aldosterone secretion than plasma potassium in normal man assuming postural changes. The results presented here can be applied to the development of a short posture test in non-hospitalized patients. (J Clin Endocrinol Metab 42: 20, 1976)
ABSTRACT. Cardiovascular parameters, hematocrit (Ht), plasma electrolytes, renin activity (PRA) and aldosterone concentration (PAC) were measured in 12 normal human subjects (6 males and 6 females) eating an ad lib diet. At 8 AM, volunteers assumed the following postural changes: 1 hour supine, then 2 hours upright and finally 1 hour supine. Orthostatism induced the following changes: heart rate, systolic and diastolic blood pressure increased immediately; Ht rose significantly at the 5th min in males but not in females; Plasma sodium showed no variations but potassium increased after 30 min; PRA rose significantly at the 5th min and, after 120 min of orthostatism, was found to be 3 times greater than its value after recumbency; and PAC increased
W
HEN man assumes the upright position, a large blood volume of about 600 to 700 ml (1,2) collects in the veins of the lower parts of the body. The organism reacts against this sharp diminution in its circulating blood volume by a sympathetic hyperactivity and an adrenal discharge (3,4), thus avoiding any fall in arterial blood pressure. The same process induces a well-documented rise in renin secretion (2,5,6) in circulating Angiotensin II (7,8), and in aldosterone secretion (9,10-12). However, the exact stimulus which originates these endocrine adaptations is still largely unknown. In the present study, we recorded in normal human subjects the evolution of renin and aldosterone secretion and of some cardiovascular and biological parameters, during the course of an active orthostatism. This study had a dual purpose. The first was theoretical; to describe the chronology of plasma renin and aldosterone variations in order to determine their origin and their interrelationship. The second was practical; orthostatism is currently used to study renin
and aldosterone reactivity in humans. Most of the protocols are long and consequently often poorly-tolerated by patients. It was thus necessary to define the shortest postural test able to give a sufficient and reproducible stimulation. Materials and Methods Twelve normal human volunteers were studied, 6 males and 6 females aged 21 to 30 years, and maintained on an ad lib diet. None of them had any history of cardiac, renal, or hepatic diseases. The females were between the 7th and 12th day of their menstrual cycle and had never used oral contraceptives. On the day of the study, the subjects awoke at 7 AM and, after a light breakfast, came to the laboratory. At 8 AM, the volunteers lay on a bed and a sterile catheter (Cathlon TV* 20 g) was inserted into a peripheral vein and closed with its Teflon stylet. After one hour supine, the subjects arose and remained standing or walking for two hours; then they resumed the supine position for one more hour. Cardiovascular parameters In order to obtain reliable results, systolic (SBP) and diastolic (DBP) blood pressure were
Received September 13, 1974. 20
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POSTURE INFLUENCE ON RENIN AND ALDOSTERONE always measured by the same person, using the same mercury manometer. Heart rate (HR) was determined by another observer. Biological parameters Using the catheter, blood samples were quickly drawn without tourniquet or antebrachial muscular exercise. All the parameters were determined on 10 ml of blood kept at + 4 C until centrifugation in a refrigerated centrifuge (Jouan K 63 F). The hematocrit (Ht) was measured using a semimicromethod in 1 ml heparinized tubes after centrifugation at 5000 rpm for exactly 10 min. Plasma sodium (PNa) and potassium (PK) were measured with an IL flame-photometer connected to an IL automatic diluter. Plasma renin activity (PRA) was determined by a radioimmunoassay of angiotensin I liberation according to our previously published technique (13) and plasma aldosterone concentration (PAC) by a solid-phase radioimmunoassay (14). Normal values in subjects maintained supine for 10 h and after intake of 100 mEq of sodium/24 hours were found to be: PRA = 25.3 ng/l/min ±3.1 (SEM) and PAC = 35 pg/ml ± 4 (SEM). All of these parameters were followed: after 45 and 60 min of clinostatism; during orthostatism at the 1st, 3rd, 5th, 7th, 15th, 30th, 60th, 90th and 120th min; and after 1,3,5,7,15,30,45 and 60 min of recumbency. Due to the frequency of sampling, subjects were able to stand only for the first 15 min of orthostatism and began to walk only after that. In four additional male subjects aged 40-53 years, two measurements of PRA were made after 60 min of suprine position and after 90 min of orthostatism. Statistical analysis Results were expressed as mean ± SEM of the absolute values. In some cases, absolute values obtained during orthostatism and the second period of supine position were calculated as percentage of the values found after the first 60 min of recumbency (% S 60). Statistical analysis used the Student's t test. In all cases, values obtained during orthostatism in males and females taken as a whole, were compared to those found after the first 60 min of clinostatism (S 60), and values measured in the last
21
period of recumbency were compared to those observed after 120 min of orthostatism (U 120). Differences were considered as non-significant (NS) for P > 0.05 significant (S) for P < 0.05 and highly significant (HS) for P < 0.005. Correlations were calculated using multiple regression analysis.
Results Influence of posture on cardiovascular parameters Values obtained are expressed in Fig. 1. Heart Rate. When supine, it was found significantly higher in females than in males. In all subjects a highly significant acceleration of HR could be noted in the 1st min of upright position. This acceleration decreased sightly during orthostatism, and when subjects returned to recumbency, HR exhibited a sharp fall, returning in 1 min to its basal values. Blood pressure. When supine, SBP was not different in males and females, but DBP was significantly higher in females. During orthostatism, SBP and DBP exhibited the same evolution as HR. However, it must be noted that SBP variations were smaller than those of DBP. Consequently, in upright position there was a reduction in pulse pressure. Influence of posture on biological parameters Mean values obtained are summarized in Table 1. Hematocrit (HT). Basal values and evolution of this parameter were found to be different in males and females. When supine, Ht was significantly higher in males (47.7 ± 0.9%) than in females (45 ± 1.2%). During orthostatism, Ht did not significantly change in females, but in males a significant increase was to be observed at the 5th min, reaching a maximum at the 15th min. It remained elevated as long as the erect position was maintained.
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SASSARD, VINCENT, ANNAT AND BIZOLLON
22 HR
JCE & M • 1976 Vol 42 • No 1
b-mm"1
FIG. 1. Influence of posture on heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure.
45
60
15
30
60
Plasma sodium. This parameter did not sig- tions, no difference could be found between male and female responses. After only 5 min nificantly change throughout the test. in the erect position, a significant rise was Plasma potassium. On the contrary, PK observed, and PRA continued to increase exhibited important variations. When supine, progressively, reaching 120 min later, values PK was significantly higher in males (4.2 three times greater than its basal values mEq/1 ± 0.1) than in females (3.9 mEq/1 (% S 60 = 408 ± 49.7 %) ± 0.1). PK increased to 4.4 ± 0.2 at 30 min, When subjects reclined, PRA decreased to 4.5 ±0.1 at 60 min in the males, and to rapidly but inconsistently, becoming signifi4.3 ± 0.1 at both times in the females. The cantly lower after 30 min of clinostatism. At mean values at 30 and 60 min (4.3 ±0.1 and the end of this last period, PRA did not reach 4.4 ±0.1 respectively) were highly signifi- its basal values, but remained slightly cantly different from the control values. elevated. In order to exclude any possible effect of Influence ofposture on endocrine parameters blood volume depletion related to the fre(Table 1, Fig. 2) quent sampling, an additional study was PRA variations. During orthostatism, these done in four male normal subjects, after 60 were expressed as absolute values and as min supine and 90 min of upright position. % S 60 in order to exclude the individual dif- Upright values, expressed as % S 60, were ferences and thus to express only the effect found to be 319 ± 51. There was no signifiof the stimulus. On the basis of these calcula- cant difference between the increase of PRA The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 March 2015. at 11:42 For personal use only. No other uses without permission. . All rights reserved.
23
POSTURE INFLUENCE ON RENIN AND ALDOSTERONE TABLE 1. Influence of posture on some parameters measured in normal man (Total mean ± SEM, compared to S 60*, compared to U 120**) Supine
Hematocrit % Plasma sodium mEq/1
1
45
60
45.8
46.5
46.3
46.3
0.4
0.3
0.9 NS*
0.8 NS*
142 1.4 NS*
142 0.7
Supine
Upright
142 1.1
15
30
60
90
120
47.7
48.5
47.6
47.3
47.3
47.2
1.0
0.9
0.3
0.9
0.9
NS*
1.2 NS*
NS*
NS*
NS*
143 0.6 NS*
143 1.0 NS*
143 1.0 NS*
142 0.7 NS*
142 0.9 NS*
3
5
5
15
30
60
46.0
45.8
46.0
45.7
45.5
1.2
0.9
0.9
NS*
NS**
NS**
NS**
0.9 NS*»
NS**
142 0.9 NS*
142
141 1.9
142 1.2
142 0.9
142 0.6
142 0.9
NS**
NS**
NS**
NS**
NS**
4.1 0.1
4.1 0.1
4.0 0.1
0.8 NS*
3
Plasma potassium mEq/1
4.1 0.1
4.0 0.1
4.1 0.1
4.2 0.1
4.1 0.1
4.1 0.1
4.3 0.1 S*
4.4 0.1 HS*
4.4 0.1 HS*
4.3 0.1 HS*
NS**
4.1 0.1 S**
NS**
4.0 0.1 S**
PRA ng/ 1/min
57.8 10.5
49.5
58.7 11.8
55.0 12.7
72.1 14.6
101.5 20.5
116.6 21.4
154.9 29.4
166.5 28.3
188.9 33.3
176.7 38.9
131.2 20.8
141
98
124 17
142.3 16.5
197.3 18.6
245
HS*
HS*
350 37 HS*
408
S*
329 38 HS*
375.9 60.0 NS**
327.3 44.6 NS**
303.6 45.6 NS**
119.7 20.2
215.7 36.9
260.3 35.1
261.8 36.1
266.3 40
216.7 31.5
231
-
63.9 10.5
238.1 26.2
408.6 67.8
558.9 77.1
S*
HS*
HS*
HS*
557.1 60.1 HS*
535.5 50.1 NS**
542.1 86.3 NS**
450
18.2
%S60
117.8
8.0 100
7.5
PAC
pg/ml %S60
35.4
49.2
6.6
5.8
72.8 9.1
100
118.5 10.6 43 7
89.6 11.3
132.2 17.6
74.3 6.9 160
24.5
49.7 HS*
25.6
32.4 45.3 NS**
19.7
1.1
NS** 82.5 18
24.3 HS**
143.5 14.6 HS**
238.8 32.6
211.5 40.3
525.5 100.6 NS**
441.1 51.7 NS**
193
Total mean ± SEM, compared to S 60*, compared to U 120**
observed in this group and in the one which was subjected to frequent blood sampling. PAC. Although individual values after 1 hour supine were slightly higher in females than in males (57.8 ± 8.4 and 42 ± 7.3 pg/ml respectively), no significant differences could be found between their responses to orthostatism. Using the same calculation as for PRA, a significant rise in PAC was noted after 15 minutes. This elevation increased progressively, reaching a plateau 90 min later. At this time, values were about 5 times greater than basal values (% S 60 = 558.9 ± 77.1). In contrast with PRA, PAC did not consistently decrease when the supine position was resumed. Correlations. No correlation was found between PRA and SBP or DBP. On the contrary, PRA in males and females was significantly correlated with Ht (r = 0.33, n = 139, P < 0.001). Furthermore, an attempt was made to correlate PRA, PAC, and PK using the values obtained between the 60th min of clinostatism and the 120th min of orthostatism.
The results were as follows: PAC-PRA: r = 0.55 n = 86 P < 0.001 r = 0.32 n = 86 P < 0.01 PAC-PK: PAC-PRA + PK: r = 0.58 n = 86 P < 0.001 A close correlation was found between PRA values obtained after 60 min of clinostatism (PRA S 60) and after 90 min of orthostatism (PRA U 90) : r = 0.81, n : 12, P < 0.001. Discussion Although the effects of posture on renin and aldosterone secretion are well documented, it must be emphasized that most previous works, having been clinically oriented, described endocrine adaptations only after a long period of active orthostatism or of passive tilting. We therefore thought it interesting to develop a kinetic study of the short-term variations of PRA and PAC induced both by orthostatism and the return to clinostatism. Protocol was chosen in order to reflect normal daily physiological activity. In this respect, we particularly prefered active ortho-
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SASSARD, VINCENT, ANNAT AND BIZOLLON
JCE & M • 1976 Vol 42 • No 1
% S60
500
.400
FIG. 2. Influence of posture on
plasma renin activity (continuous line) and plasma aldosterone concentration (dashed line).
300
200
100
TIME (min) 15 30 SUPINE
statism to passive tilt which is a more potent but non-physiological stimulus. Moreover, our human volunteers had not been hospitalized or submitted to a measured diet, so as to avoid any modifications in their habits. We carefully avoided history of illness and administration of drugs, especially oral contraceptives which can raise renin and aldosterone secretion rate (15,16). Similarly, the testing was done when females were in thefirstpart of their menstrual cycle, as it has been established that in the second part, as a result of progesterone production, there is an increase in PRA and PAC (17,18) as well as an alteration of their responsiveness to orthostatism (18,19).
The 12 tested subjects were free from orthostatic hypotension, and we found the usual cardiovascular adaptations, i.e., sharp increase of HR and BP ceasing quickly on resumption of supine position. During orthostatism, these variations reflected the autonomic stimulation induced by the decrease of circulating volemia (1,2), and especially of intrathoracic blood volume (4) due to collection of blood in the veins of the lower limbs (5). From the study of biological parameters, some interesting points arose. During orthostatism a significant increase in hematocrit was observed in males but not in females. A maximum of + 2.9% was reached after 30
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POSTURE INFLUENCE ON RENIN AND ALDOSTERONE min. This elevation is consistent with results reported, also in males, by Brown, Davies, Lever, Me Pherson and Robertson (20) and Molzahn, Dissmann, Halim Lohmann and Oelkers (4), and with the increase in colloidosmotic pressure shown by Nielsen and Moller (2). This hemoconcentration probably originates in a plasma shift which is the result of increased venous pressure in the lower part of the body. In females, an increase in Ht was also noted, but it was smaller ( + 1%) than in males. As their basal values varied more widely than in males, the elevation recorded was not significant. The second interesting parameter is the plasma potassium. When measured in precise and reproducible conditions, it has been possible to show that PK was significantly higher in males than in females, and that in the two cases, this parameter exhibited a significant increase of 0.4 mEq/1 after 60 min of orthostatism. This orthostatically induced hyperkaliemia was not due to hemoconcentration since, during the same period plasma sodium did not vary. Its origin is probably to be found in a release of intracellular K+ from exercising muscles (21). In our experiment, PK increased after the 15th min of active orthostatism, i.e., when subjects were no longer submitted to frequent blood sampling and had begun to walk freely in the laboratory. When considering endocrine parameters, very clear-cut variations were noted in spite of a protocol which could only attenuate the influence of orthostatism. At the beginning of the test the volunteers had been supine for one hour only and were not in a true basal state. Consequently, they demonstrated significantly higher PRA and PAC than normal subjects after a complete night of recumbency. Moreover, the nycthemeral cycle of renin and aldosterone secretion exhibit maximum rates at about 8 am (8,12,22) which decrease during the morning, i.e., during the test itself. Nevertheless, it was possible to find a significant increase of PRA after as little as 5 min of orthostatism. Our results are in accord with those of Oparil, Vassaux, Sanders and Haber (6),
25
although these authors used a head-up tilt. Furthermore, the rapid increase in PRA shown is consistent with the recent work of Kala, Fyhrquist, and Eisalo (8) who reported, in similar conditions to those of our experiment, an increase in plasma angiotensin II after 10 min of orthostatism. The lability of renin secretion is confirmed by the rapid fall of PRA on reclining. The values obtained are consistent with those of Oparil (6) who reported a renin half-life less than the 40 min stated by Weidman, Maxwell and Lupu (23). Similarly, PAC variations were considerable and rapid. There is no kinetic study of aldosterone secretion during orthostatism, but the finding of a significant increase after 15 min of stimulation seems logical. In the erect position, PRA increases after 5 min, angiotensin II after 10 min (8) and as observed here, PAC after 15 min. The latency of 5 min found between angiotensin II elevation and PAC increase is consistent with the results obtained after perfusion of exogenous angiotensin II (24). The magnitude of the increase in PAC reached a maximum of 4.5 times its basal values after 90 min of orthostatism. In contrast with PRA, PAC did not decrease rapidly after the end orthostatism, which indicates a lower metabolic clearance rate and/or a persistent action of the stimulus, probably potassium, whose effects on aldosterone secretion appear long lasting (24). At this point the question arises as to the mechanisms initiating these endocrine responses. In the case of aldosterone, if an orthostatism-induced decrease in metabolic clearance rate can participate in the PAC elevation it is certainly insufficient to account for the values reported here (9,23). ACTH also probably plays a minor role since, the upright position does not induce any increase in serum cortisol in normal man (2,12). On the contrary, aldosterone secretion is known to be controlled by two major parameters, potassium and renin. Like others (23,25,26), we found a significant correlation between PAC and PK (r = 0.32), but a closer correlation could be demonstrated between
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26
SASSARD, VINCENT, ANNAT AND BIZOLLON
JCE & M • 1976 Vol 42 • No 1
PAC and PRA (r = 0.55) and between PAC kidney (33) directly influence renin release, and PRA + PK (r = 0.58). These results or if they act via a modification of the renal would indicate that in normal man plasma bloodflowwhich can affect the baroreceptors potassium influences aldosterone secretion of the afferent glomerular arteriole as well during active orthostatism but that its main as the sodium delivery to the macula densa. The study presented here has both pracstimulus is renin secretion. Furthermore, the role of the renin angio- tical and theoretical implications. From a tensin system is emphasized by the kinetic practical point of view, the posture test, aspect of the endocrine adaptations ob- commonly lasting 2 or 3 hours and used in served, and by the fact that in the absence of patients rested for at least 10 hours, can userenin secretion, as seen in anephric humans, fully be replaced by a much shorter study. orthostatism induces no significant increase In a patient recumbent for one hour, an equally significant and stable increase in in PAC (9,12,25). When considering the changes in renin PRA as well as in PAC can be obtained after secretion during upright posture it is obvious 60 or 90 min of orthostatism. Ninety min that these could be explained neither by an would give more reliable results because at orthostatically-induced fall in its metabolic this time all the subjects studied exhibited clearance rate (27) nor by a drop in blood a consistent and reproducible response. The pressure nor by the slow hemorrhage induced main interest of such a simplified posture by blood sampling (as shown by our addi- test is that it can be applied in non-hospitaltional study in which repeated blood ized patients and will allow extensive sampling was avoided during the period of studies on the reactivity of the renin-angiotensin-aldosterone system in different pathoorthostatism). Thus renin secretion was probably con- logical states. The theoretical interest of our study controlled by redistribution of the circulating blood volume. The study of Gordon, Wolfe, cerns the mechanisms affecting renin and Island and Liddle (22), which showed that aldosterone secretion. It is clear that in leg bandaging prevented most of the renin normal man, during physiological changes of variations induced by orthostatism, is con- posture, the renin angiotensin system is of clusive in this respect. Moreover, the exist- greater importance than plasma potassium ence of a significant correlation between the for the control of aldosterone secretion. In increase in colloidosmotic pressure and in these conditions precise and rapid adaptaPRA found during orthostatism by Nielsen tions of renin release were observed, which and Moller (2), coupled with the correlation suggest a reflex control of renin secretion by between Ht and PRA described above the level of circulating blood volume. supports indirectly such an hypothesis. Other experiments tend to demonstrate Acknowledgments that renin secretion is sensitive to the circuare greatly indebted to pharmaceutical students lating blood volume and more precisely to andWemembers of our laboratory who were volunteers the intrathoracic blood volume (28,29). for this study; to Pr. Badinand and Dr. Paret for elecThese results, as well as ours could be trolytes determinations, to Dr. A. M. Fraysse for catheter explained on the basis of a reflex control of insertion; to Pr. A. Froment and Dr. H. Milon for staaid; to Dr. J. B. Douglas for translation; and to renin secretion, initiated by atrial volume tistical Mrs. Jarsaillon, Tapisser and Valancogne for excellent receptors (30). The efferent pathway of such technical assistance. a reflex may well be represented by the renal sympathetic nerves and by the adrenal References medulla secretion. In effect, autonomic insufficiency (31) as well as beta-blocking 1. Pannier, C , S. Seroussi, J. P. Martineaud, C. Vassilikos, and J. Durand, Les volumes sanguins circulants agents (32) are able to blunt the orthostatism chez l'Homme. II. Repartition, role et regulation du induced increase in PRA. What is not known volume sanguin circulant, Rev Fr Et Clin Biol 13: is whether the beta-2 receptors located in the 124, 1968. The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 March 2015. at 11:42 For personal use only. No other uses without permission. . All rights reserved.
POSTURE INFLUENCE ON RENIN AND ALDOSTERONE 2. Nielsen, I., and I. Moller, On the mechanism of renin stimulation: the effect of postural change, salt depletion, and exercise, Ada Med Scand 186: 493, 1969. 3. Gordon, R. D., O. Kuchel, G. W. Liddle, and D. P. Island, Role of sympathetic nervous system in regulating renin and aldosterone production in man,./ Clin Invest 46: 599, 1967. 4. Molzahn, M., T. A. Dissmann, S. Halin, F. W. Lohmann, and W. Oelkers, Orthostatic changes of hemodynamics, renal function, plasma catecholamines and plasma renin concentration in normal and hypertensive man, Clin Sci 42: 209, 1972. 5. Cohen, E. L., J. W. Conn, and D. R. Rovner, Postural augmentation of plasma renin activity and aldosterone excretion in normal people, J Clin Invest 46: 418, 1967. 6. Oparil, S., C. Vassaux, C. A. Sanders, and E. Haber, Role of renin in acute postural homeostasis, Circulation 41: 89, 1970. 7. Catt, K. J., P. Z. Zimmet, M. D. Cain, E. Cran, B. J. Best, and J. P. Coghlan, Angiotensin II blood levels in human hypertension, Lancet I: 459, 1971. 8. Kala, R., F. Fyhrquist, and A. Eisalo, Effect of shortterm upright posture on plasma angiotensin II, Scand J Clin Lab Invest 33: 87, 1974. 9. Balikian, H. M., A. H. Brodie, S. L. Dale, J. C. Melby, and J. F. Tait, Effect of posture on the metabolic clearance rate, plasma concentration and blood production rate of aldosterone in man,y Clin Endocrinol Metab 28 1630, 1968. 10. Horton, R., Laboratory determinations of aldosterone and their clinical significance, Am J Clin Pathol 54: 297, 1970. 11. Bayard, F., I. Z. Beitin, A. Kowarski, and C. J. Migeon, Measurement of plasma aldosterone by radioimmunoassay,y Clin Endocrinol Metab 31: 1, 1970. 12. Williams, G. H., J. P. Cain, R. G. Dluhy, and R. H. Underwood, Studies of the control of plasma aldosterone concentration in normal man. I. Response to posture, acute and chronic volume depletion and sodium loadingj Clin Invest 51: 1731, 1972. 13. Vincent, M., J. Sassard, and J. F. Cier, Methode rapide de determination radio-immunologique de 1'activite r6nine du plasma, Rev Eur Et Clin Biol 17: 1001, 1972. 14. Bizollon, Ch. A., J. F. Riviere, P. Franchimont, A. Favre, and B. Claustrat, A solid-phase radioimmunoassay for plasma aldosterone, Steroids 23: 809, 1974. 15. Tapia, H. R., C. E. Johnson, and C. G. Strong, Effects of oral contraceptive therapy on the reninangiotensin system in normotensive, hypertensive women, Obstet Gynecol 41: 643, 1973. 16. Beckerhoff, R., W. Vetter, H. Armbruster, J. A. Luetscher, and W. Siegenthaler, Plasma aldosterone during oral-contraceptive therapy, Lancet I: 1218, 1973. 17. Sundsfjord, J. A., and A. Aakvaag, Plasma angiotensin II and aldosterone excretion during the
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menstural cycle, Ada Endocrinol (Kbh) 64: 452, 1970. Katz, F. H., P. Romfh, P. E. Zimmering, and W. G. Kelly, Radioimmunoassay of plasma aldosterone: effect of sexual differences and increasing duration of upright posture, Steroids Lipids Res 3: 90, 1972. Edwards, O. M., and R. I. S. Bayliss, Urinary excretion of water and electrolytes in normal females during the follicular and luteal phases of the menstrual cycle: the effect of posture, Clin Sci Molec Med 45: 495, 1973. Brown, J. J., D. L. Davies, A. F. Lever, D. McPherson, and J. I. S. Robertson, Plasma renin concentration in relation to changes in posture, Clin Sci 30: 279, 1966. Ekelund, L. G., Exercise, Ann Rev Physiol 31: 85, 1969. Gordon, R. D., L. K. Wolff, D. P. Island, and G. W. Liddle, A diurnal rythm in plasma renin activity in man,y Clin Invest 45: 1587, 1966. Weidmann, P., M. H. Maxwell, and A. N. Lupu, Plasma aldosterone in terminal renal failure, Ann Intern Med 78: 13, 1973. Scholer, D., M. Birkhauser, A. Peytremann, A. M. Riondel, M. B. Vallotton, and A. F. Muller, Response to plasma aldosterone to angiotensin II, ACTH and potassium in man, Ada Endocrinol 72: 293, 1973. Bayard, F., C. R. Cooke, D. J. Tiller, I. Z. Beitins, A. Kowarski, W. G. Walker, and C. J. Migeon, The regulation of aldosterone secretion in anephric m a n j Clin Invest 50: 1585, 1971. Laragh, J. H., J. E. Sealey, and H. R. Brunner, The control of aldosterone secretion in normal and hypertensive man: abnormal renin-aldosterone patterns in low renin hypertension, Amj Med 53: 649, 1972. Kokot, F., Kuska, J., and Z. Czekala, Hepatic inactivation of renin in man, Enzymologia Biol Clin 9: 317, 1968. Fasola, A. F., and B. L. Martz, Peripheral venous renin activity during 70° tilt and lower body negative pressure, Aerosp Med 43: 513, 1972. Epstein, M., J. L. Katsikas, and D. C. Duncan, Role of mineralocorticoids in the natriuresis of water immersion in man, Circ Res 32: 228, 1973. Brennan, L. A., Jr., R. L. Malvin, K. E. Jochim, and D. E. Roberts, Influence of right and left atrial receptors on plasma concentrations of ADH and renin, Am] Physiol 221: 273, 1971. Rabinowitz, D., H. Landau, A. Rosier, S. W. Moses, Y. Rotem, and S. Freier, Preliminary reports: plasma renin activity and aldosterone in familial dysautonomia, Metabolism 23: 1, 1974. Bravo, E. L., R. L. Tarazi, and H. P. Dustan, On the mechanism of suppressed plasma-renin activity during /3 adrenergic blockade with propranolol, J Lab Clin Med 83: 119, 1974. Weber, M. A., G. S. Stokes, and J. M. Cain, Comparison of the effects on renin release of/8 adrenergic antagonists with differing properties, J Clin Invest 54: 1413, 1974.
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ABSTRACT. Cardiovascular parameters, hematocrit (Ht), plasma electrolytes, renin activity (PRA) and aldosterone concentration (PAC) were measured in 12 normal human subjects (6 males and 6 females) eating an ad lib diet. At 8 AM, volunteers assumed the following postural changes: 1 hour supine, then 2 hours upright and finally 1 hour supine. Orthostatism induced the following changes: heart rate, systolic and diastolic blood pressure increased immediately; Ht rose significantly at the 5th min in males but not in females; Plasma sodium showed no variations but potassium increased after 30 min; PRA rose significantly at the 5th min and, after 120 min of orthostatism, was found to be 3 times greater than its value after recumbency; and PAC increased
W
HEN man assumes the upright position, a large blood volume of about 600 to 700 ml (1,2) collects in the veins of the lower parts of the body. The organism reacts against this sharp diminution in its circulating blood volume by a sympathetic hyperactivity and an adrenal discharge (3,4), thus avoiding any fall in arterial blood pressure. The same process induces a well-documented rise in renin secretion (2,5,6) in circulating Angiotensin II (7,8), and in aldosterone secretion (9,10-12). However, the exact stimulus which originates these endocrine adaptations is still largely unknown. In the present study, we recorded in normal human subjects the evolution of renin and aldosterone secretion and of some cardiovascular and biological parameters, during the course of an active orthostatism. This study had a dual purpose. The first was theoretical; to describe the chronology of plasma renin and aldosterone variations in order to determine their origin and their interrelationship. The second was practical; orthostatism is currently used to study renin
and aldosterone reactivity in humans. Most of the protocols are long and consequently often poorly-tolerated by patients. It was thus necessary to define the shortest postural test able to give a sufficient and reproducible stimulation. Materials and Methods Twelve normal human volunteers were studied, 6 males and 6 females aged 21 to 30 years, and maintained on an ad lib diet. None of them had any history of cardiac, renal, or hepatic diseases. The females were between the 7th and 12th day of their menstrual cycle and had never used oral contraceptives. On the day of the study, the subjects awoke at 7 AM and, after a light breakfast, came to the laboratory. At 8 AM, the volunteers lay on a bed and a sterile catheter (Cathlon TV* 20 g) was inserted into a peripheral vein and closed with its Teflon stylet. After one hour supine, the subjects arose and remained standing or walking for two hours; then they resumed the supine position for one more hour. Cardiovascular parameters In order to obtain reliable results, systolic (SBP) and diastolic (DBP) blood pressure were
Received September 13, 1974. 20
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POSTURE INFLUENCE ON RENIN AND ALDOSTERONE always measured by the same person, using the same mercury manometer. Heart rate (HR) was determined by another observer. Biological parameters Using the catheter, blood samples were quickly drawn without tourniquet or antebrachial muscular exercise. All the parameters were determined on 10 ml of blood kept at + 4 C until centrifugation in a refrigerated centrifuge (Jouan K 63 F). The hematocrit (Ht) was measured using a semimicromethod in 1 ml heparinized tubes after centrifugation at 5000 rpm for exactly 10 min. Plasma sodium (PNa) and potassium (PK) were measured with an IL flame-photometer connected to an IL automatic diluter. Plasma renin activity (PRA) was determined by a radioimmunoassay of angiotensin I liberation according to our previously published technique (13) and plasma aldosterone concentration (PAC) by a solid-phase radioimmunoassay (14). Normal values in subjects maintained supine for 10 h and after intake of 100 mEq of sodium/24 hours were found to be: PRA = 25.3 ng/l/min ±3.1 (SEM) and PAC = 35 pg/ml ± 4 (SEM). All of these parameters were followed: after 45 and 60 min of clinostatism; during orthostatism at the 1st, 3rd, 5th, 7th, 15th, 30th, 60th, 90th and 120th min; and after 1,3,5,7,15,30,45 and 60 min of recumbency. Due to the frequency of sampling, subjects were able to stand only for the first 15 min of orthostatism and began to walk only after that. In four additional male subjects aged 40-53 years, two measurements of PRA were made after 60 min of suprine position and after 90 min of orthostatism. Statistical analysis Results were expressed as mean ± SEM of the absolute values. In some cases, absolute values obtained during orthostatism and the second period of supine position were calculated as percentage of the values found after the first 60 min of recumbency (% S 60). Statistical analysis used the Student's t test. In all cases, values obtained during orthostatism in males and females taken as a whole, were compared to those found after the first 60 min of clinostatism (S 60), and values measured in the last
21
period of recumbency were compared to those observed after 120 min of orthostatism (U 120). Differences were considered as non-significant (NS) for P > 0.05 significant (S) for P < 0.05 and highly significant (HS) for P < 0.005. Correlations were calculated using multiple regression analysis.
Results Influence of posture on cardiovascular parameters Values obtained are expressed in Fig. 1. Heart Rate. When supine, it was found significantly higher in females than in males. In all subjects a highly significant acceleration of HR could be noted in the 1st min of upright position. This acceleration decreased sightly during orthostatism, and when subjects returned to recumbency, HR exhibited a sharp fall, returning in 1 min to its basal values. Blood pressure. When supine, SBP was not different in males and females, but DBP was significantly higher in females. During orthostatism, SBP and DBP exhibited the same evolution as HR. However, it must be noted that SBP variations were smaller than those of DBP. Consequently, in upright position there was a reduction in pulse pressure. Influence of posture on biological parameters Mean values obtained are summarized in Table 1. Hematocrit (HT). Basal values and evolution of this parameter were found to be different in males and females. When supine, Ht was significantly higher in males (47.7 ± 0.9%) than in females (45 ± 1.2%). During orthostatism, Ht did not significantly change in females, but in males a significant increase was to be observed at the 5th min, reaching a maximum at the 15th min. It remained elevated as long as the erect position was maintained.
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SASSARD, VINCENT, ANNAT AND BIZOLLON
22 HR
JCE & M • 1976 Vol 42 • No 1
b-mm"1
FIG. 1. Influence of posture on heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure.
45
60
15
30
60
Plasma sodium. This parameter did not sig- tions, no difference could be found between male and female responses. After only 5 min nificantly change throughout the test. in the erect position, a significant rise was Plasma potassium. On the contrary, PK observed, and PRA continued to increase exhibited important variations. When supine, progressively, reaching 120 min later, values PK was significantly higher in males (4.2 three times greater than its basal values mEq/1 ± 0.1) than in females (3.9 mEq/1 (% S 60 = 408 ± 49.7 %) ± 0.1). PK increased to 4.4 ± 0.2 at 30 min, When subjects reclined, PRA decreased to 4.5 ±0.1 at 60 min in the males, and to rapidly but inconsistently, becoming signifi4.3 ± 0.1 at both times in the females. The cantly lower after 30 min of clinostatism. At mean values at 30 and 60 min (4.3 ±0.1 and the end of this last period, PRA did not reach 4.4 ±0.1 respectively) were highly signifi- its basal values, but remained slightly cantly different from the control values. elevated. In order to exclude any possible effect of Influence ofposture on endocrine parameters blood volume depletion related to the fre(Table 1, Fig. 2) quent sampling, an additional study was PRA variations. During orthostatism, these done in four male normal subjects, after 60 were expressed as absolute values and as min supine and 90 min of upright position. % S 60 in order to exclude the individual dif- Upright values, expressed as % S 60, were ferences and thus to express only the effect found to be 319 ± 51. There was no signifiof the stimulus. On the basis of these calcula- cant difference between the increase of PRA The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 March 2015. at 11:42 For personal use only. No other uses without permission. . All rights reserved.
23
POSTURE INFLUENCE ON RENIN AND ALDOSTERONE TABLE 1. Influence of posture on some parameters measured in normal man (Total mean ± SEM, compared to S 60*, compared to U 120**) Supine
Hematocrit % Plasma sodium mEq/1
1
45
60
45.8
46.5
46.3
46.3
0.4
0.3
0.9 NS*
0.8 NS*
142 1.4 NS*
142 0.7
Supine
Upright
142 1.1
15
30
60
90
120
47.7
48.5
47.6
47.3
47.3
47.2
1.0
0.9
0.3
0.9
0.9
NS*
1.2 NS*
NS*
NS*
NS*
143 0.6 NS*
143 1.0 NS*
143 1.0 NS*
142 0.7 NS*
142 0.9 NS*
3
5
5
15
30
60
46.0
45.8
46.0
45.7
45.5
1.2
0.9
0.9
NS*
NS**
NS**
NS**
0.9 NS*»
NS**
142 0.9 NS*
142
141 1.9
142 1.2
142 0.9
142 0.6
142 0.9
NS**
NS**
NS**
NS**
NS**
4.1 0.1
4.1 0.1
4.0 0.1
0.8 NS*
3
Plasma potassium mEq/1
4.1 0.1
4.0 0.1
4.1 0.1
4.2 0.1
4.1 0.1
4.1 0.1
4.3 0.1 S*
4.4 0.1 HS*
4.4 0.1 HS*
4.3 0.1 HS*
NS**
4.1 0.1 S**
NS**
4.0 0.1 S**
PRA ng/ 1/min
57.8 10.5
49.5
58.7 11.8
55.0 12.7
72.1 14.6
101.5 20.5
116.6 21.4
154.9 29.4
166.5 28.3
188.9 33.3
176.7 38.9
131.2 20.8
141
98
124 17
142.3 16.5
197.3 18.6
245
HS*
HS*
350 37 HS*
408
S*
329 38 HS*
375.9 60.0 NS**
327.3 44.6 NS**
303.6 45.6 NS**
119.7 20.2
215.7 36.9
260.3 35.1
261.8 36.1
266.3 40
216.7 31.5
231
-
63.9 10.5
238.1 26.2
408.6 67.8
558.9 77.1
S*
HS*
HS*
HS*
557.1 60.1 HS*
535.5 50.1 NS**
542.1 86.3 NS**
450
18.2
%S60
117.8
8.0 100
7.5
PAC
pg/ml %S60
35.4
49.2
6.6
5.8
72.8 9.1
100
118.5 10.6 43 7
89.6 11.3
132.2 17.6
74.3 6.9 160
24.5
49.7 HS*
25.6
32.4 45.3 NS**
19.7
1.1
NS** 82.5 18
24.3 HS**
143.5 14.6 HS**
238.8 32.6
211.5 40.3
525.5 100.6 NS**
441.1 51.7 NS**
193
Total mean ± SEM, compared to S 60*, compared to U 120**
observed in this group and in the one which was subjected to frequent blood sampling. PAC. Although individual values after 1 hour supine were slightly higher in females than in males (57.8 ± 8.4 and 42 ± 7.3 pg/ml respectively), no significant differences could be found between their responses to orthostatism. Using the same calculation as for PRA, a significant rise in PAC was noted after 15 minutes. This elevation increased progressively, reaching a plateau 90 min later. At this time, values were about 5 times greater than basal values (% S 60 = 558.9 ± 77.1). In contrast with PRA, PAC did not consistently decrease when the supine position was resumed. Correlations. No correlation was found between PRA and SBP or DBP. On the contrary, PRA in males and females was significantly correlated with Ht (r = 0.33, n = 139, P < 0.001). Furthermore, an attempt was made to correlate PRA, PAC, and PK using the values obtained between the 60th min of clinostatism and the 120th min of orthostatism.
The results were as follows: PAC-PRA: r = 0.55 n = 86 P < 0.001 r = 0.32 n = 86 P < 0.01 PAC-PK: PAC-PRA + PK: r = 0.58 n = 86 P < 0.001 A close correlation was found between PRA values obtained after 60 min of clinostatism (PRA S 60) and after 90 min of orthostatism (PRA U 90) : r = 0.81, n : 12, P < 0.001. Discussion Although the effects of posture on renin and aldosterone secretion are well documented, it must be emphasized that most previous works, having been clinically oriented, described endocrine adaptations only after a long period of active orthostatism or of passive tilting. We therefore thought it interesting to develop a kinetic study of the short-term variations of PRA and PAC induced both by orthostatism and the return to clinostatism. Protocol was chosen in order to reflect normal daily physiological activity. In this respect, we particularly prefered active ortho-
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24
SASSARD, VINCENT, ANNAT AND BIZOLLON
JCE & M • 1976 Vol 42 • No 1
% S60
500
.400
FIG. 2. Influence of posture on
plasma renin activity (continuous line) and plasma aldosterone concentration (dashed line).
300
200
100
TIME (min) 15 30 SUPINE
statism to passive tilt which is a more potent but non-physiological stimulus. Moreover, our human volunteers had not been hospitalized or submitted to a measured diet, so as to avoid any modifications in their habits. We carefully avoided history of illness and administration of drugs, especially oral contraceptives which can raise renin and aldosterone secretion rate (15,16). Similarly, the testing was done when females were in thefirstpart of their menstrual cycle, as it has been established that in the second part, as a result of progesterone production, there is an increase in PRA and PAC (17,18) as well as an alteration of their responsiveness to orthostatism (18,19).
The 12 tested subjects were free from orthostatic hypotension, and we found the usual cardiovascular adaptations, i.e., sharp increase of HR and BP ceasing quickly on resumption of supine position. During orthostatism, these variations reflected the autonomic stimulation induced by the decrease of circulating volemia (1,2), and especially of intrathoracic blood volume (4) due to collection of blood in the veins of the lower limbs (5). From the study of biological parameters, some interesting points arose. During orthostatism a significant increase in hematocrit was observed in males but not in females. A maximum of + 2.9% was reached after 30
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POSTURE INFLUENCE ON RENIN AND ALDOSTERONE min. This elevation is consistent with results reported, also in males, by Brown, Davies, Lever, Me Pherson and Robertson (20) and Molzahn, Dissmann, Halim Lohmann and Oelkers (4), and with the increase in colloidosmotic pressure shown by Nielsen and Moller (2). This hemoconcentration probably originates in a plasma shift which is the result of increased venous pressure in the lower part of the body. In females, an increase in Ht was also noted, but it was smaller ( + 1%) than in males. As their basal values varied more widely than in males, the elevation recorded was not significant. The second interesting parameter is the plasma potassium. When measured in precise and reproducible conditions, it has been possible to show that PK was significantly higher in males than in females, and that in the two cases, this parameter exhibited a significant increase of 0.4 mEq/1 after 60 min of orthostatism. This orthostatically induced hyperkaliemia was not due to hemoconcentration since, during the same period plasma sodium did not vary. Its origin is probably to be found in a release of intracellular K+ from exercising muscles (21). In our experiment, PK increased after the 15th min of active orthostatism, i.e., when subjects were no longer submitted to frequent blood sampling and had begun to walk freely in the laboratory. When considering endocrine parameters, very clear-cut variations were noted in spite of a protocol which could only attenuate the influence of orthostatism. At the beginning of the test the volunteers had been supine for one hour only and were not in a true basal state. Consequently, they demonstrated significantly higher PRA and PAC than normal subjects after a complete night of recumbency. Moreover, the nycthemeral cycle of renin and aldosterone secretion exhibit maximum rates at about 8 am (8,12,22) which decrease during the morning, i.e., during the test itself. Nevertheless, it was possible to find a significant increase of PRA after as little as 5 min of orthostatism. Our results are in accord with those of Oparil, Vassaux, Sanders and Haber (6),
25
although these authors used a head-up tilt. Furthermore, the rapid increase in PRA shown is consistent with the recent work of Kala, Fyhrquist, and Eisalo (8) who reported, in similar conditions to those of our experiment, an increase in plasma angiotensin II after 10 min of orthostatism. The lability of renin secretion is confirmed by the rapid fall of PRA on reclining. The values obtained are consistent with those of Oparil (6) who reported a renin half-life less than the 40 min stated by Weidman, Maxwell and Lupu (23). Similarly, PAC variations were considerable and rapid. There is no kinetic study of aldosterone secretion during orthostatism, but the finding of a significant increase after 15 min of stimulation seems logical. In the erect position, PRA increases after 5 min, angiotensin II after 10 min (8) and as observed here, PAC after 15 min. The latency of 5 min found between angiotensin II elevation and PAC increase is consistent with the results obtained after perfusion of exogenous angiotensin II (24). The magnitude of the increase in PAC reached a maximum of 4.5 times its basal values after 90 min of orthostatism. In contrast with PRA, PAC did not decrease rapidly after the end orthostatism, which indicates a lower metabolic clearance rate and/or a persistent action of the stimulus, probably potassium, whose effects on aldosterone secretion appear long lasting (24). At this point the question arises as to the mechanisms initiating these endocrine responses. In the case of aldosterone, if an orthostatism-induced decrease in metabolic clearance rate can participate in the PAC elevation it is certainly insufficient to account for the values reported here (9,23). ACTH also probably plays a minor role since, the upright position does not induce any increase in serum cortisol in normal man (2,12). On the contrary, aldosterone secretion is known to be controlled by two major parameters, potassium and renin. Like others (23,25,26), we found a significant correlation between PAC and PK (r = 0.32), but a closer correlation could be demonstrated between
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26
SASSARD, VINCENT, ANNAT AND BIZOLLON
JCE & M • 1976 Vol 42 • No 1
PAC and PRA (r = 0.55) and between PAC kidney (33) directly influence renin release, and PRA + PK (r = 0.58). These results or if they act via a modification of the renal would indicate that in normal man plasma bloodflowwhich can affect the baroreceptors potassium influences aldosterone secretion of the afferent glomerular arteriole as well during active orthostatism but that its main as the sodium delivery to the macula densa. The study presented here has both pracstimulus is renin secretion. Furthermore, the role of the renin angio- tical and theoretical implications. From a tensin system is emphasized by the kinetic practical point of view, the posture test, aspect of the endocrine adaptations ob- commonly lasting 2 or 3 hours and used in served, and by the fact that in the absence of patients rested for at least 10 hours, can userenin secretion, as seen in anephric humans, fully be replaced by a much shorter study. orthostatism induces no significant increase In a patient recumbent for one hour, an equally significant and stable increase in in PAC (9,12,25). When considering the changes in renin PRA as well as in PAC can be obtained after secretion during upright posture it is obvious 60 or 90 min of orthostatism. Ninety min that these could be explained neither by an would give more reliable results because at orthostatically-induced fall in its metabolic this time all the subjects studied exhibited clearance rate (27) nor by a drop in blood a consistent and reproducible response. The pressure nor by the slow hemorrhage induced main interest of such a simplified posture by blood sampling (as shown by our addi- test is that it can be applied in non-hospitaltional study in which repeated blood ized patients and will allow extensive sampling was avoided during the period of studies on the reactivity of the renin-angiotensin-aldosterone system in different pathoorthostatism). Thus renin secretion was probably con- logical states. The theoretical interest of our study controlled by redistribution of the circulating blood volume. The study of Gordon, Wolfe, cerns the mechanisms affecting renin and Island and Liddle (22), which showed that aldosterone secretion. It is clear that in leg bandaging prevented most of the renin normal man, during physiological changes of variations induced by orthostatism, is con- posture, the renin angiotensin system is of clusive in this respect. Moreover, the exist- greater importance than plasma potassium ence of a significant correlation between the for the control of aldosterone secretion. In increase in colloidosmotic pressure and in these conditions precise and rapid adaptaPRA found during orthostatism by Nielsen tions of renin release were observed, which and Moller (2), coupled with the correlation suggest a reflex control of renin secretion by between Ht and PRA described above the level of circulating blood volume. supports indirectly such an hypothesis. Other experiments tend to demonstrate Acknowledgments that renin secretion is sensitive to the circuare greatly indebted to pharmaceutical students lating blood volume and more precisely to andWemembers of our laboratory who were volunteers the intrathoracic blood volume (28,29). for this study; to Pr. Badinand and Dr. Paret for elecThese results, as well as ours could be trolytes determinations, to Dr. A. M. Fraysse for catheter explained on the basis of a reflex control of insertion; to Pr. A. Froment and Dr. H. Milon for staaid; to Dr. J. B. Douglas for translation; and to renin secretion, initiated by atrial volume tistical Mrs. Jarsaillon, Tapisser and Valancogne for excellent receptors (30). The efferent pathway of such technical assistance. a reflex may well be represented by the renal sympathetic nerves and by the adrenal References medulla secretion. In effect, autonomic insufficiency (31) as well as beta-blocking 1. Pannier, C , S. Seroussi, J. P. Martineaud, C. Vassilikos, and J. Durand, Les volumes sanguins circulants agents (32) are able to blunt the orthostatism chez l'Homme. II. Repartition, role et regulation du induced increase in PRA. What is not known volume sanguin circulant, Rev Fr Et Clin Biol 13: is whether the beta-2 receptors located in the 124, 1968. The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 21 March 2015. at 11:42 For personal use only. No other uses without permission. . All rights reserved.
POSTURE INFLUENCE ON RENIN AND ALDOSTERONE 2. Nielsen, I., and I. Moller, On the mechanism of renin stimulation: the effect of postural change, salt depletion, and exercise, Ada Med Scand 186: 493, 1969. 3. Gordon, R. D., O. Kuchel, G. W. Liddle, and D. P. Island, Role of sympathetic nervous system in regulating renin and aldosterone production in man,./ Clin Invest 46: 599, 1967. 4. Molzahn, M., T. A. Dissmann, S. Halin, F. W. Lohmann, and W. Oelkers, Orthostatic changes of hemodynamics, renal function, plasma catecholamines and plasma renin concentration in normal and hypertensive man, Clin Sci 42: 209, 1972. 5. Cohen, E. L., J. W. Conn, and D. R. Rovner, Postural augmentation of plasma renin activity and aldosterone excretion in normal people, J Clin Invest 46: 418, 1967. 6. Oparil, S., C. Vassaux, C. A. Sanders, and E. Haber, Role of renin in acute postural homeostasis, Circulation 41: 89, 1970. 7. Catt, K. J., P. Z. Zimmet, M. D. Cain, E. Cran, B. J. Best, and J. P. Coghlan, Angiotensin II blood levels in human hypertension, Lancet I: 459, 1971. 8. Kala, R., F. Fyhrquist, and A. Eisalo, Effect of shortterm upright posture on plasma angiotensin II, Scand J Clin Lab Invest 33: 87, 1974. 9. Balikian, H. M., A. H. Brodie, S. L. Dale, J. C. Melby, and J. F. Tait, Effect of posture on the metabolic clearance rate, plasma concentration and blood production rate of aldosterone in man,y Clin Endocrinol Metab 28 1630, 1968. 10. Horton, R., Laboratory determinations of aldosterone and their clinical significance, Am J Clin Pathol 54: 297, 1970. 11. Bayard, F., I. Z. Beitin, A. Kowarski, and C. J. Migeon, Measurement of plasma aldosterone by radioimmunoassay,y Clin Endocrinol Metab 31: 1, 1970. 12. Williams, G. H., J. P. Cain, R. G. Dluhy, and R. H. Underwood, Studies of the control of plasma aldosterone concentration in normal man. I. Response to posture, acute and chronic volume depletion and sodium loadingj Clin Invest 51: 1731, 1972. 13. Vincent, M., J. Sassard, and J. F. Cier, Methode rapide de determination radio-immunologique de 1'activite r6nine du plasma, Rev Eur Et Clin Biol 17: 1001, 1972. 14. Bizollon, Ch. A., J. F. Riviere, P. Franchimont, A. Favre, and B. Claustrat, A solid-phase radioimmunoassay for plasma aldosterone, Steroids 23: 809, 1974. 15. Tapia, H. R., C. E. Johnson, and C. G. Strong, Effects of oral contraceptive therapy on the reninangiotensin system in normotensive, hypertensive women, Obstet Gynecol 41: 643, 1973. 16. Beckerhoff, R., W. Vetter, H. Armbruster, J. A. Luetscher, and W. Siegenthaler, Plasma aldosterone during oral-contraceptive therapy, Lancet I: 1218, 1973. 17. Sundsfjord, J. A., and A. Aakvaag, Plasma angiotensin II and aldosterone excretion during the
18.
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21. 22. 23. 24.
25.
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27. 28. 29.
30.
31.
32.
33.
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