Effect Of β Adrenergic Blocking Drugs on the Renin-Aldosterone System, Sodium Excretion, and Renal Hemodynamics in Cirrhosis With Ascites

73:659-663, 1977 Copyright © 1977 by the American Gastroenterological Association

Vol. 73, No.4, Part 1 Printed in U.S A .

GASTROENTEROLOGY

EFFECT. OF p ADRENERGIC BLOCKING DRUGS ON THE RENINALDOSTERONE SYSTEM, SODIUM EXCRETION, AND RENAL HEMODYNAMICS IN CIRRHOSIS WITH ASCITES S. P. WILKINSON, B.Sc., M.B., M.R.C.P., M. BERNARDI, M .D., I. K. SMITH, PH.D., T. P . JowETT, B.Sc., J. D. H. SLATER, M.A., F.R.C.P., AND RoGER WILLIAMS, M.D., F.R.C.P. Liver Unit and Department ofBiochemical Pharmacology, King's College Hospital and Medical School, and the Thorn Institute of Clinical Science, Middlesex Hospital Medical School

As a result of effective {3 adrenergic blockade with either propranolol or practolol, plasma renin activity was suppressed in all of 11 patients with cirrhosis and ascites. In contrast, the effect on the rate of renal excretion of aldosterone was variable, suggesting that factors other than the renin-angiotension system are responsible for the control of aldosterone secretion in cirrhosis. The changes in aldosterone could not be explained on the basis of changes in the plasma concentrations of potassium or sodium. The renal sodium excretion was inversely related to the values for aldosterone both before and after {3 adrenergic blockade, indicating a major role for aldosterone in regulating sodium excretion. A number of patients had an abnormal intrarenal distribution of plasma flow with a relative hypoperfusion of the renin-secreting outer cortical nephrons. Plasma renin activity was inversely related to outer cortical plasma flow, suggesting that the reduced outer cortical flow may be a stimulus to increased renin secretion. Because the abnormal intrarenal hemodynamic pattern was not corrected by suppression of plasma renin activity, and presumably angiotension II concentrations, it is unlikely that it is attributable to the known renal vasonconstrictor effects of angiotensin II. Increased values for plasma renin activity1• 2 and for both the renal excretion3 • 4 and the plasma concentrations5· ,; of aldosterone may occur in patients with cirrhosis and ascites, and aldosterone is likely to be of major importance in the pathogenesis of the associated sodium retention. Impaired hepatic metabolism contributes toward the high levels of aldosterone/· 8 but an increased secretion is quantitatively more important.9 • 10 The relationship between plasma renin activity and aldosterone has not been reported, but the increased aldosterone secretion is generally thought to be attributable to increased activity of the renin-angiotensin system. If this assumption is correct, {3 adrenergic blocking drugs, such as propranolol, may be of therapeutic value as they are well known to suppress renin secretion in a variety of physiological and pathological states. 11- 15 Changes in the intrarenal distribution of plasma flow have also been reported in cirrhosis and we have previously shown that a reduced flow to the outer cortical nephrons is associated with an increased plasma renin

activity. 16• 17 Because renin secretion by the kidney is chiefly a function of the afferent arterioles of the outer cortical nephrons, 18 the high values for plasma renin activity may be secondary to the reduced outer cortical plasma flow. However, it is equally possible that other factors are responsible for an increased renin secretion and that the subsequent formation of increased amounts of angiotensin II within the kidney is t he cause of the reduced outer cortical flow, angiotensin II being a powerful renal vasoconstrictor substance. 19 lf the latter suggestion is correct, suppression of plasma renin activity with {3 adrenergic blockers would be expected to correct the reduced outer cortical plasma flow. In the present study we describe the effect of propranolol and practolol on plasma renin activity in patients with cirrhosis and ascites, together with the effects on the associated changes in aldosterone excretion, sodium excretion, and the intrarenal distribution of plasma flow.

Received January 27, 1977. Accepted April 6, 1977. Address requests for reprints to: Dr. S. P. Wilkinson, Liver Unit, King's College Hospital, Denmark Hill, London, SE5, England. The authors are indebted to the Wellcome Foundation and the special Trustees of the Middlesex Hospital for their support, and to Miss H. Moodie and Mrs. J . Richardson for technical assistance. Dr. Bernardi's present address is: lnstituto di Patologia, Medici III, University of Bologne, Italy.

Fifteen consecutive patients with cirrhosis and ascites were investigated. Etiological factors in the cirrhosis were alcohol (8 cases), chronic active hepatitis (2), and primary biliary cirrhosis (2). In the remaining 3 no specific cause was identified. None of the patients had renal failure, a history of recent hemorrhage, or signs of hepatic encephalopathy. If diuretics had previously been administered they were discontinued at least 2 weeks before the investigation. No patient was receiv-

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Patients and Methods

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Vol:]3 , No.4, Part 1

WILKINSON ET AL.

ing corticosteroids or other drugs known to interfere with on a 40- to 50-mmole sodium intake were 60 nmoles · day- 1 ± SE 6, n = 16) . In an investigationof32 patients\vith cirrhosis and renal function or the renin-aldosterone system. After 4 days of a controlled sodium intake (40 to 50 mmoles comparable renal function to those in the present study, we daily) renal function was evaluated on the morning of the 5th have shown that the excretion rate ofthe IS-glucuronide meday, after an overnight fast, by estimating the clearances of tabolite is closely related to the plasma concentration of aldosinulin and p-aminohippurate as previously described. 17 For terone (r = +0 .9SS, P < 0.001, unpublished observations). From the 6th to lOth days oral propranolol (up to 160 mg measurement of the intrarenal distribution of plasma flow the isotope renography technique of Britton and Brown 20 was daily) or practolol (up to 600 mg daily) were administered used. From an 131 I-hippuran renogram the uptake and removal (practolol has now been withdrawn from use in the United components of isotope by the kidney are determined. By a Kingdom), the patients being maintained "on the same sodium deconvolution analysis of these components the transit time of intake. On the lOth day the various measurements detailed for hippuran through the kidney is estimated. The latter is bimo- day 5 were repeated. dal and it has been shown by comparison with the microsphere Results technique in rabbits that the area of the first mode is a In 11 of the 15 patients effective f3 adrenergic blockade measure of plasma flow to the outer cortical nephrons whereas the second represents flow to the juxtamedullary nephrons. 21 was obtained as evidenced by a ·fall in the postexercise Normally more than 50 % of flow is distributed to the outer pulse rate, measured immediately after . a 100-yard cortical nephrons. 17· 2o walk, of 15 to 32%. Systolic arterial pressure did not fall The blood sample for estimating plasma renin activity was by more than 15 mm Hg (tablel). Severi of these 11 taken into disodium ethylenediaminetetraacetate (EDTA), patients were in positive sodium balance With a considthe patient having been supine for at least 1 hr. Plasma renin erably reduced renal sodium excretion. (1 to 18 mmoles activity was estimated by radioimmunoassay for angiotensin per day). The other 4 were innegative sodium balance I, 17 the latter being generated by incubating 1 ml of plasma at and undergoing a spontaneous diur~sis (sodium excre37°C for 3 hr with British antilewisite (BAL), 8-hydroxyquinolone, and Tris-HCl buffer. The pH of 6.6 was stable through- tion 58 to 114 mmoles per day) . In theJormer group both out. Recovery of added angiotensin I was quantitative, indicat- plasma renin activity and the rate ofrenal excretion of ing complete inhibition of angiotensinases and converting en- aldosterone were significantly greater than for control zymes. The generated angiotensin I was estimated using a subjects (3.15 nmoles ·liter.., 1 ~ hr- 1 ± SE 0.99; P < 0.05; specific antibody (supplied by Dr. S. Lader, Wellcome Re- 133 nmoles · day- 1 ± SE 32/ P <:: 0.005; respectively) agents, Beckenham, Kent, England) and expressed as the whereas these parameters were sigll.ificantly reduced in angiotensin I generation rate in nanomoles per liter per hour. the others (0.60 nmole ·liter- 1 • hr'- 1 ± ·sE 0.08, P < 0.001; The limit of detection for the assay was 0.05 nmole ·liter- 1 • 25 nmoles·day- 1 ± SE 7, P <;0.025, respectively). hr- 1 • Values for healthy control subjects under identical condiMter administration of propranolol ·or practolol there tions of sodium intake and posture were 1.82 nmole ·liter- 1 • hr- 1 ± SE 0.13, n = 20). The rate of renal excre- was invariably a marked fall in pbisma renin activity tion of both sodium and aldosterone were determined for the (P < 0.001, fig. 1, table 1}, the decrease being propor5th day, the latter measured as the IS-glucuronide metabolite tional to the height of the initial value (r = 0.995, P < by radioimmunoassay22 (values for the same control subjects 0.001). In contrast, the effect onaldosterone was variaTABLE

1. Relevant m easurements during control period (C) and after administration of {3-adrenergic bli:Jcking.drugs :{f3)"

Plasma renin activity Case

Aldosterone

c

Plasma concentration

Renal excretion

Sodium

Sodium

Potassium

Clearance Inulin

Plasma flow to outer cor- Systolic artetical nephrons . rial pressure

PAH"

{3

c nmole liter

1

hr

1

c

{3

nmole day

I

mmole day

2 3 4 5 6 7 8 9 10 11

7.96 5.32 2.83 2.53 1.91 0.80 0.75 0.69 0.61 0.59 0.53

2.90 1.52 0.80 0.43 0.35 0.13 < 0.05 0.16 < 0.05 < 0.05 0.10

139 131 68 58 123 277

140 161 96 10 57 219

18 15 45 23

22 5 16 41

1 4 66 114 65 112

12 13 14 15

11.48 7.11 2.88 1.62

12.02 11.22 3.39 2.04

213 1377 471 52

685 339 107

1 1 2 2

6 1 3 18

c

{3 1

{3

c

mmole liter

{3 1

c

c

{3

{3

ml!min

With clinically effective f3 blockade 3.9 3.6 61 5 138 133 68 139 137 3.1 3.6 96 103 1 136 136 3.6 3.4 120 108 92 78 142 140 3.5 3.5 88 4 135 134 4.5 4.3 80 83 1 131 132 3.6 3.3 182 190 4.4 16 130 130 4.2 86 90 57 138 136 3.9 3.8 118 116 167 136 137 4.0 4.0 148 158 102 141 146 4.4 4.5 84 90 5.2 4.6 140 131 83 141 138 Without clinically effective f3 blockade 4.7 3.9 81 1 123 121 5.4 85 1 127 130 5.5 4.5 4.5 249 240 1 132 134 82 4.0 4.0 79 2 132 134

" Cases 1, 2, 7, 9, 10, 11, and 12 r eceived propranolol, the others received practolol. "PAH, p-aminohippurate.

326 470 500 382 498 982 640 787 680 545 696 412 509 1533 480

c

-f3

. % total

c

{3

· · ml!min

c

{3

mmHg

299 496 481 358 450 1218 646 740 666 560 660

39 . .· · 147 '· 117 120 17 202 · 84 115 . 79 ' 130 . 380 .· 110 -35 114 ' 125 115 53 209 238 125 45 314 · . 548 ·- 105 72 384 465 ·. 115 31 496 229 115 73 510 .. 486-. 110 110 57 · 54 .· 397 .. ' 356 115

115 105 105 115 110 110 110 100 110 105 115

1212 452

45 34 25 69

105 105 105 115

45 43 26 30 ' 42 32 60 63 75

31 70

185 110 l73 105 383 . 376 ' 105 331 \ 357 120

October 1977

ble, values increasing in 5 and falling in the others, but the over-all change was not statistically significant (P > 0.2, fig. 1). The initial values for sodium excretion showed an inverse hyperbolic relationship to aldosterone (fig. 2). Mter {3 adrenergic blockade the changes in sodium excretion ranged from -29 to +60 mmoles per 24 hr, these being inversely related to the changes in aldosterone, the new values remaining within the original aldosterone-sodium excretion relationship (fig. 2) . In only one instance, however, was the fall in aldosterone so great that a patient initially in positive sodium balance lost ascites (case 4). Despite similar drug dosages, the other 4 patients showed no clinical evidence for effective {3 adrenergic blockade in that the postexercise pulse rate showed little or no change (< 10%) . They were all in marked positive sodium balance with a renal excretion of 1 to 2 mmoles per day. Values for both plasma renin activity and aldosterone were increased (5. 77 nmoles ·liter- 1 • hr- 1 ± SE 2.23, P < 0.001; 528 nmoles · day- 1 ± SE 295, P < 0.001, respectively). Plasma renin activity showed a slight, though statistically insignificant, rise after propranolol or practolol (P > 0.2), butagain there was no consistent change in the rate of aldosterone excretion (table 1). Considering the 11 patients who were accumulating ascites the mean value for the initial aldosterone excretion was 291 nmoles · day- 1 which is 4.85 times higher than values for control subjects. In the same group of patients the mean initial plasma renin activity was only 2.26 times higher (4.11 nmoles ·liter- 1 • hr- 1) than for controls. Plasma potassium and sodium. The plasma concentrations of potassium and sodium also failed to show any consistent change after administration of {3 adrenergic blockers. When changes in these did occur they were unrelated to the changes in the rate of aldosterone excretion (table 1). Renal hemodynamics. The percentage of plasma flow

to the outer cortical nephrons initially ranged from 26 to 75%. Absolute plasma flow to these nephrons (calculated from values for the percentage flow and p-aminohippurate clearance) ranged from 114 to 510 ml per min and was inversely related to the log10 of the plasma renin activity (r = -0.778, P < 0.001, fig. 3). In most patients, administration of propranolol or practolol had little effect on the percentage of plasma ~277

i

0 219

I

w

z

0 a:: w

fVl

0 0

-'

<

.. .. ISO

Vl

a::

0 I....

z "'

0

c5

a::

z

:!: i= w

u

100

X w

-'

<

zw

a::

0

40

'

\

JOO

200

'

100

FIG. 2. Relationship between the rates of excretion of sodium and aldosterone IS-glucuronide before ( e ) and after (0) effective {3 adrenergic blockade.

•

10

.."'

"'I 4

0

~

z

z

100

~

\.... 1 ..........1 ...... ..1 .....

•

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75

••

>-

'=>

•

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0

u

~ 50 u

z

...

•

<

~

•

zw a::

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25

FIG. 1. Values for plasma r enin activity, the rate of renal excretion of aldosterone IS-glucuronide, and the percentage of plasma flow to the outer cor tical nephrons before and after effective {3

--'-·--- - ---= ~

-' -'

•

z

<(

6:I:

l:

f"' 0

~

~

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,I

~

PLASMA FLOW TO OUTER CORTI CAL NEPHRONS

RENAL EXCRETION OF ALDOSTERONE

160

120

80

RENAL EXCRETION OF SODIUM MMOL. HHRs.-1

• PLASMA RENIN ACTIVIT>'

8

661

EFFECT OF {3 ADRENERGIC BLOCKING DRUGS

:!:

•

VI

< -' 0..

05 0

• •

200

100

300

OUTER CORTICAL PL ASMA FLOW

400

•• 500

ML.MIN''

FIG. 3. Relationship between plasma flow to outer cortical nephrons and plasma renin activity (log scale) before {3 adrenergic blockarlo fr =

-Cl 77R P <'

n

Clrll\

662

WILKINSON ET AL.

flow to the outer cortical nephrons ( <15% change), but in 1 this increased by 53% and in 2 other patients fell by 26 and 32% (fig. 1). Similarly, absolute plasma flow to these nephrons failed to show any over-all change. The inverse relationship between the outer cortical plasma flow and the log10 of the plasma renin activity was preserved after effective {3 adrenergic blockade ( r = :_0.646, P < 0.01). Changes in sodium excretion could not be related to changes in the intrarenal distribution of plasma flow (fig. 4). Total plasma flow (p-aminohippurate clearance) and glomerular filtration rate (inulin clearance) also showed no consistent change after treatment. Discussion The marked dissociation between the effects of propranolol or practolol on plasma renin activity and aldosterone in the "{3-blocked" patients, together with the disproportionate rise in aldosterone excretion when compared with the values for plasma renin activity, strongly suggest that factors other than the renin-angiotensin system are responsible, at least in some patients, for the control of aldosterone secretion in cirrhosis. Cha~ges in the plasma concentrations of potassium or sodium were clearly not the basis for this. Although the fall in aldosterone that was observed in some patients could be attributable to the associated suppression of plasma renin activity, the increase in the others is totally unexplained. A marked day to day variation in the renal excretion of aldosterone in cirrhosis has previously be~n reported. 23 There are other situations in which the factors responsible for the control of aldosterone secretion are unknown, including starvation, 24 sodium depletion, 25 the syndrome of inappropriate antidiuretic hormone secretion, 26 and the exposure to and return from altitude. 2 i The inverse hyperbolic relationship between the excretion rates of aldosterone and sodium is similar to that reported for normal subjects by Laragh et al. 28 The finding that the values remained within this relationship after {3 adrenergic blockade, with the sodium excretion changing as would be predicted from the aldosterone values, emphasizes the importance of aldosterone in the regulation of sodium excretion in the patients investigated. It should be pointed out, however, that anum6 SODIUM EXCRETION

60

•

• ·40 ---------.-f-'•:..e----~ 60 6 IRDPF

•

•· 30 FIG. 4..Iliustrating the absence of a relationship between changes in ·.t he if1trarenal distribution of plasma flow (!RDPF) (expressed as chiillge\n percentage of flow to outer cortical nephrons) and sodium excnition after effective {3 adrenergic blockade.

Vol. 73, No.4, Part 1

her of patients with cirrhosis have a markedly reduced renal blood flow , much lower than would be expected from the p-aminohippurate clearance values in the present group of patients, and in such cases this alone may be sufficient to account for sodium retention. 16 Rosoff et al. 10 have questioned the importance of aldosterone in mediating sodium retention in cirrhosis. They administered aminoglutethimide, a drug that interferes with steroid synthesis, to 3 patients with avid sodium retention. Although previously elevated plasma levels of aldosterone fell markedly there was no increase in sodium excretion. However, these patients were reported to have "long-standing diuretic-resistant ascites" and in our experience, and that of others, 29 such patients invariably have a markedly reduced renal blood flow . The mechanism whereby propranolol and practolol reduce plasma renin activity is uncertain, 30 but may be related to the direct {3 adrenergic innervation of the renin-secreting juxtaglomerular cellsY· 32 Failure to reduce plasma renin activity in 4 of the 15 patients was probably caused by insufficient drug dosage as they had no clinical evidence for effective {3 adrenergic blockade. The plasma levels of propranolol are poorly related to the oral dosage. 33 The finding of a suppression of plasma renin activity with effective {3 adrenergic blockade could indicate that the increased values are adrenergically mediated. Other factors may also be involved, however, inasmuch as {3 adrenergic activity is probably important in maintaining basal renin secretion, 14 • 15 and removal of this component would attenuate the effects of any other stimulus. Barnardo et al. 34 have shown the importance of a vascular receptor in the control of renin secretion in cirrhosis, in that an increased plasma renin activity was related to a reduced renal plasma flow, but when the latter was improved by an infusion of dopamine, the plasma renin activity fell to normal. Rather than a reduced total renal plasma flow, the stimulus to an increased renin secretion is more likely to be a reduced plasma flow to the renin-secreting outer cortical compartment of the kidney, and in support of this we found the latter to be inversely related to plasma renin activity both before and after effective {3 adrenergic blockade. The reduced plasma flow presumably leads to a reduction in pressure within the afferent arterioles, the proposed location of the baroreceptors that mediate renin release. Because the reduced outer cortical plasma flow was not corrected by suppression of plasma renin activity; and therefore presumably angiotensin II concentrations also, it is unlikely th at the abnormal intrarenal hemodynamic pattern is secondary to the effects of angiotensin II. The marked change in intrarenal plasma flow distribution observed after {3 blockade in 3 patients may be a manifestation of the renal "vasomotor instability" reported by others to be characteristic of cirrhosis. 35 A redistribution of plasma flow from the outer cortical to the larger juxtamedullary nephrons has also been suggested as a mechanism for an abnormal renal retention of sodium, 36 but the lack of correlation between changes in intrarenal plasma flow distribution and

October 1977

EFFECT OF {3 ADRENERGIC BLOCKING DRUGS

renal sodium excretion after f3 adrenergic blockade makes it unlikely that this is an important mechanism in cirrhosis. The low values for both plasma renin activity and aldosterone excretion in the patients undergoing a spontaneous diuresis was to be expected since mobilization of fluid from the ascitic compartment to the plasma can be regarded as equivalent to a saline infusion. In 4 of 6 patients who were previously retaining sodium, Rosoff et al. 10 found that the elevated values for plasma renin activity and the plasma aldosterone concentration fell markedly when they underwent a spontaneous diuresis. The minimal effect of effective {3 blockade on blood pressure was also of interest. This is perhaps not surprising since Leonetti et al. 37 have shown in hypertensive subjects that renin suppression occurred at a dose of propranolol lower than required to reduce blood pressure. REFERENCES 1. Brown JJ, Davis DL, Lever AF, et al: Variations in plasma renin concentration in several physiological and pathological states. Can Med Assoc J 90:201-206 , 1964 2. Fasciola JC, De Vito E, Romero JC , et al: The renin content of the blood of humans and dogs under several conditions. Can Med Assoc J 90:206-209, 1964 3. Chart JJ, Shipley ES: The mechanism of sodium retention in cirrhosis of the liver (abstr). J Clin Invest 32:560, 1953 4. Leutscher JA, Johnson BB: Observations on the sodium retain· ing corticoid (aldosterone) in the urine of children and adults in relation to sodium balance and edema. J Clin Invest 33:14411446, 1954 5. Peterson RE: Adrenocortical steroid metabolism and adrenal cortical function in liver disease. J Clin Invest 39:320-331, 1960 6. Wolff HP, Bette L, Blaise H, et al: Role of aldosterone in edema formation. Ann NY Acad Sci 139:285-294, 1966 7. Coppage WS, Island DP, Copner AE, et al: The metabolism of aldosterone in normal subjects and in patients with hepatic cirrhosis . J Clin Invest 41:1672-1680, 1962 8. Vecsei P , Dusterdieck G, Jahnecke J, et al: Secretion and turnover of aldosterone in various pathological states. Clin Sci 36:241-256, 1969 9. Ulick S, Laragh JH, Lieberman S: The isolation of a urinary metabolite of aldosterone and its use to measure the rate of secretion of aldosterone by the adrenal cortex of man. Trans Assoc Am Physicians 71:225-235, 1958 10. Rosoff L, Zia P , Reynolds T, et al: Studies of renin and aldosterone in cirrhotic patients with ascites. Gastroenterology 69:698705, 1975 11. Assay keen TA, Clayton PL, Goldfien A, et al: Effect of alpha and beta adrenergic blocking agents on the renin response to hypog· lycaemia and epinephrine in dogs. Endocrinology 87:1318-1322, 1970 12. Michelakis AM, McAllister RG: The effect of chronic adrenergic receptor blockade on plasma renin activity in man. J Clin Endocrinol Metab 34:386-394, 1972 13. Buhler FR, Laragh JH, Baer L, et al: Propranolol inhibition of renin secretion. N Engl J Med 287:1209-1214, 1972 14. Skrabal F, Czaykowska W, Dittrich P, et al: Immediate plasma renin response to propranolol: differentiation between essential and renal hypertension. Br Med J 2:144-147, 1976 15. Davis R, Slater JDH: Is the adrenergic control of renin release dominant in man? Lancet 2:594-596, 1976

663

16. Wilkinson SP, Moodie H, Alam A, et al: Renal retention of sodium in cirrhosis and fulmina nt hepatic failure. Postgrad Med J 51:527-531, 1975 17. Wilkinson SP, Smith IK, Clarke M, et al: Intrarenal distribution of plasma flow in cirrhosis as measured by transit renography: relationship with plasma renin activity, and sodium and water excretion. Clin Sci Mol Med, 52:469-475, 1977 18. Cook W, Pickering G: Location of renin within kidney (abstr) . J Physiol (Lond) 143:78P, 1958 19. Itskovitz HD, McGiff JC: Hormonal regulation of the renal circulation. Circ Res 34-35(Suppll):65-73, 1974 20. Britton KE, Brown NJG: Chap V, Chap X, in Clinical Renography. London, Lloyd-Luke, 1971 p 87-106; 207-219 21. Wilkinson SP, Bernardi M, Britton KE , et al: Validation of "transit renography" as a method for determining the intrarenal distribution of blood flow (abstr). Clin Sci Mol Med 50:13P, 1976 22. Jowett TP , SlaterJDH, Piyasene RD , et al: Radioimmunological assay of aldosterone in plasma and urine: validation of a novel separation technique and a rapid urine analysis. Clin Sci Mol Med 45:607-623 , 1973 23. Hurter R, Nabarro JDN: Aldosterone metabolism in liver disease. Acta Endocrinol (Kbh) 33:168-174, 1960 24. Boulter PR, Spark RF, Arky RA: Dissociation of the reninaldosterone system and refractoriness to the sodium-retaining action of mineralocorticoid during starvation in man. J Clin Endocrinol Metab 38:248-254, 1974 25. Blair-West JR, Coughlan JP, Crane E, et al: Increased aldosterone secretion during sodium depletion with inhibition of renin release. Am J Physiol 224:1409-1414, 1973 26 . Fichman MP, Michelakis AM, Horton R: Regulation of aldosterone in the syndrome of inappropriate antidiuretic hormone secretion (SIADH). J Clin Endocrinol Metab 39:136-144, 1974 27 . Slater JDH, Tuffley RE, Williams ES, et al: Control of aldosterone secretion during acclimatization to hypoxia in man. Clin Sci 37:327-341, 1969 28. Laragh JH, Sealey JE, Sommers SC: Patterns of adrenal secretion and urinary excretion of aldosterone and plasma renin activity in normal and hypertensive subjects. Circ Res 18(Suppl 1):158-174, 1966 29. Arroyo V, Rodes J : A rational approach to the treatment of ascites . Postgrad Med J 51:558-562, 1975 30. Shrier RW: Effects of adrenergic nervous system and catecholamines on systemic and renal haemodynamics, sodium, and water excretion and renin secretion. Kidney Int 6:291-306, 1974 31. Barajas L: The innervation of the juxtaglomerular apparatus. Lab Invest 13:916-929, 1964 32. Ganog WF: Biogenic amines, sympathetic nerves, and renin secretion. Fed Proc 32:1782-1791, 1973 33. Zanchetti A: Discussion of the antihypertensive effect of betablockers. In Beta-blockers-Present Status and Future Prospects. Edited by W Schweizer. Bern-Stuttgart-Vienna, Hans Huber, p 34, 1974 34. Barnardo DE, Summerskill WHJ, Strong CS, et al: Renal function, renin activity and endogenous vasoactive substances in cirrhosis. Am J Dig Dis 15:419-425, 1970 35. Epstein M, Berk DP, Hollenberg NK, et al: Renal failure in the patient with cirrhosis: the role of active vasoconstriction. Am J Med 49:175-185, 1970 36. Goodyer AVN, Jaeger CA: Renal response to non-shocking haemorrhage: role of autonomic nervous system and of renal circulation. Am J Physiol 180:69-74, 1955 37 . Leonetti G, Mayer G, Morganti A, et al: Hypotensive and renin suppressing activities of propranolol in hypertensive patients. Clin Sci Mol Med 48:491-499, 1975