Kidney Internazional, Vol. 9 (1976) p. 511—519

Effect of blockade of angiotensin II on blood pressure, renin and aldosterone in cirrhosis EDWARD T. SCHROEDER, GUNNAR H. ANDERSON, STEPHEN H. GOLDMAN and DAVID H. P. STREETEN Nephrology and Endocrinology Sections, Department of Medicine, Upstate Medical Center, State University of New York, Syracuse, New York

PRC. Chez deux malades atteints de cirrhose 'sans ascite, déplétés en sel, l'administration de saralasine determine une augmentation de 'Ia pression artérielle sans modifications significatives de PRA, PRC ou PA. Ces résultats apportent lapreuve'que chez les maiades .atteints de cirrhoseet d'ascite l'angiotensine 11 circulante est active dans Ic maintien de Ia pression artérielle, dans Ia suppression de Ia liberation rénale de rénine et dans Ia stimulation de Ia liberation d'aldostérone.

Effect of blockade of angiotensin II on blood pressure, refill and aldosterone in cirrhosis. l-Sar-8-ala angiotensin II (saralasin) was infused intravenously in graded doses of from 0. Ito 10 ,.ig/kg/min to five patients with cirrhosis and ascites after three days of restricted sodium intake. In each patient blockade of All by saralasin produced a marked fall in blood pressure, a rise in plasma renin activity (PRA) and plasma renin concentration (PRC) and, in four of the five, a fall in plasma aldosterone (PA). The rise in PRA and PRC correlated poorly with changes in blood pressure. The effects of saralasin rapidly reversed after cessation of the infusion. Plasma

Patients with advanced cirrhosis and ascites may have mild hypotension in the presence of normal or high total plasma volume [1—5]. In such cases, decreased "effective." plasma volume and/or decreased systemic vascular resistance have been suggested as 'causes of the low blood pressure [5]. Recent studies using i.v. infusion of an angiotensin antagonist suggest that in condictions with low plasma volume or low 'cardiac output, maintenance 'of normal blood pressure is dependent upon the vasoconstrictor effect of circulating angiotensin II (All) [6, 7]. The purpose of this study was to determine, by use of a specific antagonist of All (the All analqgue l-sar-8-ala angiotensin II), whether the control of blood pressure in patients with cirrhosis and ascites is angiotensin-dependent. By assessment of changes in blood levels of certain parameters of the renin-an'giotensin system in

volume was normal or high in each case. Three patients were mildly hypotensive in the control state, and all five were resistant to the pressor effect of infused All. After three days of salt loading, the above effects of saralasin were diminished but not abolished, in

four normal subjects, after salt depletion, saralasin infusion induced qualitatively similar but much smaller changes in blood pressure, PRA and PRC. In two cirrhotic patients without ascites, after salt depletion, saralasin infusion caused a rise in blood pressure with no significant changes in PRA, PRC or PA. These results provide evidence that in patients with cirrhosis and ascites circulating All is active in support of blood pressure, in direct suppression of renal renin release, and in stimulation of aldosterone release. Effets du blocage de l'angiotensine II sur Ia pression artérielle,, 'Ia refine et l'aldostérone au cours de Ia cirrhose. La l-sar-8-ala angiotensine II (saralasine) a été administrée par voie intra-veineuse a doses croissantes de 0,1 a l0jsg/kg/min a cinq malades atteints de

cirrhose ascitique après trois jours de restriction des apports de sodium. Chez tous les malades le blocage de l'A II par Ia sara'lasine

determine une baisse importante de Ia pression artérielle, une augmentation del'activité rCnine plasmatique (PRA) et de Ia

concentration plasmatique de rénine (PRC). Une baisse de

response to blockade of circulating All, we also

l'aldostérone plasmatique (PA) est observée chez quatre des cinq malades. L'augmentation de PRA et PRC n'est pas bien corrélée avec Ia baisse de Ia pression artérielle. L'effet de Ia saralasine est

sought to determine if a 'defective or inadequate response of the renin-angiotensin system may be re-

rapidement reversible après Ia fin de Ia perfusion. Le volume plasmatique dans chacun de ces cas était normal ou augmenté.

sponsible in some patients for failure to maintain

Trois de ces malades avaient un abaissement modéré de Ia pression

blood pressure at a normal level.

artérielle a l'état basal et tous les cinq étaient résistants a l'effet presseur de l'angiotensine 11. Après trois jours de charge en sel les effets de Ia saralasine décrits 'ci-dessus sont diminués mais non abolis. Chez quatre sujets normaux déplétés en sel l'administràtion de saralasine a produit des modifications quaiitativementsimilaires mais très attCnuées en ce qui concerne Ia pression artérielie, PRA et

Methods

Seven patients were selected from 'the medical wards

at the State University and the Vteran's Administration Hospitals, Syracuse, New York, and were studied in the Clinical Research Center. Each had historical, physical and laboratory evidence of chronic cirrhosis of the liver, confirmed by biopsy in most cases, and due to excessive alcohol intake in all but one case.

Received for publication November 5, 1975; and in revised form January 22, 1976.

© 1976, by the international Society of Nephrology.

511

Schroeder et al

512

Five patients (cases 1—5, Table 1) had moderate to marked ascites with urinary sodium excretion of less than 10 mEq per day. Two of these (cases 2 and 4) had evidence of hepatocellular dysfunction with mild jaundice. Cases 6 and 7 had cirrhosis without ascites. Each patient was medically stable at the

at the end of each hour and one hour following discontinuation of the drug. Oral fluids were allowed

ad lib throughout the procedure. For comparison, four normal volunteers were given an infusion of saralasin as described above after three days of low

time of study, and none had intrinsic renal disease or abnormal serum sodium, potassium, chloride, calcium or bicarbonate concentration. In one patient

salt intake (10 mEq dietary Na per day). Some of the data obtained from studies in these normal subjects have been previously reported [8]. On each blood sample renin activity (PRA), renin

(case 1), observations were repeated after two months during which general clinical improvement was noted.

concentration (PRC), renin substrate and aldosterone were measured. PRA was determined in dupli-

All medications were discontinued on admission to

cate on each sample by radioimmunoassay of angio-

the Clinical Research Center and a constant diet

tensin I (Al) generated during incubation for two

containing 10 mEq of sodium and 90 mEq of potassium daily was started, with fluid ad lib. After three to five days, the effects of an i.v. infusion of the angiotensin analogue were determined. Five of these patients were then given a daily dietary supplement of 150 to 190 mEq of Na as sodium chloride for three days, resulting in an average weight gain of 2.1 kg.

hours using a modification of the method of Cohen et

given one to two liters of 0.9% sodium chloride i.v. over a period of eight hours. After conclusion of the second infusion study, diuretics were used to remove

(Miles Laboratories) was added to plasma to obviate possible effects of deficient endogenous substrate on

excess fluid.

dioimmunoassay was used to determine the amount of Al generated after incubation for two hours at a pH of 7.4. The mean + SD for morning samples from recumbent normal subjects deprived of salt was 9.2 + 3.0 ng/ml/hr and salt-loaded normal subjects 1.3 + 0.7 ng/m I/hr. We chose to express values for PRC in this study in terms of the Al generation rate rather than in renin units because of multiple factors, possibly independent of the plasma concentration of renin, which might influence Al generation in this type of assay [11]. Plasma renin substrate was determined by the method of Tree [12] as modified by Waite, Tree

Prior to a repeat infusion study, each patient was

Infusion protocol. Upon waking, the patient ate breakfast and remained in bed in a comfortable recumbent position. Needles were inserted into veins for infusion of the All analogue and for collection of blood samples. Brachial artery systolic and diastolic blood pressures were then recorded automatically every two minutes by the Arteriosonde 1216 (Roche) during a one-hour control period and during the i.v. infusion of saralasin (1-sar-8-ala angiotensin II, Ea-

ton Laboratories) given initially at 0.1 g/kg/min. If no significant change in mean blood pressure (10 mm

Hg or more) was noted after one hour, the rate was increased to 1 tg/kg/min for one hour and then to 10 zg/kg/min for one hour. Blood samples were drawn

al [9]. In our laboratory the mean SD for morning samples taken from recumbent normal subjects was 5.3 + 0.44 ng/ml/hr after five days of low sodium intake (10 mEq/day) and 1.0 + 0.1 ng/ml/hr after three days of salt loading (150 mEq Na/day). PRC was measured by a modification of the method of Gould, Skeggs and Kahn [10]. Hog renin substrate

the in vitro generation of angiotensin. The Al ra-

and McDermott [13] using the A! radioimmunoassay. The mean SD in our laboratory for normal subjects deprived of salt and on no medication was

Table 1. Baseline data after salt deprivation in patients with cirrhosis

Patient 1

la 2 3

4 5 6 7 Normalsubjects;

Blood pressure, mm Hg

Plasma renin activity,

Plasma renin content,

Plasma renin substrate,

Plasma aldosterone,

ng/ml/hr

ng/ml/hr

moles/liter

ng/IOO ml

14

41

50

4

8 77 30 26

0.21 0.23 0.0 0.29 0.27 0.73 0.21

100/65 115/70 105/70

95/60

14 10

110/45 100/65

18

3

115/70 112/65

Mean sn

57 6 8

1

3 5.3

0.44

9.2 + 3.0

Case Ia represents a repeat study in case I after a two-month interval.

0.27 1.26

0.56

Angioterisin 11

sensitivity,

ng/kg/min 47

60



106 118

54 28

55



159 12

48

33

II

21.1 + 8.3

7 < 12

513

Angiotensin blockade in cirrhosis 1.2 0.56 tmole/1iter. Plasma aldosterone was determined by the radioimmunoassay method of Under-

wood and Williams [14]. The mean + SD for saltdeprived normal subjects recumbent at 8 to 9 AM 8.3 ng/l00 ml. was 21.1 The pressor response to graded i.v. infusion of All (l-asp-5-val angiotensin II, Ciba) was determined in six of the seven patients in the salt-deprived state. The

rate of All infusion required to raise the diastolic blood pressure 20 mm Hg was recorded as a measure of the All sensitivity. In our laboratory, the All sensitivity in salt-deprived normal subjects was less than 12 ng/kg/min. Mean blood pressure was calculated as:

Fig. 1. In the salt-deprived state (Fig. IA) the All analogue caused a fall in blood pressure in all six studies in patients with ascites. The average of the mean blood pressures in this group fell from a baseline value of 77 mm Hg to 58.3 mm Hg. In patients I, 3 and 5, the minimum recorded blood pressure was reached at an All analogue infusion rate of only 1.0 ig/kg/min, and in cases 1 and 3 the onset of hypotension was precipitous and this dose level was not exceeded. By comparison, in four normal patients similarly salt-deprived, the maximum fall in mean

CD

0

diastolic pressure + (systolic pressure — diastolic pressure)

0 0

0

-o

0

Plasma renin and aldosterone were within normal limits in the two patients without ascites. Plasma

CD

C

0— —

Co

rized in Table 1. In patients with ascites the baseline blood pressure was somewhat low, only case la having a systolic pressure greater than 110 mm Hg. The baseline PRA was high in four and PRC was high in five of the six patients with ascites, and plasma aldosterone was elevated in each patient with ascites.

CD

Selected baseline data obtained after salt deprivation and just prior to the infusion test are summa-

-o

Results

0

nurse were in attendance at the bedside throughout the study.

0

Medical Center. Prior to study, fully informed consent was obtained from each patient. A physician and

ci

These studies were approved by the Committee for

the Protection of Human Subjects of the Upstate

Mean blood pressure, mm Hg a' -J

3

somewhat decreased (70 to 75 mI/mm) in three patients with ascites. In five of the cirrhotic patients, after salt deprivation, plasma volume using '251-labeled serum albumin ranged from 48 to 70 mI/kg dry weight (weight minus estimated weight of ascitic fluid). This compares to a range for plasma volume from 39 to 49 mI/kg in normal subjects on salt-restricted diet in our laboratory. Cardiac output, measured by '251-RISA dilution in one patient (case 5) after salt deprivation, was 7.07 liters/mm with a predicted output of 6.26 liters/rn in.

The maximum change in blood pressure in response to infusion of the All analogue is shown in

0 0

to Al!. Renal function, as estimated by 24-hr clearance of creatinine, was normal in four patients but

o

with ascites were resistant to the pressor effect of All, whereas those without ascites were normally sensitive

ci o

patients tested for response to All infusion, those

Mean blood pressure, mm Hg

renin substrate was low in six of the seven patients. In

Fig. 1. Response of blood pressure to infusion of the All analogue 1-

sar-8-ala angiotensin 11 in patients with cirrhosis. A. After salt deprivation. B. After salt repletion. (Shaded area defines the range for four normal subjects.)

514

Schroeder

el al

pressure at a dose of 10tg/kg/min averaged only 5.2

while in cases 6 and 7 (Fig. 4A) levels were initially

mm Hg. In the two patients with cirrhosis but no

within the normal range and showed no definite change during infusion. Changes were variable in

after salt repletion. In most cases where blood pressure was altered by the All analogue, return to baseline levels occurred

0 0, -J I /

a

usually within 15 mm after the drug was stopped. There was no significant change in pulse rate or rhythm in any patient throughout the study, and

C

-o

patients experienced no symptoms during infusion of the All analogue. Figures 2 and 3 show the effects of infusion of the

change in mean blood pressure or only a slight decrease (3 mm Hg or less). Also in six of these eleven studies, the peak plasma renin level appeared during the first hour at an infusion rate of 0.1 tg/kg/min. In

contrast, none of the normal subjects showed a

a 0

fusion rates of the analogue which produced no

Plasma renin

(50% or more above control values) occurred at in-

0

analogue (Figs. 2A and 3A). In six of eleven studies in the patients with ascites, a significant increase in PRA

activity,ng/mMir

patients (Figs. 2A and 3A) a definite increase in PRA and PRC was noted during infusion of the analogue in most patients. Following salt repletion, increases in PRA and PRC of a similar nature were noted (Figs. 2B and 3B). In patients 6 and 7 no significant change

I

0

All analogue on PRA and PRC. In salt-deprived

in PRA or PRC occurred during infusion of the

L

no significant change in blood pressure during infusion of the All analogue at a rate of 10 tg/kg/min

2=

sensitive to the analogue when salt-deprived, showed

I

with cirrhosis and ascites showed a definite fall in mean blood pressure (ranging from 7 to 13 mm Hg) in response to infusion of the All analogue at a rate of 10 g/kg/min. This is in sharp contrast to the rise in blood pressure noted in four normal subjects receiving high salt intake. In cirrhotics salt repletion reduced the sensitivity of the blood pressure to the All analogue, in that doses of 1.0 g/kg/min failed to affect the mean pressure. Case 5, who was quite

three studies.

Plasma renin activity, ng/rn//hr

ascites (cases 6 and 7), baseline levels of blood pressure, PRA, PRC and plasma aldosterone were normal, and the blood pressure rose in response to the All analogue. After salt repletion (Fig. 1B) four of five patients

change in PRA at this dose level. Thus, the effect of the All analogue on plasma renin correlated poorly with changes in blood pressure and was considerably more potent in some patients with cirrhosis and ascites than it was in normal subjects. Plasma renin substrate was measured before, during and after infusion of the analogue, and there was

no change from the baseline value in any case. Plasma aldosterone level (Figs. 4A and 4B) fell during infusion of the All analogue in seven of twelve cases,

Fig. 2. Response of plasma renin activity to infusion of the All analogue I-sar-8-ala angiotensin 11 in patients with cirrhosis. A. After salt deprivation. B. After salt repletion. (Shaded area defines the range for four normal subjects.)

515

A ngiolensin blockade in cirrhosis

0

In certain types of hypertension associated with high plasma renin activity there is indirect evidence linking the elevation in blood pressure with circulating angiotensin II (All) [15—18]. Recently, evidence has been obtained suggesting that this potent vasoconstrictor may be important in maintaining normal blood pressure under certain conditions. In salt-depleted dogs and in dogs with low cardiac output due to ligation of the thoracic inferior vena cava, i.v. infusion of the specific antagonist of All used in the present studies, 1-sar-8-ala angiotensin 11 (saralasin),

0

-o 0

5

CD

C

5——

>

-v

I I

07

0

0 0

Plasma renin concentration, ag/mi/hr

0

Discussion

E

3 2

I

I

8

120

la 4

I

8

80

:1

7

I

40 6 Pre

0

'.3

Plasma renin concentration,

ng/mflhr

0I

160

A.

-

E

5

1a

120

2 3

CD

0 CD

The statistical significance of the changes induced by saralasin in patients with ascites was determined using two-way analysis of variance. In the salt-depleted state, changes were significant for blood pressure and PRA (P < 0.005) and for PRC and aldosterone(P E

cci cci

60 40 20

0

:fl H

:ifI

ilfinni

80 40 0

40

C

I

5

a,— 120

60 20

I

4

160

•E .2 . 80

'E

I

3 Hours

100

c:c'

I

2

120 100

L

80

c, caC

60

E

E

40 20 0

n

100 a,-

80

0.

E 60 40

.2

-

E

0.1

1.0

All analogue,

10.0

60 40 20

cci

pg/kg/rn/n

.

nHFi.I[1

Fig. 5. Results of a representative study of infusion of the All

analogue I -sar-8-ala angiotensin II in a patient with cirrhosis and ascites after salt deprivation. Shading in the bars corresponds to rates of infusion of the analogue.

100

Thus, a blood level of All possibly insufficient to maintain normal blood pressure in an angiotensindependent patient may be sufficient to suppress renin release, and may prevent maximum generation of All in response to the stimulus of hypotension. It would be of interest to know the actual level of circulating All in these patients particularly considering that low plasma renin substrate concentration

in cirrhotic patients may affect angiotensin gener-

80

o

E a,

40

20

0.1

A

1.0

10.0

II analogue, pg/kg/rn/n

Fig. 6. Results of a representative study of infusion of the All

analogue I .sar-8-a/a angiolensin II in a patient with cirrhosis and ascites after salt repletion. Shading in the bars corresponds to rates of infusion of the analogue.

518

Schroeder

PRA. Thus, the elevated baseline PRA found in many of our patients is consistent with high blood All levels. Whether or not the All level was appropriate to the stimulus of hypotension in our patients is not clear. The resistance to the pressor effect of i.v. administered All noted in our angiotensin-dependent pa-

tients may also be indirect evidence of high ambient blood All levels, since in several animal models

All resistance has been attributed to saturation of All receptors by endogenously generated All [6, 7, 34]. This may be the cause of the marked resistance to All previously noted in cirrhosis [35]; however, our study does not address itself to this question.

Saralasin effectively blocked aldosterone release and/or synthesis in four of five salt-deprived patients who had elevated baseline serum aldosterone levels, in spite of increased PRC and PRA (Fig. 4A). Thus, in cirrhotic humans, as in dogs with plasma volume

depletion or low cardiac output [6, 7], aldosterone secretion is sensitive to blockade by the octapeptide analogue, l-sar-8-ala ALL, even though a heptapeptide metabolite of All may contribute to stimulation of aldosterone secretion [36—38].

The physiological and hormonal responses to All blockade in our patients with cirrhosis and ascites noted above were similar in evety way to those of animal models with plasma volume depletion or low cardiac output [6, 7]. Since plasma volume was normal or high in our patients and presumably cardiac output was adequate [2—5], the concept of deficient "effective" plasma volume might be proposed as an

explanation for angiotensin dependency of blood

et a!

upon All for control of blood pressure in these patients is probably a normal compensatory mechanism in response to some derangement of fluid or hemodynamic balance. The data obtained from these preliminary studies do not allow for definitive conclusions concerning the possible role of a defective response of the renin-angiotensin system in causing low baseline blood pressure noted in some patients

with cirrhosis and ascites. The circulatory abnormalities in cirrhosis are probably multifactorial in origin, and further studies of the effects of All block-

ade might contribute to a clearer understanding of the role of the renin-angiotensin system in vasomotor control in patients with cirrhosis. Since this study was completed, however, it has come to our attention that occasionally dogs with ligation of the thoracic vena cava may be very sensitive to All blockade. In a study of one such animal under anesthesia, infusion of saralasin in a dose of 6 tg/kg/min resulted in profound hypotension and death within ten minutes [personal communication, James 0. Davis]. Because of phys-

iological similarities between this dog model and patients with cirrhosis and ascites, it might be anticipated that some patients with cirrhosis and ascites, particularly when depleted of salt, might be extremely sensitive to blockade of AU by saralasin. Acknowledgments

This study was supported by a grant from the Kidney Disease Institute, New York State Department of Health, grant RR-229, from the Division of Research Facilities, Clinical Research Centers Branch, National Institutes of Health, and a graduate training

pressure in cirrhosis with ascites. The salt load given to our patients may have been inadequate to restore "effective" plasma volume to normal and to normalize their response to All blockade. Deficient "effec-

grant, AM-07l46, from the National Institute of

tive" plasma volume, however, cannot explain the

technical assistance of Mrs. T. Walsh, Mr. P. Hueber,

decreased systemic resistance noted in some cirrhotic

Ms. Carol Jones and Ms. B. Cheetham; to Mrs. C. Nicita for secretarial assistance; and to Drs. Robert Keenan and Joseph DiNardo of Eaton Laboratories, Norwich, New York, who generously furnished the

patients with hypotension [2—5]. In addition, although the sensitivity of blood pressure to All blockage was decreased following salt repletion, it is not clear whether this was due to plasma volume expansion or to a direct action of sodium ion on vascular

smooth muscle cells or on All vascular receptors [39, 40].

In summary, these studies provide evidence that in

Arthritis, Metabolism and Digestive Diseases. We are indebted to the nursing staff of the Clinical Research Center, Mrs. V. Beasley, Head Nurse, for the

saralasin. Reprint requests to Dr. Edward T. Schroeder, Nephrology Section, Department of Medicine. State University Hospital, Syracuse, New York 132/0, U.S.A.

patients with cirrhosis and ascites, circulating All plays an important role in support of blood pressure, in maintenance of plasma aldosterone level, and in direct suppression of renal renin release. These effects are apparently influenced by the state of sodium bal-

ance, and they were not demonstrable in patients with cirrhosis but without ascites. The dependency

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Kidney Internazional, Vol. 9 (1976) p. 511—519 Effect of blockade of angiotensin II on blood pressure, renin and aldosterone in cirrhosis EDWARD T. S...
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