Effect of sodium depletion on plasma renin concentration before and during adrenergic β-receptor blockade with propranolol in normotensive man

Effect of Sodium Depletion on Plasma Renin Concentration Before and During Adrenergic P-Receptor Blockade with Propranolol in Normotensive Man

Plasma renin levels have been used to discriminate between different forms of hypertension, but how to define the normal range of plasma renin levels has not been agreed upon. Sodium depletion stimulates renin release. Evaluation of plasma renin would, therefore, seem possible only in relation to sodium balance. Plasma renin concentration and concurrent daily sodium excretion were determined in 33 healthy normotensive subjects (control group) ingesting high, normal and low sodium diets. A well-defined hyperbolic relationship was found between the two variables indicating that the physiologic level of plasma renin concentration depends on the state of sodium balance. An increase in plasma potassium concentration may reduce plasma renin concentration, but this appeared to be overruled by the stimulating effect of sodium depletion. To examine whether &adrenergic stimulation contributes to the increase in plasma renin concentration during sodium depletion, the relationship between plasma renin concentration and concurrent sodium excretion was studied during P-receptor blockade with propranolol. In 20 healthy normotensive subjects in whom &receptor blockade was verified by a significant reduction in pulse rate, the same hyperbolic relationship was found between plasma renin concentration and sodium excretion as in the control group showing that sodium depletion stimulates renin release independent of sympathetic nervous activity.

PER OMVIK, M.D.’ ERIK ENGER, M.D. WAR EIDE, M.D. Oslo, Norway

From the Medical Department VII, Ullevaal Hospital, Oslo, and Institute for Experimental Medical Research, University of Oslo, Ullevaal Hospital, Oslo, Norway. Requests for reprints should be addressed to Dr. lvar Eide, Medical Department VII, Ullevaal Hospital, Oslo, Norway. Manuscript accepted March 3, 1976. Present address: Medical Department A, Haukeland Hospital, 5000 Bergen, Norway. l

609

November 1976

Plasma renin activity increases during sodium depletion both in experimentai animals [1,2] and in man [3-51, but the mechanisms involved have not been fully elucidated. In man, the relationship between sodium balance and plasma renin has been most extensively studied by Laragh and associates [4,6] _They have repeatedly claimed a hyperbolic correlation between urinary sodium excretion and plasma renin activity. The significance of this correlation has been challenged [ 71, and other measures of sodium balance have been used to define the normal range of plasma renin [3,5,8]. The first aim of this study was, therefore, to re-examine the changes in plasma renin in normotensive man in response to changes in sodium excretion. Various stimuli, including a decrease in sodium excretion [6], activation of the sympathetic nervous system [9, lo] and autoregulated

The American Journal of Medicine

Volume 61

PLASMA

RENIN, SODIUM DEPLETION AND &ADRENERGIC

renal vasodilatation by reducing blood pressure [ ll131, increase plasma renin concentration by increasing the release of renin from the kidney. A negative sodium balance reduces tubular sodium delivery at the macula densa. This might stimulate the release of renin from juxtaglomerular cells [ 141, but since a negative sodium balance also leads to a reduction in plasma volume and thereby to increased sympathetic activity, the inverse relationship between plasma renin concentration and sodium excretion might be caused by stimulation of the sympathetic nervous system [ 15,161. These possibilities were examined by comparing the effect of sodium depletion on plasma renin concentration in nOrKIOtensive man before and during adrenergic P-receptor blockade with propranolol. METHODS Plasma renin concentration was determined in 53 healthy normotensive medical students and members of the medical staff ingesting high, normal and low sodium diets. In 33 subjects adrenergic P-receptor blockade was not given (control group) whereas 20 subjects received P-receptor blockade with propranolol (Inderale, Imperial Chemical Industries). The drug was administered orally at 40 mg/day, divided into two daily doses for two days and then gradually increased to 160 mglday. This dosage was reached within two days prior to the study and was maintained for one week. The volunteers were of both sexes (nine female and 44 male), ranging in age between 20 and 36 years with an average of 25 f 3 years (mean f SD). Only volunteers with blood pressure levels less than 140/90 mm Hg were accepted. Blood pressure levels and pulse rate were measured after the subject had had 5 minutes of rest in a chair. Systolic and diastolic (fifth phase) blood pressure levels were determined with a conventional mercury sphygmomanometer. The relationship between plasma renin activity and daily sodium excretion has previously been shown to be similar in outpatients and in subjects examined in metabolic wards [6]. Therefore, in this study, the subjects were treated as outpatients, but the meals were prepared at the hospital by the dietitian. Three different diets were used, calculated to contain approximately 15, 150 and 250 meq sodium/day, respectively. Potassium intake was approximately 80 meq/ day under all three dietary regimens. The control group was studied during the ingestion of all three diets, whereas the subjects blocked with propranolol were examined during the ingestion of low and normal sodium diets only. Each diet was administered for five days except to four students who, during the last two days of the low salt diet period, received an almost sodium-free rice and fruit diet. Plasma concentrations of renin, electrolytes and creatinine were determined in venous blood samples drawn at 12 noon on the fifth day (experimental day) of the respective sodium diet. The students were ambulatory from 7 A.M. and were seated during blood samplings. They received their meals as usuill. A 24 hour urine sample was collected from 7 A.M. to determine creatinine clearance and daily excretion rates of sodium and potassium. Concentrations of electrolytes and

BLOCKADE-OMVIK

ET AL.

creatinine in plasma and urine were measured with a Technicon@ autoanalyzer (Ardsley, New York). Peripheral venous plasma renin concentrations were determined by radioimmunoassay according to the method of Haber et al. [ 171 following incubation of the buffered plasma samples with an excess of exogenous renin substrate. Angiotensinases were inhibited by ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), and &hydroxyquinoline as previously described [ 111. Internal standards of human renin (Dr. Erwin Haas, Mt. Sinai Hospital, Cleveland, Ohio) were used according to Haas and co-workers [la]. Analysis of urinary sodium concentrations and plasma renin concentration were performed at different laboratories. Data are presented as means & 1 standard error (SE) of the mean. The statistical probability (P) of differences was calculated with Wilcoxon’s tests for two samples and for paired comparison [ 191. The differences were regarded as significant at P <0.05. Correlation coefficients were calculated by the method of least squares. RESULTS

Effect of Sodium Depletion on Plasma Renin Concentration. Figure 1 depicts the inverse relationship between plasma renin concentration and sodium excretion in 33 normotensive, healthy subjects, each given three different sodium diets. Sodium depletion led to a marked decrease in urinary sodium excretion and an increase in plasma renin concentration. Despite a fixed sodium content of the diet for five days, the sodium excretion on the experimental day varied widely due to

2.0

PRC G.U..10-4 per ml

1.0

0.5

0

I

0

I

I

100

200

1

300

1

400

Sodium Excretion, mEq per day Figure 1. Relationship between plasma renin concentration (PRC) expressed in Goldblatt Units (GlJ) and daily sodium excretion in 33 healthy normotensive subjects of both sexes (control group). The dots indicate single observations during high, normal and low sodium diets. Curves are drawn as the visual best fit of the range of observations.

November 1976

The American Journal of Medicine

Volume 61

609

PLASMA RENIN, SODIUM DEPLETION AND SADRENERGIC

l l

BLOCKADE-OMVIK

Control

0

Propranolol

0

ET AL.

2.0 0

1.5 PRC

PRC

G.U..10-4 per ml

G.U:lO-4

per ml 1.0

0.5

0

100

200

300

0 Low Sodium Diet

Normal Sodium Diet 150

15

Sodium Excretion, mEq per day Figure 3, Relationship between plasma renin concentration and daily sodium excretion in 20 healthy normotensive subjects of both sexes during adrenergic p-receptor blockade with propranolol. The dots indicate single observations during normal or low sodium diets. Curves show the range of observations in the control group.

High Sodium Diet 250

mEq Na per day Figure 2. Filled circles represent rearrangement of the plasma renin concentrations of Figure 1 according to sodium intake during high (250 meq/day), normal (150 megMay) and low sodium (15 meq/day) diets, respectively. Open circles represent observations during p-receptor blockade with propranolol(160 mg/day).

I

TABLE

Effect of Dietary Concentrations

Sodium in Healthy

Intake

on Urinary

Normotensive

Electrolyte

Subjects

Excretion,

and on Plasma Renin and Electrolyte

Before and During Adrenergic

&Receptor

Blockade

with Propranolol Pulse Rate (beats/

Blood Pressure

(mm Hg)

Plasma Renin

min)

Systolic

Diastolic

(GU . 1 O-‘/ per ml)

Control Propranolol P

72 c 2 52 * 2 <0.05

119 * 3 117+ 2 NS

83 2 2 79 i 1 NS

0.96 ? 0.10 0.90 t 0.09 NS

Control Propranolol P

71 f 3 53 + 2 co.05

122* 2 118~ 2 NS

8Oi: 1 77 + 2 NS

0.41 * 0.03 0.28 * 0.03 <0.05

Control

72 f 4

115’5

81 + 1

0.23 c 0.02

Period

Plasma

Concentration

U,,V

U,V

Cr

(meq/

(mes/ 24 hr)

24 hr)

(mesiter)

(mg/lOO ml)

(mF/%in)

139 ?r 0.4 139 * 0.1 NS

4.3 + 0.1 4.4 + 0.1 NS

1.0 z 0.03 1.2 ?- 0.1 co.05

112+4 107+ 6

140 ? 0.4 144 f 0.1 <0.05

4.1 + 0.1 4.1 i 0.04 NS

0.9 * 0.04 1.0 ? 0.03 NS

119r 4 125+ 4 NS

139 f 0.6

4.1 + 0.1

1.1 i 0.03

114?

(me$iterI

Low Sodium Diet 12+ 2 29I! 3 <0.05

73 + 4 89 ? 4 co.05

<0.05

Normal Sodium Diet IO 150* 148+ 13 NS

82 ? 4 92 * 4 co.05

High Sodium Diet 255?

13

84 i 5

5

NOTE: Each diet was used for five days. Control = 33 subjects without P-adrenergic blockade. Propranolol = 20 subjects blocked with propranolol at 160 mg/day. Data represent mean values c 1 SE. U N~V = urinary sodium excretion and UKV = urinary potassium excretion. Na+, K+ and Cr = plasma concentrations of sodium, potassium and creatinine, respectively. CCr = endogenous creatinine clearance where V = urine flow. NS = not significant. GU = Goldblatt units. according to Ccr = Plasmac, .V/UrineC,

610

November 1976

The American Journal of Medicine

Volume 61

PLASMA RENIN, SODIUM DEPLETION AND &ADRENERGlC

BLOCKADE-OMVIK

ET AL.

1.5 PRC G.U. 1O-4 per ml

1.0 -

0.5 -

3.5 Plasma

4

4.5

[Kl,mEq

5

0

50

100

150

Potassium Excretion, mEq per day

per I.

Figure 4. A, relationship between plasma renin concentration and plasma potassium concentration (K+) in 33 normotensive healthy subjects during high, normal and low sodium diets. Curve indicates the regression line of the data (y = 1.72~ - 4.07, r = 0.63, P
a different intake of food: during the period of low sodium intake, sodium excretion ranged between 0 and 43 meq/24 hours and during the period of high sodium intake, sodium excretion ranged between 109 and 376 meq/24 hours. Thus, a less consistent relationship was found when plasma renin concentration was plotted against calculated daily sodium intake (Figure 2) than against daily sodium excretion. At a sodium excretion below 100 meq/24 hours plasma renin concentration increased significantly in all subjects studied: with a sodium excretion between 0 and 49 meq/24 hours, plasma renin concentration averaged 0.95 f 0.09 Goldblatt Units (GUk10-4/ml; between 50 and 99 meq/24 hours, plasma renin concentration averaged 0.53 f 0.12 GU~10-4/ml; and above 100 meq/24 hours, plasma renin concentration averaged 0.29 f 0.02 GU.10-4/ml. Although plasma renin concentration decreased when daily sodium intake increased, the concentration of renin, measured in the plasma of all subjects, was significant. Effect of Propranolol on the Relationship Between Sodium Excretion and Plasma Renln Concentration. Twenty healthy normotensive subjects were studied during the intake of normal and low sodium diets after @receptor blockade with propranolol. During a normal sodium intake, with a sodium excretion rate exceeding 100 meq/24 hours, plasma renin concentration was lower (P KO.05) in subjects receiving propranolol than in the control group (Table I, Figure 2). However, when sodium intake was reduced, plasma renin concentration increased and, as shown in Figure 3, the same hyper-

November

bolic relationship between urinary sodium excretion and plasma renin concentration was found in patients during @-blockade with propranolol as in those who did not receive ,&blockade. During low sodium intake there was no significant difference between the plasma renin concentration in the two groups (Table I). In all subjects, P-adrenergic blockade was indicated by a decrease in pulse rate during propranolol administration: from the control conditions with the resting pulse rate averaging 72 f 2 beats/min, the pulse rate decreased during /3blockade by an average of 28 per cent to 52 f 2 and 53 f 2 beats/min during the intake of low and normal sodium diets, respectively. After the administration of propranolol had been discontinued for 10 days, the resting pulse rate returned to an average of 69 f 2 beats/min. P-receptor blockade did not reduce blood pressure, which averaged 121179 mm Hg before and 117179 mm Hg during the administration of propranolol, respectively. Table I summarizes blood pressures and laboratory data of the two groups during the intake of the different sodium diets. Urinary potassium excretion was not significantly altered during sodium depletion whereas plasma potassium concentration increased slightly. Consequently, a low but significant correlation was found between plasma renin concentration and plasma potassium concentration both without (r = 0.63, P
1976

The American

Journal

ol Medicine

Volume

61

611

PLASMA

RENIN.

SODIUM 0~pLET10f.4 AND /J-ADRENERGIC

BLOCKADE-•

potassium excretion (Figure 48). Blood pressure remained constant during the decrease in sodium excretion, with mean arterial pressure averaging 91 f 2 mm Hg. During propranolol administration, sodium depletion led to slight decreases in plasma sodium concentration and creatinine clearance, but apart from plasma renin concentration and urinary sodium excretion, the other parameters summarized in Table I remained unchanged. COMMENTS In normotensive man, plasma renin concentration increases during reduced sodium intake. This study shows that sodium depletion may increase plasma renin concentration independent of sympathetic nervous activity. In agreement with Laragh et al. [4,6], we found that the relationship between plasma renin concentration and urinary sodium excretion is curvilinear and that the normal range of plasma renin concentration is determined by the rate of sodium excretion. The same hyperbolic relationship between plasma renin concentration and sodium excretion applies after p-adrenergic blockade. Finally, it might appear that the stimulating effect of reduced sodium excretion on plasma renin concentration is stronger than the inhibitory effect exerted by the accompanying increase in plasma potassium concentration during sodium depletion. During antinatriuresis due to sodium depletion, the concentration of renin in plasma may be more than ten times the concentration during natriuretic conditions (Figure 1). Thus, to evaluate plasma renin concentration as high, normal or low, it is essential to relate plasma renin concentration to sodium balance. This has also been achieved by relating plasma renin to dietary sodium [3,5]. As shown in Figure 2, plasma renin concentration is inversely correlated to sodium intake (Figure 2) but a more consistent relationship is found when plasma renin concentration is related to sodium excretion (Figure 1). At a sodium intake of about 150 meq/day, 20 per cent of the observations of plasma renin concentration exceeded the upper range of normal when compared to the relationship between plasma renin concentration and sodium excretion. This indicates that the exact intake of sodium is difficult to assess despite a fixed sodium content of the diet for five days, and that sodium excretion is a better index of sodium balance. Sodium depletion led to an increase in plasma potassium concentration [20,21], and positive correlations between plasma potassium and plasma renin concentration were observed. However, these correlations were low and might depend on extreme single observations (Figure 4A). The correlation between potassium concentration and plasma renin concen-

612

November 1976

The American Journal of Medicine

MVIK ET AL.

tration could not account for the increase in plasma renin concentration during antinatriuresis since an increase in potassium concentration has been found to reduce rather than increase renal renin release [ 22,231. Thus, the decrease in sodium excretion might overrule the effect of plasma potassium on plasma renin concentration. Plasma renin concentration might have been even more increased by low sodium excretion if plasma potassium concentration had remained constant. Indeed, in a recent study [24], plasma renin in sodiumdepleted subjects increased during the reduction of potassium concentration by the intravenous infusion of glucose, suggesting that the plasma renin concentration observed when sodium excretion is low is the net result of sodium-linked stimulation and potassium-linked inhibition. The increase in plasma renin concentration during sodium depletion is probably due to increased renin secretion from the kidney [2,25], although an effect of reduced inactivation by the liver cannot be ruled out [26]. In addition to sympathetic stimulation [9, lo], two intrarenal mechanisms might account for an increase in renin release: the renal autoregulation mechanism [ 1 l-131 and reduction of tubular sodium delivery at the macula densa [ 141. Renin release increases as the blood pressure level falls towards the lower limit of renal blood flow autoregulation, but this mechanism was obviously not activated in the present study since blood pressure remained unchanged during sodium depletion both before and during P-adrenergic blockade. During sodium depletion and decrease in plasma volume, sympathetic nervous activity increases and might thereby contribute to the increase in plasma renin concentration [9, lo]. Previously, attempts have therefore been made to block the possible stimulating effect of sodium depletion on plasma renin by the administration of propranolol to different groups of patients, but the results are conflicting. In hypertensive subjects given low sodium diets combined with diuretic treatment [27] or in patients with hypoparathyroidism [28], propranolol was found to reduce peripheral plasma renin activity, whereas in hypertensive patients receiving long-term propranolol therapy no such reduction was observed [29]. Thiazides and loop diuretics [30,31] might increase renin release considerably by stimulating /3-adrenergic receptors. A reduction of plasma renin by P-receptor blockade might, therefore, be anticipated during combined dietary sodium depletion and administration of diuretics. In the present study of 20 normotensive subjects, propranolol reduced plasma renin concentration by about 30 per cent (Table I) during normal, unrestricted sodium intake. Statistically, this might not be significantly different from the reduction observed in three normotensive subjects by Michelakis and McAllister

Volume 61

PLASMA

RENIN, SODIUM DEPLETION AND B-ADRENERGIC BLOCKADE-OMVIK

[32]. However, by relating plasma renin concentration to the urinary excretion of sodium we found that sodium depletion had the same stimulating effect on plasma renin concentration whether propranolol was used or not. In the three normotensive subjects of Michelakis and McAllister [32], sodium depletion increased plasma renin during P-receptor blockade approximately three times. This increase might well fall within the range limits in Figure 1. Thus, the increase in plasma renin concentration during sodium depletion seems to be virtually unaffected by the @-adrenergic nervous system. Adequate P-receptor blockade of propranolol was indicated by a significant decrease in pulse rate since lower plasma concentrations of propranolol are needed to produce maximum suppression of adrenergicallymediated increases in plasma renin than to reduce the heart rate [33]. Arterial blood pressure remained normal during propranolol administration. Thus, the finding of a small reduction in plasma renin concentration following @receptor blockade when sodium excretion is normal is in agreement with the previous observations that the inhibitory effect of P-adrenergic blockade with propranolol [34,35] and the stimulating effect of p-adrenergic activation with isoproterenol [35] on renin release is small at normal blood pressure levels compared to the respective effects at low arterial blood pressure levels. In normotensive subjects, therefore,

ET AL.

a decrease in sodium excretion

seems to be a more potent stimulus to increase plasma renin concentration than activation of the fi-adrenergic nervous system. Propranolol may be a potent antihypertensive agent. Buhler et al. [36] found roughly proportional reductions in blood pressure and plasma renin activity suggesting a better effect of &receptor blockade in patients with high renin hypertension than in patients with other subgroups of hypertension. In other studies, however, such a positive correlation between changes in plasma renin and blood pressure were not observed [27,32,33]. As different estimates of sodium balance were used, part of the discrepancies might be due to dissimilar criteria in evaluating plasma renin. Since in the present investigation propranolol had no significant effect on plasma renin concentration during low sodium excretion, different mechanisms seem to be responsible for the increase in plasma renin concentration during high renin hypertension and during normotensive subjects.

sodium

depletion

in

ACKNOWLEDGMENT

We thank The Central Laboratory, Ullevaal Hospital for analysis of electrolytes and creatinine. The skilled assistance of Mrs. Ellen Dahl, Mrs. Irene Eggen, Mrs. Mildred Lewis and Mrs. Ellen Schinnes is gratefully acknowledged. This work was supported by the Norwegian Council for the Promotion of Science.

REFERENCES

5.

6.

7.

8.

9.

Peart WS: The reninsngiotensin system. Pharmacol Rev 17: 143, 1965. Brubacher ES, Vander AJ: Sodium deprivation and renin secretion in unanesthetized dogs. Am J Physiol 214: 15. 1968. Brown JJ, Davies DL, Lever AF, et al.: Influence of sodium loading and sodium depletion on plasma-renin in man. Lancet 2: 278, 1963. 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 18-19 (suppl 1): 158, 1966. Gunnells JC, Grim CE, Robinson RR, et al.: Plasma renin activity in healthy subjects and patients with hypertension. Arch Intern Med 119: 232, 1967. Laragh JH, Baer L, Brunner HR, et al.: Renin, angiotensin and aldosterone system in pathogenesis and management of hypertensive vascular disease. Am J Med 52: 633, 1972. Doyle AE, Chua KG, Duffy S, et al.: Plasma renin, urinary sodium excretion and vascular disease. Clin Sci Molec Med 48: 127s 1975. Davies DL, Schalekamp MA, Beevers DG, et al.: Abnormal relations between exchangeable sodium and the reninangiotensin system in malignant hypertension and in hypertension with chronic renal failure. Lancet 1: 683, 1973. Vander AJ: Effect of catecholamines and the renal nerves on renin secretion in anesthetized dogs. Am J Physiol 209: 659, 1965.

10. 11. 12.

13.

14. 15.

16.

17.

18. 19. 20.

November 1976

Davis JO: The control of renin release. Am J Med 55: 333. 1973. Eide I, Leyning E, Kiil F: Evidence for hemodynamic autoregulation of renin release. Circ Res 32: 237, 1973. Ayers CR, Harris RH, Lefer LG: Control of renin release in experimental hypertension. Circ Res 24 (suppl): 103, 1969. Gottschall RW, Davis JO, Blaine EH, et al.: Increased renin release during renal arteriolar dilatation in dogs. Am J Physiol 227: 251. 1974. Vander AJ. Miller R: Control of renin secretion in the anesthetized dog. Am J Physiol 207: 537, 1964. Vander AJ, Luciano JR: Neural and humoral control of renin release in salt depletion. Circ Res 20-21 (suppl 2): 69, 1967. Mogil RA, ltskovitz HD, Russell JH, et al.: Renal innervation and renin activity ih salt metabolism and hypertension. Am J Physiol 216: 693, 1969. Haber E, Koerner T, Page LB, et al.: Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects. J Clin Endocrinol Metab 29: 1349, 1969. Haas E. Gould AB, Goldblatt H: Estimation of endogenous renin in human blood. Lancet 1: 657, 1968. Snedecor GW, Cochran WG: Statistical Methods, 6th ed. Iowa State University Press, 1967. Howell DS, Davis JO: Relationship of sodium retention to potassium excretion by the kidney during administration of desoxycorticosterone acetate to dogs Am J Physiol 179: 359, 1954.

The American Journal of Medicine

Volume 61

613

PLASMA

21.

22.

23. 24.

25. 26.

27.

RENIN, SODIUM DEPLETION AND &ADRENERGIC

Anderson HM, Laragh JH: Renal excretion of potassium in normal and sodium depleted dogs. J Clin Invest 37: 323, 1958. Brunner HR, Baer L, Sealey JE, et al.: The influence of potassium loading and potassium deprivation on plasma renin in normal and hypertensive subjects. J Clin Invest 49: 2128, 1970. Vander AJ: Direct effects of potassium on renin secretion and renal function. Am J Physiol 219: 455, 1970. Himathongkam T, Dluhy RG, Williams GH: Potassium-aldosterone-renin interrelationships. J Clin Endocrinol Metab 41: 153, 1975. Vander AJ: Control of renin release. Physiol Rev 47: 359, 1967. Johnson JA, Davis JO, Baumber JS, et al.: Effects of hemorrhage and chronic sodium depletion on hepatic clearance of renin. Am J Physiol 220: 1677. 1971. Geyskes GG, Boer P, Leenen FHH, et al.: Effect of volume depletion and subsequent propranolol treatment on blood pressure and plasma renin activity in patients with essential and with renovascular hypertension. Clin Sci Molec Med 48: 69s,

28.

29.

614

BLOCKADE-OMVIK

30.

31.

November

1976

The American Journal ol Medlclne

pressed plasma-renin activity during b-adrenergic blockade with propranolol. J Lab Clin Med 83: 119, 1974. Attman PO, Aurell M, Johnsson G: Effects of metoprolol and propranolol on furosemide-stimulated renin release in healthy subjects. Europ J Clin Pharmacol 8: 201, 1975. Eide I, Leyning E, Langaard 0. et al.: Influence of ethacrynic acid on intrarenal renin release mechanisms. Kidney Int a: 158, 1975.

32.

33.

34.

35.

1975.

Weber MA, Kleerekoper M, Thornell IR, et al.: Effects of sodium depletion on plasma renin activity and on the urinary excretion of cyclic AMP and aldosterone in hypoparathyroid patients. J Clin Endocrinol Metab 40: 982, 1975. Bravo EL, Tarazi RC, Dustan HP: On the mechanism of sup-

ET AL.

36.

Volume 61

Michelakis AM, McAllister RG: The effect of chronic adrenergic receptor blockade on plasma renin activity in man. J Clin Endocrinol 34: 386, 1972. Bravo EL, Tarazi RC, Dustan HP, et al.: Dissociation between renin and arterial pressure responses to @-adrenergic blockade in human essential hypertension. Circ Res 36-37 (suppl 1): 241, 1975. *La Grange RG, Sloop CH, Schmid HE: Selective stimulation of renal nerves in the anesthetized dog. Effect on renin release during controlled changes in renal hemodynamics. Circ Res 33: 704, 1973. Eide I, Leyning E, Kiil F: Potentiation of renin release by combining renal arterial constriction and &adrenergic stimulation. Stand J Clin Lab Invest 34: 301, 1974. Biihler FR, Laragh JH, Vaughan ED Jr. et al.: Antihypertensive action of propranolol. Specific antirenin responses in high and normal renin forms of essential, renin, renovascular and malignant hypertension. Am J Cardiol 32: 511, 1973.