European Journal of Clinical Pharmacology
Eur. J. Clin. Pharmacol. 16, 305-3t0 (1979)
© by Springer-Verlag I979
Effect of Oral Labetalol on Plasma Catecholamines, Renin and Aldosterone in Patients with Severe Arterial Hypertension H. J. Kornerup, E. B. Pedersen, N. J. Christensen, A. Pedersen, and G. Pedersen Departments of Medicine C and M, Aarhus Kommunehospital and Aarhus University, and Department of Internal Medicine and Endocrinology, Herlev Hospital Copenhagen, Denmark
Summary. Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined aand/3-adrenergic receptor blockade induced by oral labetalol treatment for 2 months. Furosemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined a- and /3adrenergic receptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances the antihypertensive effect of labetalot, and partly modifies both renin and sympathetic nervous activity. Key words: labetalol, furosemide, hypertension; aldosterone, blood pressure, plasma catechotarnines, renin
In the majority of patients with untreated essential hypertension sympathetic nervous activity is normal [1, 2], and it has recently been suggested that activity of the renin system declines with the progression of essential hypertension, except in the malignant phase
[3]. During antihypertensive therapy, however, blood pressure (BP) regulation may be influenced by alteration in the activity of the sympathetic nervous system and the renin system. Suppression of the renin system has been suggested as being responsible for at least part of the antihypertensive effect of/3-adrenergic receptor blockers [4, 5]. On the other hand, activation of the renin system by vasodilators has been suggested as counterbalancing the antihypertensive effect of these agents [6]. In the present study, arterial BP, plasma catecholamines, renin activity and aldosterone concentration were studied in patients with severe essential hypertension, before and after combined a- and /3-adrenergic receptor blockade induced by oral labetalol treatment for 2 months.
Material and Methods Twelve patients with severe essential hypertension, 10 males and 2 females, aged 32-67 years, were included in the study. Prior to the study, 8 patients had received oral diazoxide therapy for several months, and the remaining 4 were candidates for aggressive vasodilator therapy because of their resistance to conventional antihypertensive treatment, which included combinations of 2-3 antihypertensive agents (propranolol or alprenolol, hydralazine, cyclopenthiazide or furosemide, a-methyldopa, bethanidine or guanethidine) given in maximal doses to each patient in several different combinations. On such conventional antihypertensive treatment, diastolic BP in all the patients remained above 120 mmHg. Seven patients had previously exhibited severe hypertensive retinal changes (grade III-IV), but at the time of study all had grade I-II retinal changes (Keith-Wagener). Cardiac enlargement on 0031-6970/79/0016/0305/$01.20
306
H.J. Kornerup et al.: Labetalol in Severe Hypertension
Table 1. Effect of labetalol on blood pressure (BP), pulse rate (PR), and body weight (BW). A: Before labetalol. B: After Iabetalol for 2 months Patient no.
Supine BP (mmHg)
Standing BP (mmHg)
Supine PR (per rain)
Standing PR (per min)
BW
(kg)
A
B
A
B
A
B
A
B
A
B
1 2 3 4 5 6 7 8 9 10 11 12
230/150 220/135 190/130 200/140 230/150 200/120 210/140 190/120 240/150 210/150 210/130 240/170
1.90/130 220/125 180/140 220/140 200/130 180/100 170/120 160/110 190/105 180/110 t40/110 140/105
210/150 220/135 190/135 200/130 230/140 190/120 210/140 170/120 240/150 205/150 200/135 235/165
170/130 150/90 180/140 180/135 175/125 155/105 160/110 160/105 180/90 160/100 100/60 100/80
100 92 88 80 76 88 72 80 88 72 80 76
76 72 72 84 60 68 56 68 70 76 64 76
108 96 94 84 82 96 76 84 92 76 84 82
84 80 80 88 76 76 56 72 72 84 60 84
91.6 73.5 96.7 71.4 66.5 78.4 78.0 67.6 80.9 52.5 65.5 113.0
92.7 73.5 99.6 74.8 69.5 78.9 79.8 71.7 81.5 55.5 66.0 113.3
Mean ±SD
214/140 18/15
181/119 26/14
208/139 20/13
156/106 28/24
83 9
70 8
88 9
76 t0
77.9 16.2
79.7 15.7
Table 2. Effect of labetalol on plasma noradrenaline (PNA), adrenaline (PA), renin activity (PRA) and aIdosterone concentration (PAC) and blood glucose and plasma potassium. A: Before labetaloh B: After labetalol for 2 months
PNA (ng/ml)
PA (ng/ml)
PRA (ng Ang I 80%ml lh-1)
PAC (ng/100 ml)
Blood glucose (rag/100 mI)
Plasma potassium (mmol/1)
A
B
A
B
A
B
A
A
B
A
B
1 2 3 4 5 6 7 8 9 10 11 12
0.30 0.21 0.24 0.37 0~67 0.14 0.25 0.40 0.25 0.16 . .
0.29 0.24 0.15 0.12 0.30 0.10 0.22 0.16 0.30 0.11
0.08 0.07 0.05 0.07 0.05 0.01 0.04 0.07 0.02 0.03
0.11 0.07 0.06 0.05 0.10 0.08 0.07 0.11 0.02 0.00
2.00 0.68 2.51 2.58 3.20 0.82 0.69 2.12 1.26 1.13 2.72 1.66
1.02 1.03 1.41 1.24 1.51 0.84 0.56 1.66 2.12 1.06 5.93 2.55
14.0 13.3 18.6 17.9 28.5 17.6 20.2 11.6 37.2 33.1 13.4 8.9 18.9 I8.9 21.2 13.9 6.5 13.4 29.0 15.4 17.3 50.6 21.5 41.1
125 106 102 97 104 102 99 102 115 98 100 93
121 94 100 94 106 99 91 119 93 95 97 95
3.1 2.4 3.4 2.8 3.3 3.8 2.9 4.0 4.t 3.3 3.4 3.2
3.4 2.9 3.2 2.8 3.7 4.0 3.6 3.6 4.5 3.6 4.2 4.2
Mean _+SD
0.30 0.15
0.05 0.02
0.07 0.04
1.78 0.87
1.74 1.43
20.5 8.1
104 9
100 10
3.3 0.5
3.6 0.5
Patient no.
. .
. . 0.20 0.08
. .
X - r a y , a n d / o r h y p e r t r o p h y or strain o n E C G , w e r e p r e s e n t i n all b u t o n e subject. C r e a t i n i n e c l e a r a n c e e x c e e d e d 50 m l / m i n a n d p r o t e i n u r i a was a b s e n t in all, e x c e p t o n e p a t i e n t in w h o m c r e a t i n i n e c l e a r a n c e was d e c r e a s e d t o 41 m l / m i n a n d urinalysis disclosed a slight p r o t e i n u r i a of 0 . 5 - 1 . 0 g/day. I n this p a t i e n t , a n d 3 o t h e r s o n w h o m p e r c u t a n e o u s r e n a l b i o p s y was p e r f o r m e d , severe n e p h r o s c l e r o s i s was d e m o n strated. A l l a n t i h y p e r t e n s i v e a g e n t s except f u r o s e m i d e w e r e g r a d u a l l y d i s c o n t i n u e d o v e r several weeks b e f o r e t h e study, while the p a t i e n t s w e r e f o l l o w e d i n
B
21.3 13.1
t h e o u t - p a t i e n t clinic. F u r o s e m i d e 8 0 - 2 5 0 m g / d a y and an oral potassium supplement were then cont i n u e d t h r o u g h o u t t h e s t u d y p e r i o d , i n the s a m e dose for e a c h p a t i e n t . A f t e r t r e a t m e n t for 2 w e e k s with f u r o s e m i d e as t h e o n l y drug, l a b e t a l o l was g i v e n in i n c r e a s i n g doses f r o m 300 to 1 2 0 0 - 2 4 0 0 m g / d a y ( m e a n 2 1 7 5 ) , d i v i d e d i n t h r e e daily doses, for the n e x t m o n t h , a n d this t r e a t m e n t was c o n t i n u e d u n c h a n g e d d u r i n g the s e c o n d m o n t h . B l o o d s a m p l e s for m e a s u r e m e n t of p l a s m a n o r adrenaline concentration (PNA), adrenaline conc e n t r a t i o n ( P A ) , r e n i n activity ( P R A ) , a l d o s t e r o n e
H. J. Kornerup et al.: Labetalol in Severe Hypertension
concentration (PAC), blood glucose concentration and plasma potassium concentration were collected by an indwelling peripheral venous catheter at 9.00 a. m., after recumbency for one hour, and after an 8h fast, just before and after treatment with labetalol for 2 months. No dietary restrictions were prescribed. Plasma catecholamines were determined by a sensitive double-isotope derivative technique [7], normal mean PNA 0.254 ng/ml (range 0.08-0.75, n = 32) and normal mean PA 0.047 ng/ml (range 0.00-0.19, n = 32). P R A was measured radioimmunologically, as described by Giese et al. [8], normal mean 1.32 ng angiotensin I (Ang I) 80%ml-lh -I (range 0.47-2.78, n = 29). PAC was measured radioimmunologically according to the method of Damkja~r Nielsen [9], normal mean 13.6 ng/100 ml (range 4.6-25.9, n = 23). Blood glucose was determined by a glucose oxidase method, and plasma potassium by flame photometry. BP, measured by sphygmomanometry, and pulse rate were determined after one hour in the supine position and after 2 min in the upright position. Mean BP was defined as diastolic BP + 1/3 BP amplitude. In association with the BP readings body weight (BW) was measured. Mann-W]fitney's rank sum test, Wilcoxon's signed rank test and Spearman's test were used for statistical analysis. Informed consent to the procedure was obtained from all patients examined.
307 Table 3. Correlation analyses (Spearrnan's test) between changes (A) in the variables studied after treatment with labetalol for 2 months Variables Y
X
Coefficient of correlation (rho)
Level of significance (P = 2 a )
AMBP (supine) AMBP (standing) zl Mt3P (supine)
ABW ABW APNA
0.50 0.59 -0.58
n.s. (P > 0.10) P < 0.05 n.s. (0.10 > P
AM]3P (supine) ZlMBP (supine) zl PNA ZlPRA APAC APNA APRA
APRA ziPAC ABW ABW zlBW ziPRA zlPAC
-0.63 -0.61 -0.82 -0.75 -0.34 0.82 0.66
P < P < P < P < n.s. P < P
o.05) 0.05 0.05 0.01 0.01 (P > 0.10) 0.01 0.05
MBP = mean blood pressure
25i O
p o
-25 to
.__q
e
g¢- -50 Results
Blood Pressure, Pulse Rate and Body Weight (Table 1) Labetalol reduced the supine and standing diastolic BP to a level at or below 110mmHg in 6 patients. Standing diastolic BP also decreased to a level at or below 110mmHg, whereas supine diastolic BP remained above 110 mmHg in 2 other patients. In the remaining 4 patients, the reduction in supine and standing BP was minimal. The decrease in average supine BP from 214/140 to 181/119mmHg, and in average standing BP from 208/139 to 156/ 106 mmHg, were significant (P < 0.01). Average supine and standing pulse rates decreased significantly during labetalol therapy (P < 0.01). The rise in mean BW from 77.9 to 79.7 kg during treatment with labetalol was significant (P < 0.01). In 6 patients BW increased by more than 1.5 kg.
Plasma Catecholamines (Table 2) Before treatment with labetalol, PNA and PA were normal in all subjects. No difference between the
-75 0
20
40
60
change in body weight {%d Fig. L Relationship between changes in pIasma noradrenaiine concentration and in body weight during labetalol treatment
pretreatment values of PNA or PA was present in patients whose BP responded to labetalol and those in whom BP was unresponsive to labetalol. Labetalol induced a significant fall in the mean value of PNA, from 0.30 to 0.20 ng/ml (P < 0.05). P A and blood glucose concentration did not change significantly during treatment with labetaloI (P > 0.10).
Renin-Aldosterone System (Table 2) Before treatment with labetalol, P R A and PAC were within normal range, in all except one subject, in whom P R A was increa.sed to 3.20 ng Ang I 80%ml-lh q, and 3 in whom PAC was increased to 28.5-37.2 ng/100 ml. No difference in the pretreat-
308 ment values of P R A or PAC was present between patients whose BP did not respond to labetalol and those whose BP did respond to it. The changes in P R A and PAC during treatment with labetaloI varied greatly, but the mean values did not alter significantly (P > 0.I0). Labetalol induced a slight but significant increase in plasma potassium concentration from 3.3 to 3.6 mmol/1 (P < 0.05).
Relationship Between the Variables Studied (Table 3) No correlation was found between the basal values of the variables studied. However, changes in the variables during treatment with labetalol disclosed certain significant correlations, which are summarized in Table 3. The rise in BW correlated inversely with the fall in standing mean BP, whereas the corresponding correlation between change in BW and in supine mean BP was not significant. Changes in BW correlated inversely with changes in PNA (Fig. 1) and with changes in PRA. Changes in P R A correlated positively with changes in PNA and in PAC. Finally, changes in supine mean BP correlated inversely with changes in P R A and in PAC.
Discussion
In the present study oral Iabetaiol provided an adequate or satisfactory antihypertensive effect in only half of the patients with severe arterial hypertension. The purpose of the furosemide therapy was an attempt to prevent the expansion of extracellular and intravascular volume due to sodium and fluid retention, which usually accompanies therapy with vasodilators, including labetalol, whereby the hypotensive effect may be counterbalanced [10, 11, 12]. This intention was probably not achieved, since BW increased during treatment with labetalol, and the rise in BW correlated inversely with the fall in standing mean BP. More intense furosemide therapy might have reduced BP in those patients who did not respond to labetalol. Labetalol is believed to induce a combined aand nonselective fi-adreno-receptor blockade [13]. The presence of such an a- and fi-adrenergic receptor blockade during treatment with labetalol in the majority of our patients was indicated by a postural decrease in BP, and a decrease in pulse rate. Pure a-adrenergic receptor blockade has previously been demonstrated to increase PNA both at rest and during exercise in normal subjects [14], whereas pure fi-adrenergic receptor blockade increases P N A only during exercise, but not at rest, in normal and hypertensive subjects [2, 15, 16]. In
H. J. Kornerup et al.: Labetalolin SevereHypertension patients with ischaemic heart disease, resting PNA also increases during pure /3-adrenergic receptor blockade [17]. The rise in PNA after a-adrenergic receptor blockade is partly due to a compensatory rise in s?nnpathetic nervous activity, as BP decreases after postsynaptic blockade, and partly due to blockade of the presynaptic a-receptors, which regulate noradrenaline release from the adrenergic nerve terminals. During acute combined a- and fi-adrenergic receptor blockade induced by intravenous labetatol, PNA increases in patients with moderate essential hypertension at supine rest, as well as during supine exercise, resembling the response to pure a-adrenoreceptor blockade [18]. However, during long-term treatment with tabetalol, PNA and catecholamines in urine, measured by sensitive, specific radioenzymatic methods as used in this study, have been reported as being normal [19]. Labetalol administered orally for 2 months in the present study caused a decrease in PNA. This might have been caused by interference with sympathetic nervous activity by sodium and fluid retention. Thus, increases in BW were correlated closely with decreases in PNA, which suggests that PNA decreased in patients with sodium and fluid retention, whereas PNA was unchanged in those with minimal sodium and fluid retention, in accordance with an inverse relationship between sympathetic nervous activity and sodium. Circulating P A is dependent both on the level of sympathetic nervous activity and the blood glucose concentration [16]. The lack of alteration in PA during labetalol therapy in this study is not surprising, as PNA decreased and blood glucose concentration was unchanged. The reports of other investigators" [12, 20, 21], of markedly increased urinary excretions of adrenaline and other catecholamines during treatment with labetalol, may be explained by interference by metabolite(s) of labetalol with the nonspecific fluorimetric and spectrophotometric assay methods used [19]. The normal values of P R A and PAC before labetalol in the majority of our patients, even though they were treated with furosemide, might be explained by a low-renin state due to the severity of the hypertension, according to the hypothesis of Birkenhfiger and Schalekamp [3]. The very variable response of P R A to labetalol, and some of the correlations found between the variables in our study, suggest the presence of a complex of interrelated factors which are involved in renin release during treatment with labetalol. Thus, sodium and fluid retention might have modified renin release during treatment with labetalol, as indicated by a negative correlation between change in BW and in PRA. This suggests
H. J. Kornerup et al.: Labetalol in Severe Hypertension
that renin release was suppressed in patients with sodium and fluid retention in contrast to those with minimal sodium and fluid retention, in accordance with the well-known inverse relationship between renin and sodium [22]. A pronounced increase in PRA occurred in some of our patients during treatment with labetalol, in spite of the fi-adrenergic receptor blockade, which usually suppresses renin release [4, 5, 23]. According to baroreceptor-theory [22], a decrease in BP might have contributed to the stimulatory effect on renin release in these patients, and this is supported by the finding of a negative correlation between changes in mean BP and in PRA. These results suggest that the antihypertensive effect of labetalol may be renin-independent. Catecholamines stimulate renin release [24, 25] and vice versa [26]. The positive correlation between changes in PNA and in PRA found in the present study, however, might be due to a common action of alterations in sodium and fluid balance upon renin and catecholamine release, since the renal sympathetic innervation might conceivably have been blocked by labetalol. Aldosterone secretion is dependent both on renin release and plasma potassium level [27]. The slight but significant increase in plasma potassium during labetalol therapy, which has also been demonstrated during pure /3-adrenergic receptor blockade [28], might have tended to stimulate aldosterone secretion, although this effect was probably negligible. The close positive correlation between changes in PRA and in PAC is indicative of an intact relationship between renin and aldosterone during treatment with labetalol. In conclusion, the present study suggests that labetalol through its combined a- and /3-adrenoreceptor-blocking action induces a rise in BW, probably due to sodium and fluid retention, which in part counterbalances the antihypertensive effect of labetalol, and which in part affects renin as well as sympathetic nervous activity. Further investigation by direct measurement of body sodium and fluid content are necessary to verify this hypothesis.
Acknowledgments. Glaxo A/S, Denmark, and Allen & Hanbury, United Kingdom kindly supplied labetalol. References 1. Lake, C.R., Kopin, I.J., Ziegler, M.G., Coleman, M.D.: Plasma catecholamines and neurogenic hypertension. New Engl. J. Med. 297, 53-54 (1977) 2. Pedersen, E. B., Christensen, N. J.: Catecholamines in plasma and urine in patients with essential hypertension determined
309 by double-isotope derivative techniques. Acta Med. Scand. 198, 373-377 (1975) 3. Birkenh~iger,W. H., Schalekamp, M. A.: Control mechanisms in essential hypertension, p. 111. Amsterdam: Elsevier 1976 4. Biihler, F. R., Laragh, J. H., Baer, L., Vaughan, E. D., Brunnet, It. R.: Propranotol inhibitionof renin secretion. A specific approach to diagnosis and treatment of renindependenthypertensive diseases. New Engl. J. Meal. 287, 1209-1214 (1972) 5. Shand, D., Frisk-Holmberg, M., McDevitt, D., Sherman, K., Hollifield, J.: A dual antihypertensive mechanism for propranolol based on plasma level/response relationships. In: Pathophysiology and management of arterial hypertension. Berglund, G., Hansson, L., Werk6, L. (ed.), pp. 175-182. G6teborg: Lindgren & S6ner 1975 6. Pettinger, W.A., Keeton, K.: Altered renin release and propranolol potentiation of vasodilatory drug hypotension. J. Ctin. Invest. 55, 236-243 (1975) 7. Christensen, N.J.: Plasma noradrenaline and adrenaline in patients with thyreotoxicosis and myxoedema. Clin. Sci. Mot. IVied. 45, 163-171 (1973) 8. Giese, J., Jorgensen, M., Nielsen, M. D., Lund, J. O., Munck, O.: Plasma renin concentration measured by use of radioimmunoassay for angiotensin I. Scand. J. Clin. Lab. Invest. 26, 355-368 (1970) 9. Rask-Madsen, J, Bruusgaard, A., Munck, O., Nielsen, M. D., Woming, H.: The significanceof bile acids and aldosterone for the electrical hyperpolarization of human rectum in obese patients treated with intestinal by-pass operation. Scand. J. Gastroenterol. 9, 417-426 (1974) t0. Ibsen, H., Rasmussen, K., Jensen, H. AE.,Leth, A.: Changes in plasma volume and extracellular fluid volume after addition of pr~osin to propranolol treatment in patients with hypertension. Scand. J. Clin. Lab. Invest. 38, 425-429 (1978) 11. Ibsen, H., Rasmussen, K., Jensen, H. ~E.,Leth, A.: Changes in plasma volume and extracellular fluid volume after addition of hydralazine to propranolol treatment in patients with hypertension. Acta Med. Scand. 203, 419-423 (1978) 12. Weidmann, P., De Chatel, R., Ziegler, W.H., Flammer, J., Reubi, F.: Alpha and beta adrenergic blockade with orally administered labetalol in hypertension. Studies on blood volume, plasma renin and aldosterone and catecholamine excretion. Am. J. Cardiol. 41, 570-576 (1978) 13. Richards, D.A.: Pharmacological effects of labetalol in man. Br. J. Clin. Pharmacol. 3, Suppl. 3, 721-723 (1976) 14. Galbo, H., Christensen, N. J., Hoist, J. J.: Catecholamines and pancreatic hormones during autonomic blockade in exercising man. Acta Physiol. Scand. 101, 428-437 (1977) 15. Christensen, N.J., Trap-Jensen, J., Clausen, J.P., Noer, I., Krogsgaard, A.R., Larsen, O.A.: Effect of beta-receptor blockade on heart rate, hepatic blood flow and circulating noradrenatine during exercise in man. Acta Physiol. Scand. 95, 62A-63A (1975) 16. Gatbo, H., Christensen, N.J., Holst, J.J.: Glucose-induced decrease in glucagon and epinephrine responses to exercise in man. J. Appl. Physiol. 42, 525-530 (1977) 17. Hansen, J.F., Itesse, B., Christensen, N.J.: Enhanced sympathetic nervous activity after intravenous propranolol in ischaemic heart disease: Plasma noradrenaline, splanchnic blood flow and pulmonary artery Oxygensaturation at rest and during exercise. Eur. J. Clin. Invest. 8, 31-36 (1978) 18. Christensen, N. J., Trap-Jensen, J., Svendsen, T. L., Rasmussen, S., Nielsen, P.E.: Effect of labetaloI on plasma noradrenaline and adrenaline in hypertensive man. Eur. J. Clin. Pharmacol. 14, 227-230 (1978) 19. Hamilton, C. A., Jones, D. H., Dargie, H. J., Reid, J. L.: Does labetalol increase excretion of urinary catecholamines. Br. Med. J. 1978/11, 800
310 20. Harris, D., Richards, D.A. Labetalol and urinary catecholamines. Br. Med. J. 1977/1[I, 1673 21. Chapman, B.P., Veitch, A.G., Shepherd, B.: Labetalol and urinary catecholamines. Br. Med. J. 1978/I, 364 22. Davis, J.O., Freeman, R.H.: Mechanisms regulating renin release. Physiol. Rev. 56, 1-56 (1976) 23. Pedersen, E.B., Kornerup, H. J.: Plasma renin concentration in essential hypertension during beta-adrenergic blockade and vasodilator therapy. Eur. J. Clin. Pharmacol. 12, 93-96 (1977) 24. Hedeland, H., Dymling, J. F., H6kfelt, B.: The effect of insulin-induced hypoglycaemia on plasma renin activity and urinary" catecholamines before and following clonidine in man. Acta Endocrinol. (Kbh.) 71, 321-330 (1972) 25. Vander, A, J.: Effect of catecholamines and the renal nerves on renin secretion in anesthetized dogs. Am. J. Physiol. 209, 659-662 (1965) 26. Peach, M.J.: Adrenal medullary stimulation induced by angiotensin. Circ. Res. Suppl. lI, 107-117 (1971)
H.J. Kornerap et al.: Labetalol in Severe Hypertension 27. Williams, G.H., Dtuhy, R.G.: Aldosterone biosynthesis. Interrelationship of regulatory factors. Am. J. Med. 53, 595-605 (1972) 28. Pedersen, E. B., Kornerup, H. J. Relationship between plasma aldosterone concentration and plasma potassium in patients with essential hypertension during alprenolol treatment. Acta Med. Scand. 200, 263-267 (1976)
Received: May 4, 1979 accepted: July 24, 1979
Dr. H. J. Komerup Department of Medicine C Kommunehospital DK-8000 Aarhus C, Denmark
Eur. J. Clin. Pharmacol. 16, 305-3t0 (1979)
© by Springer-Verlag I979
Effect of Oral Labetalol on Plasma Catecholamines, Renin and Aldosterone in Patients with Severe Arterial Hypertension H. J. Kornerup, E. B. Pedersen, N. J. Christensen, A. Pedersen, and G. Pedersen Departments of Medicine C and M, Aarhus Kommunehospital and Aarhus University, and Department of Internal Medicine and Endocrinology, Herlev Hospital Copenhagen, Denmark
Summary. Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined aand/3-adrenergic receptor blockade induced by oral labetalol treatment for 2 months. Furosemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined a- and /3adrenergic receptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances the antihypertensive effect of labetalot, and partly modifies both renin and sympathetic nervous activity. Key words: labetalol, furosemide, hypertension; aldosterone, blood pressure, plasma catechotarnines, renin
In the majority of patients with untreated essential hypertension sympathetic nervous activity is normal [1, 2], and it has recently been suggested that activity of the renin system declines with the progression of essential hypertension, except in the malignant phase
[3]. During antihypertensive therapy, however, blood pressure (BP) regulation may be influenced by alteration in the activity of the sympathetic nervous system and the renin system. Suppression of the renin system has been suggested as being responsible for at least part of the antihypertensive effect of/3-adrenergic receptor blockers [4, 5]. On the other hand, activation of the renin system by vasodilators has been suggested as counterbalancing the antihypertensive effect of these agents [6]. In the present study, arterial BP, plasma catecholamines, renin activity and aldosterone concentration were studied in patients with severe essential hypertension, before and after combined a- and /3-adrenergic receptor blockade induced by oral labetalol treatment for 2 months.
Material and Methods Twelve patients with severe essential hypertension, 10 males and 2 females, aged 32-67 years, were included in the study. Prior to the study, 8 patients had received oral diazoxide therapy for several months, and the remaining 4 were candidates for aggressive vasodilator therapy because of their resistance to conventional antihypertensive treatment, which included combinations of 2-3 antihypertensive agents (propranolol or alprenolol, hydralazine, cyclopenthiazide or furosemide, a-methyldopa, bethanidine or guanethidine) given in maximal doses to each patient in several different combinations. On such conventional antihypertensive treatment, diastolic BP in all the patients remained above 120 mmHg. Seven patients had previously exhibited severe hypertensive retinal changes (grade III-IV), but at the time of study all had grade I-II retinal changes (Keith-Wagener). Cardiac enlargement on 0031-6970/79/0016/0305/$01.20
306
H.J. Kornerup et al.: Labetalol in Severe Hypertension
Table 1. Effect of labetalol on blood pressure (BP), pulse rate (PR), and body weight (BW). A: Before labetalol. B: After Iabetalol for 2 months Patient no.
Supine BP (mmHg)
Standing BP (mmHg)
Supine PR (per rain)
Standing PR (per min)
BW
(kg)
A
B
A
B
A
B
A
B
A
B
1 2 3 4 5 6 7 8 9 10 11 12
230/150 220/135 190/130 200/140 230/150 200/120 210/140 190/120 240/150 210/150 210/130 240/170
1.90/130 220/125 180/140 220/140 200/130 180/100 170/120 160/110 190/105 180/110 t40/110 140/105
210/150 220/135 190/135 200/130 230/140 190/120 210/140 170/120 240/150 205/150 200/135 235/165
170/130 150/90 180/140 180/135 175/125 155/105 160/110 160/105 180/90 160/100 100/60 100/80
100 92 88 80 76 88 72 80 88 72 80 76
76 72 72 84 60 68 56 68 70 76 64 76
108 96 94 84 82 96 76 84 92 76 84 82
84 80 80 88 76 76 56 72 72 84 60 84
91.6 73.5 96.7 71.4 66.5 78.4 78.0 67.6 80.9 52.5 65.5 113.0
92.7 73.5 99.6 74.8 69.5 78.9 79.8 71.7 81.5 55.5 66.0 113.3
Mean ±SD
214/140 18/15
181/119 26/14
208/139 20/13
156/106 28/24
83 9
70 8
88 9
76 t0
77.9 16.2
79.7 15.7
Table 2. Effect of labetalol on plasma noradrenaline (PNA), adrenaline (PA), renin activity (PRA) and aIdosterone concentration (PAC) and blood glucose and plasma potassium. A: Before labetaloh B: After labetalol for 2 months
PNA (ng/ml)
PA (ng/ml)
PRA (ng Ang I 80%ml lh-1)
PAC (ng/100 ml)
Blood glucose (rag/100 mI)
Plasma potassium (mmol/1)
A
B
A
B
A
B
A
A
B
A
B
1 2 3 4 5 6 7 8 9 10 11 12
0.30 0.21 0.24 0.37 0~67 0.14 0.25 0.40 0.25 0.16 . .
0.29 0.24 0.15 0.12 0.30 0.10 0.22 0.16 0.30 0.11
0.08 0.07 0.05 0.07 0.05 0.01 0.04 0.07 0.02 0.03
0.11 0.07 0.06 0.05 0.10 0.08 0.07 0.11 0.02 0.00
2.00 0.68 2.51 2.58 3.20 0.82 0.69 2.12 1.26 1.13 2.72 1.66
1.02 1.03 1.41 1.24 1.51 0.84 0.56 1.66 2.12 1.06 5.93 2.55
14.0 13.3 18.6 17.9 28.5 17.6 20.2 11.6 37.2 33.1 13.4 8.9 18.9 I8.9 21.2 13.9 6.5 13.4 29.0 15.4 17.3 50.6 21.5 41.1
125 106 102 97 104 102 99 102 115 98 100 93
121 94 100 94 106 99 91 119 93 95 97 95
3.1 2.4 3.4 2.8 3.3 3.8 2.9 4.0 4.t 3.3 3.4 3.2
3.4 2.9 3.2 2.8 3.7 4.0 3.6 3.6 4.5 3.6 4.2 4.2
Mean _+SD
0.30 0.15
0.05 0.02
0.07 0.04
1.78 0.87
1.74 1.43
20.5 8.1
104 9
100 10
3.3 0.5
3.6 0.5
Patient no.
. .
. . 0.20 0.08
. .
X - r a y , a n d / o r h y p e r t r o p h y or strain o n E C G , w e r e p r e s e n t i n all b u t o n e subject. C r e a t i n i n e c l e a r a n c e e x c e e d e d 50 m l / m i n a n d p r o t e i n u r i a was a b s e n t in all, e x c e p t o n e p a t i e n t in w h o m c r e a t i n i n e c l e a r a n c e was d e c r e a s e d t o 41 m l / m i n a n d urinalysis disclosed a slight p r o t e i n u r i a of 0 . 5 - 1 . 0 g/day. I n this p a t i e n t , a n d 3 o t h e r s o n w h o m p e r c u t a n e o u s r e n a l b i o p s y was p e r f o r m e d , severe n e p h r o s c l e r o s i s was d e m o n strated. A l l a n t i h y p e r t e n s i v e a g e n t s except f u r o s e m i d e w e r e g r a d u a l l y d i s c o n t i n u e d o v e r several weeks b e f o r e t h e study, while the p a t i e n t s w e r e f o l l o w e d i n
B
21.3 13.1
t h e o u t - p a t i e n t clinic. F u r o s e m i d e 8 0 - 2 5 0 m g / d a y and an oral potassium supplement were then cont i n u e d t h r o u g h o u t t h e s t u d y p e r i o d , i n the s a m e dose for e a c h p a t i e n t . A f t e r t r e a t m e n t for 2 w e e k s with f u r o s e m i d e as t h e o n l y drug, l a b e t a l o l was g i v e n in i n c r e a s i n g doses f r o m 300 to 1 2 0 0 - 2 4 0 0 m g / d a y ( m e a n 2 1 7 5 ) , d i v i d e d i n t h r e e daily doses, for the n e x t m o n t h , a n d this t r e a t m e n t was c o n t i n u e d u n c h a n g e d d u r i n g the s e c o n d m o n t h . B l o o d s a m p l e s for m e a s u r e m e n t of p l a s m a n o r adrenaline concentration (PNA), adrenaline conc e n t r a t i o n ( P A ) , r e n i n activity ( P R A ) , a l d o s t e r o n e
H. J. Kornerup et al.: Labetalol in Severe Hypertension
concentration (PAC), blood glucose concentration and plasma potassium concentration were collected by an indwelling peripheral venous catheter at 9.00 a. m., after recumbency for one hour, and after an 8h fast, just before and after treatment with labetalol for 2 months. No dietary restrictions were prescribed. Plasma catecholamines were determined by a sensitive double-isotope derivative technique [7], normal mean PNA 0.254 ng/ml (range 0.08-0.75, n = 32) and normal mean PA 0.047 ng/ml (range 0.00-0.19, n = 32). P R A was measured radioimmunologically, as described by Giese et al. [8], normal mean 1.32 ng angiotensin I (Ang I) 80%ml-lh -I (range 0.47-2.78, n = 29). PAC was measured radioimmunologically according to the method of Damkja~r Nielsen [9], normal mean 13.6 ng/100 ml (range 4.6-25.9, n = 23). Blood glucose was determined by a glucose oxidase method, and plasma potassium by flame photometry. BP, measured by sphygmomanometry, and pulse rate were determined after one hour in the supine position and after 2 min in the upright position. Mean BP was defined as diastolic BP + 1/3 BP amplitude. In association with the BP readings body weight (BW) was measured. Mann-W]fitney's rank sum test, Wilcoxon's signed rank test and Spearman's test were used for statistical analysis. Informed consent to the procedure was obtained from all patients examined.
307 Table 3. Correlation analyses (Spearrnan's test) between changes (A) in the variables studied after treatment with labetalol for 2 months Variables Y
X
Coefficient of correlation (rho)
Level of significance (P = 2 a )
AMBP (supine) AMBP (standing) zl Mt3P (supine)
ABW ABW APNA
0.50 0.59 -0.58
n.s. (P > 0.10) P < 0.05 n.s. (0.10 > P
AM]3P (supine) ZlMBP (supine) zl PNA ZlPRA APAC APNA APRA
APRA ziPAC ABW ABW zlBW ziPRA zlPAC
-0.63 -0.61 -0.82 -0.75 -0.34 0.82 0.66
P < P < P < P < n.s. P < P
o.05) 0.05 0.05 0.01 0.01 (P > 0.10) 0.01 0.05
MBP = mean blood pressure
25i O
p o
-25 to
.__q
e
g¢- -50 Results
Blood Pressure, Pulse Rate and Body Weight (Table 1) Labetalol reduced the supine and standing diastolic BP to a level at or below 110mmHg in 6 patients. Standing diastolic BP also decreased to a level at or below 110mmHg, whereas supine diastolic BP remained above 110 mmHg in 2 other patients. In the remaining 4 patients, the reduction in supine and standing BP was minimal. The decrease in average supine BP from 214/140 to 181/119mmHg, and in average standing BP from 208/139 to 156/ 106 mmHg, were significant (P < 0.01). Average supine and standing pulse rates decreased significantly during labetalol therapy (P < 0.01). The rise in mean BW from 77.9 to 79.7 kg during treatment with labetalol was significant (P < 0.01). In 6 patients BW increased by more than 1.5 kg.
Plasma Catecholamines (Table 2) Before treatment with labetalol, PNA and PA were normal in all subjects. No difference between the
-75 0
20
40
60
change in body weight {%d Fig. L Relationship between changes in pIasma noradrenaiine concentration and in body weight during labetalol treatment
pretreatment values of PNA or PA was present in patients whose BP responded to labetalol and those in whom BP was unresponsive to labetalol. Labetalol induced a significant fall in the mean value of PNA, from 0.30 to 0.20 ng/ml (P < 0.05). P A and blood glucose concentration did not change significantly during treatment with labetaloI (P > 0.10).
Renin-Aldosterone System (Table 2) Before treatment with labetalol, P R A and PAC were within normal range, in all except one subject, in whom P R A was increa.sed to 3.20 ng Ang I 80%ml-lh q, and 3 in whom PAC was increased to 28.5-37.2 ng/100 ml. No difference in the pretreat-
308 ment values of P R A or PAC was present between patients whose BP did not respond to labetalol and those whose BP did respond to it. The changes in P R A and PAC during treatment with labetaloI varied greatly, but the mean values did not alter significantly (P > 0.I0). Labetalol induced a slight but significant increase in plasma potassium concentration from 3.3 to 3.6 mmol/1 (P < 0.05).
Relationship Between the Variables Studied (Table 3) No correlation was found between the basal values of the variables studied. However, changes in the variables during treatment with labetalol disclosed certain significant correlations, which are summarized in Table 3. The rise in BW correlated inversely with the fall in standing mean BP, whereas the corresponding correlation between change in BW and in supine mean BP was not significant. Changes in BW correlated inversely with changes in PNA (Fig. 1) and with changes in PRA. Changes in P R A correlated positively with changes in PNA and in PAC. Finally, changes in supine mean BP correlated inversely with changes in P R A and in PAC.
Discussion
In the present study oral Iabetaiol provided an adequate or satisfactory antihypertensive effect in only half of the patients with severe arterial hypertension. The purpose of the furosemide therapy was an attempt to prevent the expansion of extracellular and intravascular volume due to sodium and fluid retention, which usually accompanies therapy with vasodilators, including labetalol, whereby the hypotensive effect may be counterbalanced [10, 11, 12]. This intention was probably not achieved, since BW increased during treatment with labetalol, and the rise in BW correlated inversely with the fall in standing mean BP. More intense furosemide therapy might have reduced BP in those patients who did not respond to labetalol. Labetalol is believed to induce a combined aand nonselective fi-adreno-receptor blockade [13]. The presence of such an a- and fi-adrenergic receptor blockade during treatment with labetalol in the majority of our patients was indicated by a postural decrease in BP, and a decrease in pulse rate. Pure a-adrenergic receptor blockade has previously been demonstrated to increase PNA both at rest and during exercise in normal subjects [14], whereas pure fi-adrenergic receptor blockade increases P N A only during exercise, but not at rest, in normal and hypertensive subjects [2, 15, 16]. In
H. J. Kornerup et al.: Labetalolin SevereHypertension patients with ischaemic heart disease, resting PNA also increases during pure /3-adrenergic receptor blockade [17]. The rise in PNA after a-adrenergic receptor blockade is partly due to a compensatory rise in s?nnpathetic nervous activity, as BP decreases after postsynaptic blockade, and partly due to blockade of the presynaptic a-receptors, which regulate noradrenaline release from the adrenergic nerve terminals. During acute combined a- and fi-adrenergic receptor blockade induced by intravenous labetatol, PNA increases in patients with moderate essential hypertension at supine rest, as well as during supine exercise, resembling the response to pure a-adrenoreceptor blockade [18]. However, during long-term treatment with tabetalol, PNA and catecholamines in urine, measured by sensitive, specific radioenzymatic methods as used in this study, have been reported as being normal [19]. Labetalol administered orally for 2 months in the present study caused a decrease in PNA. This might have been caused by interference with sympathetic nervous activity by sodium and fluid retention. Thus, increases in BW were correlated closely with decreases in PNA, which suggests that PNA decreased in patients with sodium and fluid retention, whereas PNA was unchanged in those with minimal sodium and fluid retention, in accordance with an inverse relationship between sympathetic nervous activity and sodium. Circulating P A is dependent both on the level of sympathetic nervous activity and the blood glucose concentration [16]. The lack of alteration in PA during labetalol therapy in this study is not surprising, as PNA decreased and blood glucose concentration was unchanged. The reports of other investigators" [12, 20, 21], of markedly increased urinary excretions of adrenaline and other catecholamines during treatment with labetalol, may be explained by interference by metabolite(s) of labetalol with the nonspecific fluorimetric and spectrophotometric assay methods used [19]. The normal values of P R A and PAC before labetalol in the majority of our patients, even though they were treated with furosemide, might be explained by a low-renin state due to the severity of the hypertension, according to the hypothesis of Birkenhfiger and Schalekamp [3]. The very variable response of P R A to labetalol, and some of the correlations found between the variables in our study, suggest the presence of a complex of interrelated factors which are involved in renin release during treatment with labetalol. Thus, sodium and fluid retention might have modified renin release during treatment with labetalol, as indicated by a negative correlation between change in BW and in PRA. This suggests
H. J. Kornerup et al.: Labetalol in Severe Hypertension
that renin release was suppressed in patients with sodium and fluid retention in contrast to those with minimal sodium and fluid retention, in accordance with the well-known inverse relationship between renin and sodium [22]. A pronounced increase in PRA occurred in some of our patients during treatment with labetalol, in spite of the fi-adrenergic receptor blockade, which usually suppresses renin release [4, 5, 23]. According to baroreceptor-theory [22], a decrease in BP might have contributed to the stimulatory effect on renin release in these patients, and this is supported by the finding of a negative correlation between changes in mean BP and in PRA. These results suggest that the antihypertensive effect of labetalol may be renin-independent. Catecholamines stimulate renin release [24, 25] and vice versa [26]. The positive correlation between changes in PNA and in PRA found in the present study, however, might be due to a common action of alterations in sodium and fluid balance upon renin and catecholamine release, since the renal sympathetic innervation might conceivably have been blocked by labetalol. Aldosterone secretion is dependent both on renin release and plasma potassium level [27]. The slight but significant increase in plasma potassium during labetalol therapy, which has also been demonstrated during pure /3-adrenergic receptor blockade [28], might have tended to stimulate aldosterone secretion, although this effect was probably negligible. The close positive correlation between changes in PRA and in PAC is indicative of an intact relationship between renin and aldosterone during treatment with labetalol. In conclusion, the present study suggests that labetalol through its combined a- and /3-adrenoreceptor-blocking action induces a rise in BW, probably due to sodium and fluid retention, which in part counterbalances the antihypertensive effect of labetalol, and which in part affects renin as well as sympathetic nervous activity. Further investigation by direct measurement of body sodium and fluid content are necessary to verify this hypothesis.
Acknowledgments. Glaxo A/S, Denmark, and Allen & Hanbury, United Kingdom kindly supplied labetalol. References 1. Lake, C.R., Kopin, I.J., Ziegler, M.G., Coleman, M.D.: Plasma catecholamines and neurogenic hypertension. New Engl. J. Med. 297, 53-54 (1977) 2. Pedersen, E. B., Christensen, N. J.: Catecholamines in plasma and urine in patients with essential hypertension determined
309 by double-isotope derivative techniques. Acta Med. Scand. 198, 373-377 (1975) 3. Birkenh~iger,W. H., Schalekamp, M. A.: Control mechanisms in essential hypertension, p. 111. Amsterdam: Elsevier 1976 4. Biihler, F. R., Laragh, J. H., Baer, L., Vaughan, E. D., Brunnet, It. R.: Propranotol inhibitionof renin secretion. A specific approach to diagnosis and treatment of renindependenthypertensive diseases. New Engl. J. Meal. 287, 1209-1214 (1972) 5. Shand, D., Frisk-Holmberg, M., McDevitt, D., Sherman, K., Hollifield, J.: A dual antihypertensive mechanism for propranolol based on plasma level/response relationships. In: Pathophysiology and management of arterial hypertension. Berglund, G., Hansson, L., Werk6, L. (ed.), pp. 175-182. G6teborg: Lindgren & S6ner 1975 6. Pettinger, W.A., Keeton, K.: Altered renin release and propranolol potentiation of vasodilatory drug hypotension. J. Ctin. Invest. 55, 236-243 (1975) 7. Christensen, N.J.: Plasma noradrenaline and adrenaline in patients with thyreotoxicosis and myxoedema. Clin. Sci. Mot. IVied. 45, 163-171 (1973) 8. Giese, J., Jorgensen, M., Nielsen, M. D., Lund, J. O., Munck, O.: Plasma renin concentration measured by use of radioimmunoassay for angiotensin I. Scand. J. Clin. Lab. Invest. 26, 355-368 (1970) 9. Rask-Madsen, J, Bruusgaard, A., Munck, O., Nielsen, M. D., Woming, H.: The significanceof bile acids and aldosterone for the electrical hyperpolarization of human rectum in obese patients treated with intestinal by-pass operation. Scand. J. Gastroenterol. 9, 417-426 (1974) t0. Ibsen, H., Rasmussen, K., Jensen, H. AE.,Leth, A.: Changes in plasma volume and extracellular fluid volume after addition of pr~osin to propranolol treatment in patients with hypertension. Scand. J. Clin. Lab. Invest. 38, 425-429 (1978) 11. Ibsen, H., Rasmussen, K., Jensen, H. ~E.,Leth, A.: Changes in plasma volume and extracellular fluid volume after addition of hydralazine to propranolol treatment in patients with hypertension. Acta Med. Scand. 203, 419-423 (1978) 12. Weidmann, P., De Chatel, R., Ziegler, W.H., Flammer, J., Reubi, F.: Alpha and beta adrenergic blockade with orally administered labetalol in hypertension. Studies on blood volume, plasma renin and aldosterone and catecholamine excretion. Am. J. Cardiol. 41, 570-576 (1978) 13. Richards, D.A.: Pharmacological effects of labetalol in man. Br. J. Clin. Pharmacol. 3, Suppl. 3, 721-723 (1976) 14. Galbo, H., Christensen, N. J., Hoist, J. J.: Catecholamines and pancreatic hormones during autonomic blockade in exercising man. Acta Physiol. Scand. 101, 428-437 (1977) 15. Christensen, N.J., Trap-Jensen, J., Clausen, J.P., Noer, I., Krogsgaard, A.R., Larsen, O.A.: Effect of beta-receptor blockade on heart rate, hepatic blood flow and circulating noradrenatine during exercise in man. Acta Physiol. Scand. 95, 62A-63A (1975) 16. Gatbo, H., Christensen, N.J., Holst, J.J.: Glucose-induced decrease in glucagon and epinephrine responses to exercise in man. J. Appl. Physiol. 42, 525-530 (1977) 17. Hansen, J.F., Itesse, B., Christensen, N.J.: Enhanced sympathetic nervous activity after intravenous propranolol in ischaemic heart disease: Plasma noradrenaline, splanchnic blood flow and pulmonary artery Oxygensaturation at rest and during exercise. Eur. J. Clin. Invest. 8, 31-36 (1978) 18. Christensen, N. J., Trap-Jensen, J., Svendsen, T. L., Rasmussen, S., Nielsen, P.E.: Effect of labetaloI on plasma noradrenaline and adrenaline in hypertensive man. Eur. J. Clin. Pharmacol. 14, 227-230 (1978) 19. Hamilton, C. A., Jones, D. H., Dargie, H. J., Reid, J. L.: Does labetalol increase excretion of urinary catecholamines. Br. Med. J. 1978/11, 800
310 20. Harris, D., Richards, D.A. Labetalol and urinary catecholamines. Br. Med. J. 1977/1[I, 1673 21. Chapman, B.P., Veitch, A.G., Shepherd, B.: Labetalol and urinary catecholamines. Br. Med. J. 1978/I, 364 22. Davis, J.O., Freeman, R.H.: Mechanisms regulating renin release. Physiol. Rev. 56, 1-56 (1976) 23. Pedersen, E.B., Kornerup, H. J.: Plasma renin concentration in essential hypertension during beta-adrenergic blockade and vasodilator therapy. Eur. J. Clin. Pharmacol. 12, 93-96 (1977) 24. Hedeland, H., Dymling, J. F., H6kfelt, B.: The effect of insulin-induced hypoglycaemia on plasma renin activity and urinary" catecholamines before and following clonidine in man. Acta Endocrinol. (Kbh.) 71, 321-330 (1972) 25. Vander, A, J.: Effect of catecholamines and the renal nerves on renin secretion in anesthetized dogs. Am. J. Physiol. 209, 659-662 (1965) 26. Peach, M.J.: Adrenal medullary stimulation induced by angiotensin. Circ. Res. Suppl. lI, 107-117 (1971)
H.J. Kornerap et al.: Labetalol in Severe Hypertension 27. Williams, G.H., Dtuhy, R.G.: Aldosterone biosynthesis. Interrelationship of regulatory factors. Am. J. Med. 53, 595-605 (1972) 28. Pedersen, E. B., Kornerup, H. J. Relationship between plasma aldosterone concentration and plasma potassium in patients with essential hypertension during alprenolol treatment. Acta Med. Scand. 200, 263-267 (1976)
Received: May 4, 1979 accepted: July 24, 1979
Dr. H. J. Komerup Department of Medicine C Kommunehospital DK-8000 Aarhus C, Denmark
