Acta Med Scand 200: 263-267, 1976
Relationship between Plasma Aldosterone Concentration and Plasma Potassium in Patients with Essential Hypertension during Alprenolol Treatment E. B. Pedersen and H. J. Kornerup From First University Clinic of Internal Medicine, Kommunehospitulet, Arhus, Denmark
ABSTRACT. Plasma aldosterone concentration (PAC), plasma renin concentration (PRC), plasma potassium, plasma sodium and blood pressure (BP) have been measured in 22 patients with essential hypertension before and after treatment for one month with alprenolol. PAC, PRC and BP decreased and plasma potassium increased significantly during treatment. Plasma sodium, however, was unchanged. Changes in PAC were inversely correlated to changes in plasma potassium. No relationship could be demonstrated between PAC and plasma sodium. Mean BP was inversely correlated to PAC during alprenolol treatment, but not before treatment. No relationship was found between changes in BP and changes in PRC. The results suggest that plasma potassium is an important regulatory factor for aldosterone secretion during alprenolol treatment. Other factors, however, must have a modulating influence and since the renin-angiotensin system is not suppressed to very low values, this system is possibly the most important of these factors. It is suggested that aldosterone secretion is not of primary importance in BP regulation during alprenolol treatment.
Aldosterone secretion is regulated mainly by the renin-angiotensin system and plasma potassium, while the adrenocorticotrophic hormone (ACTH) and plasma sodium are less important (15, 17). Several investigations (2, 3, 6, 10, 12) have shown that treatment with p-adrenergic blocking agents suppresses plasma renin in patients with essential hypertension. One of these agents, propranolol. appears to increase plasma potassium in most patients (3, 4). Thus the influence of p-adrenergic blocking agents on plasma aldosterone concentration (PAC) is difficult t o predict because the ten-
dency to reduction in aldosterone production mediated via the renin-angiotensin system would be antagonized by the increase in plasma potassium. The purpose of the present investigation was to measure the effect of alprenolol on PAC, plasma renin concentration (PRC), plasma potassium, plasma sodium and BP in patients with essential hypertension, and to study the relationship between PAC on the one hand and plasma potassium, plasma sodium and BP on the other before and during treatment with alprenolol.
PATIENTS Twenty-two patients with essential hypertension, 11 males and 11 females, mean age 40 yearsf13 (1 S.D.), were examined. Hypertension due to aortic coarctation or diseases of the kidneys, renal arteries or suprarenal glands were excluded by physical examination, measurement of serum electrolytes, creatinine clearance, screening of urine for protein, i.v. urography and measurement of the urinary excretion of catecholamines. None of the females received oral contraceptives. The known duration of hypertension varied greatly, 23 monthsk37 (1 S.D.).
Seven patients had been treated previously with amethyldopa and/or diuretics, whereas 15 had never received antihypertensive agents. Seven patients had retinal lesions corresponding to grade 1 (Keith-Wagener), 11 to grade 2, and one to grade 3. Three had no retinal lesions. Left ventricular hypertrophy or strain pattern was present in 9 patients, and 4 had an increased cardiothoracic ratio. Nonc: had cardiac failure. Proteinuria was not present in any of the patients. Creatinine clearance was 102 ml/minf25 (1 S.D.). All patients were told about the nature of the study before the investigations were performed, and informed consent was obtained from all. Acta Med Scand 200
264
E. B. Pedersen and H . J.-KoFnerup
Table I. Plasma aldosterone concentration (PAC), plasma potassium, plasma sodium, BP and plasma renin concentration (PRC) before ( A ) and during treatment with alprenolol (B) PAC (ng/100 ml)
Plasma potassium (mEq/l)
Plasma sodium (mEq/l)
BP (mmHg)
PRC @GU/ml)
A
B
A
B
A
B
A
B
A
B
15.5
11.9 19.7 14.8 16.5 16.4 12.9 17.2 16.4 20.9 18.6 8.8 17.6 12.8 3.7 21.2 13.5 4.5 29.0 10.8 3.8 17.4 19.0 14.9 6.1
3.6 3.2 4.3 3.5 4.6 4.0 4.0 4.1 4.4 3.4 3.8 4.1 3.9 3.0 3.2 4.1 3.6 3.8 3.8 4.4 4.0 3.7 3.8 0.4
4.0 3.5 4.5 3.8 3.9 3.9 4.0 3.6 5.2 3.6 4.3 4.7 3.7 3.2 4.1 4.4 3.6 3.9 4.1 5.8 4.6 4.1 4.1 0.6
140 141 132 137 143 141 140 138 140 142 139 141 137 145 140 136 141 140 137 140 139 141 140 2.7
140 143 142 140 141 142 139 140 145 140 134 144 143 145 142 137 138 141 137 140 140 141 141 2.7
180/125 170/120 190/120 2 lo/ I30 190/125 200/110 160/125 160/110 l60/110 160/1I5 200/ 130 170/110 220/ 120 170/115 180/115 2 lo/ 125 180/120 160/110 l5O/llO 2 lo/ 130 200/ 130 l70/ 125 182/120 20/8
l50/l10
49 28 24 36 31 40 24 39 23 116 45 28 26 7 60 21 14 35 25 29 28
15
Pat.
no. I 2 3 4
27.9 17.8 20.2 13.9 14.0 21.8
5 6 7 8 9
15.8
10
11 12 13 14
15 16 17 18 19 20 21 22
Mean S.D.
23.9 27.7 17.1 25.9 18.2 8.7 31.8 16.0 8.1 25.2 14.7 13.9 34.8 15.9 19.5 7.1
Procedure All participants were out-patients on liberal sodium and potassium intake and all were seen weekly for 2 months. The first month was a control period during which all drugs were discontinued. During the second month the patients were treated with alprenolol (Aptin Duretter”), average dosage 964 mg/day, divided into two or three daily doses. Blood samples for determination of PAC, PRC, sodium and potassium were collected at the end of the control period and after one months treatment with alprenolol. Blood was drawn in the morning at 9 a.m. after the patients had been in the supine position for at least one hour and after approximately 8 hours’ fast. Urine was collected for a 24-hour period on the day before blood sampling.
METHODS PAC was measured using Damkjrer Nielsen’s method (13) -a radioimmunological measurement performed on plasma after previous extraction with dichloromethane, purification on silica-gel columns and chromatographic separation on paper. The position of aldosterone on the paper was located by scanning. Aldosterone antiserum was obtained from Research Plus Laboratories, Denville, New Jersey. The coefficient of variation was 15%. PAC in 23 normal healthy control subjects was 13.5 ng/ Actu
Med Scund 200
160/110 170/110 180/120 180/130 190/110 130/l00 130/90 135/95 140/100 200/ 130 170/110 170/120 l80/110 145/95 190/115 170/115 140/95 135/95 190/120 190/1 I5 135/110 163/109 23/l I
55
36 22
5
30 8 14 30 35 34 9 50 12 21 23 5 26 28 40 46 24
I5 29 28 24 13
100 ml (range 4.625.9) after one hour in the supine position. PAC in samples from the same patients was determined during the same analytic run. PRC was measured using the method described by Giese et al. (9). This involves radioimmunological measurement of angiotensin I after previous dialysis of plasma, incubation at 37°C and pH 7.4 both with and without addition of a human standard and extraction of angiotensin I produced. PRC is given in Goldblatt units (GU) using the above mentioned human renin as reference. Dr J. Giese, Department of Clinical Physiology, Amtssygehuset, Glostrup, Denmark, provided antiserum against angiotensin I and the Medical Research Council, Division of Biological Standards, National Institute for Medical Research, Mill Hill, London, placed Renin Human 68/356 at our disposal. The coefficient of variation was 11 %. PRC in 15 healthy control subjects was 36 pGU/ml (range 1&79). Sodium, potassium and creatinine in serum and urine were determined by conventional Auto‘Analyzer technique (Dept. of Clinical Chemistry, Kommunehospitalet, h h u s , Denmark). BP was measured by sphygmomanometer after at least one hour’s rest in the supine position. Several measurements were performed at each session and the lowest readings were used. Mean BP was calculated a s diastolic pressure plus of the pulse pressure. Wilcoxon’s signed rank test and Spearmann’s test were used in the statistical calculations.
Plasma aldoster .one and potassium during alprenolol treatment A
PLASMA ALOOSTERONE CONCENTRATION
-05
+
.
--&
'0 5
-
'1 5 rnEq/l
I****
-15.0
i *
265
PAC was not correlated to mean BP (rho= -0.139,p>0.05) before treatment. During alprenolol treatment, however, a significant correlation was found between mean BP and PAC (rho=-0.471, p 0.05). PRC was not correlated to mean BP either before (rho=O.O79, p>0.05) or after alprenolol treatment (rho=-0.347, p>0.05) and changes in PRC were not correlated to changes in mean BP (rho=O. 159, p >0.05).
-
Fig. 1 . Relationship between changes in plasma aldosterone concentration and changes in plasma potassium induced by alprenolol in 22 patients with essential hypertension.
RESULTS Table I shows PAC, PRC, plasma potassium, plasma sodium and BP before and after treatment with alprenolol. PAC decreased significantly from 19.5k7.1 (1 S.D.) to 14.9 ngl100 mlk6.1 (1 S.D.) @0.05). Plasma potassium and PAC were not significantly correlated either before (rho= -0.147, p>0.05) or after treatment with alprenolol (rho=0.088, p > 0.05). Fig. 1 shows, however, that changes in PAC were significantly correlated to changes in plasma potassium concentration (rho= -0.516, p0.05) or after treatment (rho =0.201, p>0.05). Changes in plasma sodium did not correlate with changes in PAC (rho=-O.O4O,p>O.O5).
DISCUSSION The present results show that one month's therapy with alprenolol induces a significant reduction in BP, associated with a decrease in both PAC and PRC and an increase in plasma potassium, whereas plasma sodium remains unchanged. Evidence of decreasing secretion of aldosterone during treatment of hypertensive patients with a P-adrenergic blocking agent has also been obtained by Buhler et al. (3), who found a decreasing urinary excretion of aldosterone in patients with essential hypertension during treatment with propranolol. They suggested that the decrease in PRA and urinary aldosterone excretion produced by propranolol bore a causal relationship to the antipressor effect. Although this is possible, it should be mentioned that neither the present study nor several others (2, 10, 12) have been able to demonstrate a significant correlation between the suppression of plasma PLASMA ALDOSTERONE CONCENTRATION
20 .
.e
. * 10
.
0 .
. .
.
1 .
1 0
-
.
1.
.
L
Acta Med Scand 200
266
- E , B . Pedersen and H . J . Kornerup
renin and the BP reduction during /3-adrenergic blockade. In this study, statistical analysis did not reveal any correlation between levels of PAC and BP during the control period. During alprenolol treatment, however, a significantly inverse correlation was found between these parameters. Thus, the lower the BP obtained, the higher the PAC. In all but one patient (no. 18), however, PAC was within the normal range after treatment. The results suggest that PAC is not of primary importance for the regulation of BP during alprenolol treatment. Although plasma sodium and ACTH influence aldosterone secretion, the renin-angiotensin system and plasma potassium are the most important regulatory factors of aldosterone secretion (IS, 17). Plasma potassium appears to be the dominant factor influencing aldosterone secretion in patients with primary hyperaldosteronism (14) and in anephric man ( I ) , conditions where plasma renin is very low. According to Buhler et al. (3) the renin suppressive action of /3-adrenergic blocking agents constitutes a pharmacological analogue to nephrectomy. With regard to the above it might be supposed that plasma potassium was the most important regulatory factor for the aldosterone secretion in patients treated with P-adrenergic blocking agents. In the present study we found an increase in plasma potassium during alprenolol treatment but no correlation was found between PAC and plasma potassium concentration either before or after this treatment. It has been shown that potassium has a direct effect on aldosterone secretion (8), and thus a rise in the level of plasma potassium might stimulate and a fall inhibit aldosterone production. An increase in plasma potassium during alprenolol treatment might be accompanied by an increase in PAC. However, the present results have shown that the opposite takes place, i.e. a decrease in PAC in spite of an increase in plasma potassium. The changes in PAC induced by alprenolol treatment correlate inversely with the changes in plasma potassium, and the results suggest that plasma potassium may have some importance for the regulation of aldosterone secretion during alprenolol treatment. Since, however, the correlation between changes in plasma potassium and PAC is negative, plasma potassium cannot be the sole regulatory factor and the changes in PAC during P-adrenergic blockade must be attributed to other aldosterone regulatory factors. Acta Med Scand 200
Most studies show that plasma sodium is of little importance for the regulation of aldosterone secretion. This agrees with the present results in which no relationship could be demonstrated between plasma sodium and PAC either before or during alprenolol treatment. Changes in sodium and potassium intake induce changes in PAC ( 5 , 11). All patients in this study were on a liberal sodium and potassium intake, but the 24-hour urinary excretion of sodium and potassium was unaffected by alprenolol therapy. All patients were examined after at least one hour in the supine position at the same time in the morning. Differences in posture as a cause of the changes in PAC can thus be ignored. It has been shown earlier that ACTH can stimulate aldosterone secretion (7, 16). The dose required, however, induces extemely high levels of ACTH compared with the level under normal physiological circumstances. Since all patients were investigated at the same time in the morning, the hypothetical influence of changes in PAC due to the circadian rhythm in ACTH secretion can be ruled out. In good agreement with previous reports (2, 3 , 6 , 10, 12), the plasma content of renin was suppressed by P-adrenergic blockade. This suppression, however, was not always to very low values either in this study or in the studies mentioned above. Thus the renin-angiotensin system may still influence the aldosterone secretion during P-adrenergic blockade. The relationship between PAC and plasma potassium during P-adrenergic blockade appears to be interfered by the renin-angiotensin system, and P-adrenergic blockade may not represent a pharmacological analogue to bilateral nephrectomy. ACKNOWLEDGEMENTS This work was supported by grants from Statens Liegevidenskabelige ForskningsrSid, Hjerteforeningen and F. L. Smidth & Co’s Jubilieumsfond. REFERENCES Bayard, F., Cooke, C. R., Tiller, T. J., Beitins, I. Z., Kowarski, A., Walker, W. G . & Migeon, C. J.: The regulation of aldosterone secretion in anephric man. J. clin. Invest. 50: 1585, 1971. Bravo, E. L., Tarazi, R. C. & Dustan, H. P.: Betaadrenergic blockade in diuretic treated patients with essential hypertension. New Engl. J. Med. 292:66, 1975.
Plasma aldosterone and potassium during alprenolol treatment 3. Buhler. F. R.. Laragh. J. H.. Baer. L., Vaughan, E. D. & Brunner. H. R.: Propranolol inhibition of renin secretion. New Engl. J. Med. 287: 1209, 1972. 4. Buhler. F. R., Laragh, J. H.. Vaughan, E. D., Brunner. H. R.. Gavras. H. & Baer, L.: The antihypertensive action of propranolol. In: Hypertension manual (ed. J. H. Laragh), p. 873. Dun-Donnelley, New York 1973. 5. Cannon, P. J.. Ames. R. P. & Laragh, J. H.: Relation between potassium balance and aldosterone secretion in normal subjects and in patients with hypertensive or renal tubular disease. J. clin. Invest. 45:865, 1%6. 6. Castenfors. J.. Johnson, H. & Oro, L.: Effect of alprenolol on blood pressure and plasma renin activity in hypertensive patients. Acta med. scand. 193: 189. 1973. 7. Crabbe. J.. Reddy. W. J., Ross, E. J . & Thorn, G . W.: The stimulation of aldosterone secretion by adrenocorticotrophic hormone (ACTH). J. clin. Endocr. 19: 1185, 1959. 8. Davis, J. 0.. Urquhart, J . & Higgins, J. T.: The effects of alterations of plasma sodium and potassium concentration on aldosterone secretion. J . clin. Invest. 42: 597, 1%3. 9. Giese, J., Jorgensen, M.. Nielsen, M. D. & Lund, J. 0.: Plasma renin concentration measured by use of radioimmunoassay for angiotensin I. Scand. J. din. Lab. Invest. 26: 355, 1970. 10. Hanson, L., Zweifler, A. J., Julius, S. & Hunyor, S. N.: Hemodynamic effects of acute and prolonged
267
P-adrenergic blockade in essential hypertension. Acta med. scand. 1%: 27, 1974. 1 I . Muller, J.: Regulation of aldosterone biosynthesis. Springer-Verlag. New York 1971, 12. Pedersen, E. B. & Kornerup, H. J.: Effect of alprenolo1 and hydralazine on plasma renin concentration in patients with essential hypertension. Acta med. scand. 198: 379, 1975. 13. Rask-Madsen, J.. Bruusgaard, A,. Munck, 0.. Nielsen, M. D. & Worming, H.: The significance of bile acids and aldosterone for the electrical hyperpolarization of human rectum in obese patients treated with intestinal bypass operation. Scand. J. Gastroent. 9: 417, 1974. 14. Slaton, P. E., Schamberlan, M. & Biglieri, E. G . : Stimulation and suppression of aldosterone secretion in patients with an aldosterone producing adenoma. J. clin. Endocr. 29: 239, 1969. 15. Stockigt, J. R.: The regulation of aldosterone secretion. In: Hypertension: Mechanisms and management (ed. G . Onesti, K. E. Kim and J. H. Moyer), p. 451. Grune & Stratton, New York 1973. 16. Tucci. J. R., Espiner, E. A,, Jagger, P. I., Pauk, G . L. & Lauler, D. P.: ACTH stimulation of aldosterone secretion in normal subjects and in patients with chronic adrenocortical insufficiency. J. clin. Endocr. 27: 568, 1967. 17. Williams, G . H. & Dluhy, R. G . : Aldosterone biosynthesis. Interrelationship of regulatory factors. Amer. J. Med. 53: 595, 1972.
Acra Mrd ScandZOO
Relationship between Plasma Aldosterone Concentration and Plasma Potassium in Patients with Essential Hypertension during Alprenolol Treatment E. B. Pedersen and H. J. Kornerup From First University Clinic of Internal Medicine, Kommunehospitulet, Arhus, Denmark
ABSTRACT. Plasma aldosterone concentration (PAC), plasma renin concentration (PRC), plasma potassium, plasma sodium and blood pressure (BP) have been measured in 22 patients with essential hypertension before and after treatment for one month with alprenolol. PAC, PRC and BP decreased and plasma potassium increased significantly during treatment. Plasma sodium, however, was unchanged. Changes in PAC were inversely correlated to changes in plasma potassium. No relationship could be demonstrated between PAC and plasma sodium. Mean BP was inversely correlated to PAC during alprenolol treatment, but not before treatment. No relationship was found between changes in BP and changes in PRC. The results suggest that plasma potassium is an important regulatory factor for aldosterone secretion during alprenolol treatment. Other factors, however, must have a modulating influence and since the renin-angiotensin system is not suppressed to very low values, this system is possibly the most important of these factors. It is suggested that aldosterone secretion is not of primary importance in BP regulation during alprenolol treatment.
Aldosterone secretion is regulated mainly by the renin-angiotensin system and plasma potassium, while the adrenocorticotrophic hormone (ACTH) and plasma sodium are less important (15, 17). Several investigations (2, 3, 6, 10, 12) have shown that treatment with p-adrenergic blocking agents suppresses plasma renin in patients with essential hypertension. One of these agents, propranolol. appears to increase plasma potassium in most patients (3, 4). Thus the influence of p-adrenergic blocking agents on plasma aldosterone concentration (PAC) is difficult t o predict because the ten-
dency to reduction in aldosterone production mediated via the renin-angiotensin system would be antagonized by the increase in plasma potassium. The purpose of the present investigation was to measure the effect of alprenolol on PAC, plasma renin concentration (PRC), plasma potassium, plasma sodium and BP in patients with essential hypertension, and to study the relationship between PAC on the one hand and plasma potassium, plasma sodium and BP on the other before and during treatment with alprenolol.
PATIENTS Twenty-two patients with essential hypertension, 11 males and 11 females, mean age 40 yearsf13 (1 S.D.), were examined. Hypertension due to aortic coarctation or diseases of the kidneys, renal arteries or suprarenal glands were excluded by physical examination, measurement of serum electrolytes, creatinine clearance, screening of urine for protein, i.v. urography and measurement of the urinary excretion of catecholamines. None of the females received oral contraceptives. The known duration of hypertension varied greatly, 23 monthsk37 (1 S.D.).
Seven patients had been treated previously with amethyldopa and/or diuretics, whereas 15 had never received antihypertensive agents. Seven patients had retinal lesions corresponding to grade 1 (Keith-Wagener), 11 to grade 2, and one to grade 3. Three had no retinal lesions. Left ventricular hypertrophy or strain pattern was present in 9 patients, and 4 had an increased cardiothoracic ratio. Nonc: had cardiac failure. Proteinuria was not present in any of the patients. Creatinine clearance was 102 ml/minf25 (1 S.D.). All patients were told about the nature of the study before the investigations were performed, and informed consent was obtained from all. Acta Med Scand 200
264
E. B. Pedersen and H . J.-KoFnerup
Table I. Plasma aldosterone concentration (PAC), plasma potassium, plasma sodium, BP and plasma renin concentration (PRC) before ( A ) and during treatment with alprenolol (B) PAC (ng/100 ml)
Plasma potassium (mEq/l)
Plasma sodium (mEq/l)
BP (mmHg)
PRC @GU/ml)
A
B
A
B
A
B
A
B
A
B
15.5
11.9 19.7 14.8 16.5 16.4 12.9 17.2 16.4 20.9 18.6 8.8 17.6 12.8 3.7 21.2 13.5 4.5 29.0 10.8 3.8 17.4 19.0 14.9 6.1
3.6 3.2 4.3 3.5 4.6 4.0 4.0 4.1 4.4 3.4 3.8 4.1 3.9 3.0 3.2 4.1 3.6 3.8 3.8 4.4 4.0 3.7 3.8 0.4
4.0 3.5 4.5 3.8 3.9 3.9 4.0 3.6 5.2 3.6 4.3 4.7 3.7 3.2 4.1 4.4 3.6 3.9 4.1 5.8 4.6 4.1 4.1 0.6
140 141 132 137 143 141 140 138 140 142 139 141 137 145 140 136 141 140 137 140 139 141 140 2.7
140 143 142 140 141 142 139 140 145 140 134 144 143 145 142 137 138 141 137 140 140 141 141 2.7
180/125 170/120 190/120 2 lo/ I30 190/125 200/110 160/125 160/110 l60/110 160/1I5 200/ 130 170/110 220/ 120 170/115 180/115 2 lo/ 125 180/120 160/110 l5O/llO 2 lo/ 130 200/ 130 l70/ 125 182/120 20/8
l50/l10
49 28 24 36 31 40 24 39 23 116 45 28 26 7 60 21 14 35 25 29 28
15
Pat.
no. I 2 3 4
27.9 17.8 20.2 13.9 14.0 21.8
5 6 7 8 9
15.8
10
11 12 13 14
15 16 17 18 19 20 21 22
Mean S.D.
23.9 27.7 17.1 25.9 18.2 8.7 31.8 16.0 8.1 25.2 14.7 13.9 34.8 15.9 19.5 7.1
Procedure All participants were out-patients on liberal sodium and potassium intake and all were seen weekly for 2 months. The first month was a control period during which all drugs were discontinued. During the second month the patients were treated with alprenolol (Aptin Duretter”), average dosage 964 mg/day, divided into two or three daily doses. Blood samples for determination of PAC, PRC, sodium and potassium were collected at the end of the control period and after one months treatment with alprenolol. Blood was drawn in the morning at 9 a.m. after the patients had been in the supine position for at least one hour and after approximately 8 hours’ fast. Urine was collected for a 24-hour period on the day before blood sampling.
METHODS PAC was measured using Damkjrer Nielsen’s method (13) -a radioimmunological measurement performed on plasma after previous extraction with dichloromethane, purification on silica-gel columns and chromatographic separation on paper. The position of aldosterone on the paper was located by scanning. Aldosterone antiserum was obtained from Research Plus Laboratories, Denville, New Jersey. The coefficient of variation was 15%. PAC in 23 normal healthy control subjects was 13.5 ng/ Actu
Med Scund 200
160/110 170/110 180/120 180/130 190/110 130/l00 130/90 135/95 140/100 200/ 130 170/110 170/120 l80/110 145/95 190/115 170/115 140/95 135/95 190/120 190/1 I5 135/110 163/109 23/l I
55
36 22
5
30 8 14 30 35 34 9 50 12 21 23 5 26 28 40 46 24
I5 29 28 24 13
100 ml (range 4.625.9) after one hour in the supine position. PAC in samples from the same patients was determined during the same analytic run. PRC was measured using the method described by Giese et al. (9). This involves radioimmunological measurement of angiotensin I after previous dialysis of plasma, incubation at 37°C and pH 7.4 both with and without addition of a human standard and extraction of angiotensin I produced. PRC is given in Goldblatt units (GU) using the above mentioned human renin as reference. Dr J. Giese, Department of Clinical Physiology, Amtssygehuset, Glostrup, Denmark, provided antiserum against angiotensin I and the Medical Research Council, Division of Biological Standards, National Institute for Medical Research, Mill Hill, London, placed Renin Human 68/356 at our disposal. The coefficient of variation was 11 %. PRC in 15 healthy control subjects was 36 pGU/ml (range 1&79). Sodium, potassium and creatinine in serum and urine were determined by conventional Auto‘Analyzer technique (Dept. of Clinical Chemistry, Kommunehospitalet, h h u s , Denmark). BP was measured by sphygmomanometer after at least one hour’s rest in the supine position. Several measurements were performed at each session and the lowest readings were used. Mean BP was calculated a s diastolic pressure plus of the pulse pressure. Wilcoxon’s signed rank test and Spearmann’s test were used in the statistical calculations.
Plasma aldoster .one and potassium during alprenolol treatment A
PLASMA ALOOSTERONE CONCENTRATION
-05
+
.
--&
'0 5
-
'1 5 rnEq/l
I****
-15.0
i *
265
PAC was not correlated to mean BP (rho= -0.139,p>0.05) before treatment. During alprenolol treatment, however, a significant correlation was found between mean BP and PAC (rho=-0.471, p 0.05). PRC was not correlated to mean BP either before (rho=O.O79, p>0.05) or after alprenolol treatment (rho=-0.347, p>0.05) and changes in PRC were not correlated to changes in mean BP (rho=O. 159, p >0.05).
-
Fig. 1 . Relationship between changes in plasma aldosterone concentration and changes in plasma potassium induced by alprenolol in 22 patients with essential hypertension.
RESULTS Table I shows PAC, PRC, plasma potassium, plasma sodium and BP before and after treatment with alprenolol. PAC decreased significantly from 19.5k7.1 (1 S.D.) to 14.9 ngl100 mlk6.1 (1 S.D.) @0.05). Plasma potassium and PAC were not significantly correlated either before (rho= -0.147, p>0.05) or after treatment with alprenolol (rho=0.088, p > 0.05). Fig. 1 shows, however, that changes in PAC were significantly correlated to changes in plasma potassium concentration (rho= -0.516, p0.05) or after treatment (rho =0.201, p>0.05). Changes in plasma sodium did not correlate with changes in PAC (rho=-O.O4O,p>O.O5).
DISCUSSION The present results show that one month's therapy with alprenolol induces a significant reduction in BP, associated with a decrease in both PAC and PRC and an increase in plasma potassium, whereas plasma sodium remains unchanged. Evidence of decreasing secretion of aldosterone during treatment of hypertensive patients with a P-adrenergic blocking agent has also been obtained by Buhler et al. (3), who found a decreasing urinary excretion of aldosterone in patients with essential hypertension during treatment with propranolol. They suggested that the decrease in PRA and urinary aldosterone excretion produced by propranolol bore a causal relationship to the antipressor effect. Although this is possible, it should be mentioned that neither the present study nor several others (2, 10, 12) have been able to demonstrate a significant correlation between the suppression of plasma PLASMA ALDOSTERONE CONCENTRATION
20 .
.e
. * 10
.
0 .
. .
.
1 .
1 0
-
.
1.
.
L
Acta Med Scand 200
266
- E , B . Pedersen and H . J . Kornerup
renin and the BP reduction during /3-adrenergic blockade. In this study, statistical analysis did not reveal any correlation between levels of PAC and BP during the control period. During alprenolol treatment, however, a significantly inverse correlation was found between these parameters. Thus, the lower the BP obtained, the higher the PAC. In all but one patient (no. 18), however, PAC was within the normal range after treatment. The results suggest that PAC is not of primary importance for the regulation of BP during alprenolol treatment. Although plasma sodium and ACTH influence aldosterone secretion, the renin-angiotensin system and plasma potassium are the most important regulatory factors of aldosterone secretion (IS, 17). Plasma potassium appears to be the dominant factor influencing aldosterone secretion in patients with primary hyperaldosteronism (14) and in anephric man ( I ) , conditions where plasma renin is very low. According to Buhler et al. (3) the renin suppressive action of /3-adrenergic blocking agents constitutes a pharmacological analogue to nephrectomy. With regard to the above it might be supposed that plasma potassium was the most important regulatory factor for the aldosterone secretion in patients treated with P-adrenergic blocking agents. In the present study we found an increase in plasma potassium during alprenolol treatment but no correlation was found between PAC and plasma potassium concentration either before or after this treatment. It has been shown that potassium has a direct effect on aldosterone secretion (8), and thus a rise in the level of plasma potassium might stimulate and a fall inhibit aldosterone production. An increase in plasma potassium during alprenolol treatment might be accompanied by an increase in PAC. However, the present results have shown that the opposite takes place, i.e. a decrease in PAC in spite of an increase in plasma potassium. The changes in PAC induced by alprenolol treatment correlate inversely with the changes in plasma potassium, and the results suggest that plasma potassium may have some importance for the regulation of aldosterone secretion during alprenolol treatment. Since, however, the correlation between changes in plasma potassium and PAC is negative, plasma potassium cannot be the sole regulatory factor and the changes in PAC during P-adrenergic blockade must be attributed to other aldosterone regulatory factors. Acta Med Scand 200
Most studies show that plasma sodium is of little importance for the regulation of aldosterone secretion. This agrees with the present results in which no relationship could be demonstrated between plasma sodium and PAC either before or during alprenolol treatment. Changes in sodium and potassium intake induce changes in PAC ( 5 , 11). All patients in this study were on a liberal sodium and potassium intake, but the 24-hour urinary excretion of sodium and potassium was unaffected by alprenolol therapy. All patients were examined after at least one hour in the supine position at the same time in the morning. Differences in posture as a cause of the changes in PAC can thus be ignored. It has been shown earlier that ACTH can stimulate aldosterone secretion (7, 16). The dose required, however, induces extemely high levels of ACTH compared with the level under normal physiological circumstances. Since all patients were investigated at the same time in the morning, the hypothetical influence of changes in PAC due to the circadian rhythm in ACTH secretion can be ruled out. In good agreement with previous reports (2, 3 , 6 , 10, 12), the plasma content of renin was suppressed by P-adrenergic blockade. This suppression, however, was not always to very low values either in this study or in the studies mentioned above. Thus the renin-angiotensin system may still influence the aldosterone secretion during P-adrenergic blockade. The relationship between PAC and plasma potassium during P-adrenergic blockade appears to be interfered by the renin-angiotensin system, and P-adrenergic blockade may not represent a pharmacological analogue to bilateral nephrectomy. ACKNOWLEDGEMENTS This work was supported by grants from Statens Liegevidenskabelige ForskningsrSid, Hjerteforeningen and F. L. Smidth & Co’s Jubilieumsfond. REFERENCES Bayard, F., Cooke, C. R., Tiller, T. J., Beitins, I. Z., Kowarski, A., Walker, W. G . & Migeon, C. J.: The regulation of aldosterone secretion in anephric man. J. clin. Invest. 50: 1585, 1971. Bravo, E. L., Tarazi, R. C. & Dustan, H. P.: Betaadrenergic blockade in diuretic treated patients with essential hypertension. New Engl. J. Med. 292:66, 1975.
Plasma aldosterone and potassium during alprenolol treatment 3. Buhler. F. R.. Laragh. J. H.. Baer. L., Vaughan, E. D. & Brunner. H. R.: Propranolol inhibition of renin secretion. New Engl. J. Med. 287: 1209, 1972. 4. Buhler. F. R., Laragh, J. H.. Vaughan, E. D., Brunner. H. R.. Gavras. H. & Baer, L.: The antihypertensive action of propranolol. In: Hypertension manual (ed. J. H. Laragh), p. 873. Dun-Donnelley, New York 1973. 5. Cannon, P. J.. Ames. R. P. & Laragh, J. H.: Relation between potassium balance and aldosterone secretion in normal subjects and in patients with hypertensive or renal tubular disease. J. clin. Invest. 45:865, 1%6. 6. Castenfors. J.. Johnson, H. & Oro, L.: Effect of alprenolol on blood pressure and plasma renin activity in hypertensive patients. Acta med. scand. 193: 189. 1973. 7. Crabbe. J.. Reddy. W. J., Ross, E. J . & Thorn, G . W.: The stimulation of aldosterone secretion by adrenocorticotrophic hormone (ACTH). J. clin. Endocr. 19: 1185, 1959. 8. Davis, J. 0.. Urquhart, J . & Higgins, J. T.: The effects of alterations of plasma sodium and potassium concentration on aldosterone secretion. J . clin. Invest. 42: 597, 1%3. 9. Giese, J., Jorgensen, M.. Nielsen, M. D. & Lund, J. 0.: Plasma renin concentration measured by use of radioimmunoassay for angiotensin I. Scand. J. din. Lab. Invest. 26: 355, 1970. 10. Hanson, L., Zweifler, A. J., Julius, S. & Hunyor, S. N.: Hemodynamic effects of acute and prolonged
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P-adrenergic blockade in essential hypertension. Acta med. scand. 1%: 27, 1974. 1 I . Muller, J.: Regulation of aldosterone biosynthesis. Springer-Verlag. New York 1971, 12. Pedersen, E. B. & Kornerup, H. J.: Effect of alprenolo1 and hydralazine on plasma renin concentration in patients with essential hypertension. Acta med. scand. 198: 379, 1975. 13. Rask-Madsen, J.. Bruusgaard, A,. Munck, 0.. Nielsen, M. D. & Worming, H.: The significance of bile acids and aldosterone for the electrical hyperpolarization of human rectum in obese patients treated with intestinal bypass operation. Scand. J. Gastroent. 9: 417, 1974. 14. Slaton, P. E., Schamberlan, M. & Biglieri, E. G . : Stimulation and suppression of aldosterone secretion in patients with an aldosterone producing adenoma. J. clin. Endocr. 29: 239, 1969. 15. Stockigt, J. R.: The regulation of aldosterone secretion. In: Hypertension: Mechanisms and management (ed. G . Onesti, K. E. Kim and J. H. Moyer), p. 451. Grune & Stratton, New York 1973. 16. Tucci. J. R., Espiner, E. A,, Jagger, P. I., Pauk, G . L. & Lauler, D. P.: ACTH stimulation of aldosterone secretion in normal subjects and in patients with chronic adrenocortical insufficiency. J. clin. Endocr. 27: 568, 1967. 17. Williams, G . H. & Dluhy, R. G . : Aldosterone biosynthesis. Interrelationship of regulatory factors. Amer. J. Med. 53: 595, 1972.
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