Acta Med Scand 204: 151-157, 1978
Influence of Sodium Intake on Hydrochlorothiazide-Induced Changes in Blood Pressure, Serum Electrolytes, Renin and Aldosterone in Essential Hypertension P. van Brummelen, M. Schalekamp and J. de Graeff From the Deparlment of Nephrology, University Hospital, Leiden, and the Department of Internal Medicine, Erasmus University, Rotterdam, The Netherlands
ABSTRACT. To determine the influence of dietary sodium intake on the effects of hydrochlorothiazide (HCT) on blood pressure (BP), serum electrolytes, renin and aldosterone, nine male patients with uncomplicated essential hypertension were studied during the following therapeutic regimes: 1) sodium restriction alone (50 mmol/day), 2) sodium restriction combined with HCT (50 mg twice daily), 3) HCT alone, and 4) sodium restriction combined with HCT. Low sodium diet alone and HCT alone lowered BP to the same extent. The combination of HCT and sodium restriction had no extra effect on supine BP, but elicited complaints of dizziness and weakness in each patient, and overt orthostatic hypotension in three cases. Sodium restriclon during HCT treatment caused hyponatraemia and aggravated hypokalaemia. Hyponatraemia could not be accounted for solely by changes in cumulative sodium balance. Plasma renin concentration rose markedly during the combined treatment. Plasma aldosterone was normal during HCT alone, but elevated when HCT was combined with sodium restriction. These results cast some doubt on the therapeutic value of prescribing a low sodlum diet to patients with essential hypertension treated with thiazide diuretics. Overactivity of the renin-angiotensin-aldosterone system during this regime might explain both the lack of a beneficial effect on BF and the adverse influence on serum potassium. Thiazide diuretics are widely used in the treatment of hypertension. Although most investigators agree that the antihypertensive effect of these drugs is somehow related to the urinary loss of sodium (7, 19,35,37), the efficacy of dietary sodium restriction during thiazide treatment has not been extensively studied and is subject to controversy (8, 21, 22.27). Moreover, pertinent data on the metabolic consequences of combined thiazide therapy and salt restriction are lacking. Therefore we studied the in-
fluence of sodium intake on BP, serum electrolytes and the plasma concentrations of renin and aldosterone in patients with uncomplicated essential hypertension treated with hydrochlorothiazide.
PATIENTS Nine patients (male, age 20-50 years) were studied, both under standardized conditions in a metabolic ward and as outpatients. A diagnosis of essential hypertension was made after a search for secondary causes, using investigations that included excretory urography ,radioisotope renography and urinary excretion of vanillylmandelic acid. Serum creatinine was normal in all patients (less than 120 pmol/l). Three cases showed ECG signs of left ventricular hyperthophy (SV1+RV,>3.5 mV). Eye ground changes were of grade I or 11.
STUDY PROTOCOL In the first study period, patients were seen weekly in the Outpatient Clinic for a period of four weeks. At each visit BP (supine and standing, pulse rate and body weight were measured and blood was drawn for determination of serum electrolytes. Patients had no medication and dietary sodium intake was not restricted. Urinary sodium excretion varied between 150 and 200 mmol/day. r9fter this period, patients were admitted to the metabolic ward and were put on a fixed diet containing 50 mmol of sodium and 90 mmol of potassium per day. Sodium excretion was measured daily. BP and pulse rate were measured daily at 11 a.m. and 4 p.m. Hydrochlorothiazide (HCT), 50 mg twice daily, was given after nine days for a period of eight days. On the day before HCT was started and after seven days of treatment, blood samples for determination of plasma renin concentration (PRC) and plasma aldsterone (PA) were taken at 9 a.m. after at least ten hours of recumbency. Blood for determination of serum electrolytes was taken at regular intervals. Abbreviations: HCT= hydrochlorothiazide, BP= blood pressure, PRC=plasma renin concentration, PA=plasma aldosterone. Acto Med Scand 204
152
P . van Brummelen et al.
Table I. Blood pressure (mmHg), pulse rate ( P R , beatslmin) and body weight (kg) before treatment, durini sodium restriction and during hydrochlorothiazide with and without sodium restriction sup= supine, st =standing
1 sup
3 4 5 6
During HCT (50 mg twice daily)
Sodium intake (mmol)
Sodium intake (mmol)
150-200
Case no.
2
Without HCT
St sup st sup st sup st sup st sup st
7 sup st 8" sup st 9 sup st Mean sup st
50
50
150-200
BP
PR
B.wt.
BP
PR
B.wt.
BP
PR
B.wt.
BP
PR
B.wt.
I681101 166111 1 1721112 1791113 1681116 1691117 1471102 15011I6 I40199 1391109 142195 1501105 137192 1541110 1741117 IWll38 1641122 1661130 1561106 16311I7
80 92 57 55 63 84 68 86 75 85 67 77 69 76 77 83 77 78 70 80
61 .O
1591104 161/109 132197 134189 1341% 117191 1461104 1531119 121191 1301109 133179 141199 127187 141I103 1701111 180/131 137195 1351103 1401% 1441106
81 95 61 74 69 1 I9 65 79 76 96 60 67 73 89 75 90 62 73 69 87
61.0
1591105 I20188 142191 150/98 124198 92/84 1421106 143111 I 103183 97/85 137192 122197 128190 140/105 163/109 I6 11134 137199 1 18/95 137197 127/100
89 116 75 102 85 138 72
59.7
1531103 1361101 149199 149199 136189 126192 138199 1441111 124191 1271106 137192 1421106 1361% 1481111 1631107 1701127 1421102 1431112 142198 1431107
84 100 66 75 75; Ill 72 87 81 105 67 78 69 81 73 85 75 88 74 90
60.1
75.0 77.9 74.8 82.7 80.3 84.7 106.7 85.6 77.7
74.0 74.9 74.5 82.1 80.8 83.0 104.1 83.8 76.8
72.5 72.3 70.8
%
84 127 70 92 70 98 80 102 75 105 77
79.3 78.4 81.9 101.2 80.5 74.4
108
73.7 78.6 75.6 83.2 82.4 83.2 88.1 83.9 77.6
" Body weight not used for calculating mean value because of deliberate weight loss.
During a subsequent period of four months, patients were seen biweekly in the Outpatient Clinic while HCT treatment was continued. Dietary sodium intake at that time was not restricted. Again, daily sodium excretion varied between 150 and 200 mmol. Halfway through this period, blood samples for determination of PRC and PA were taken at noon after three hours of recumbency. Finally the patients were readmitted to the metabolic ward for a period of nine days. Again a fixed diet containing 50 mmol of sodium and 90 mmol of potassium per day was given while HCT was continued. Measurements of BP, pulse rate, serum electrolytes, sodium excretion, PRC and PA were repeated.
METHODS BP was measured with a mercury sphygmomanometer after 10 min supine rest and 1 min standing. Pulse rate was recorded at the same time. Phase IV Korotkoff sounds were taken as diastolic BP. BP and pulse rate figures used for subsequent analysis were I) the mean of the values during the last two visits to the Outpatient Clinic, and 2 ) the mean of the values during the last two days of each study period in the metabolic ward. PRC was determined by radioimmunoassay (29, 32) after processing the plasma according to Skinner (30). PA Acru Med Sccrnd 204
was determined in the laboratory of M. Frolich by radioimmusoassay as described by Bayard et al. (2) and Friilich et al. (1 1) Student's I-test for paired observations was used to determine statistical signiftcance of differences. Values of pC0.05 were regarded as significant.
RESULTS BP, pulse rate and body weight
Individual data are summarized in Table I. Mean values +S.E.M. in each study period are shown in Fig. 1 and levels of significance for differences in Table 11. Admission to the metabolic ward with the institution of a low sodium diet lowered BP significantly. A similar fall in BP was observed after four months of treatment with HTC alone. Dietary sodium restriction during diuretic treatment caused a distinct fall in body weight but had little additional effect on supine BP. Standing BP was slightly but significantly reduced. This reduction in BP was most pro-
Sodium intake and hydrochlorothiazide treatment
153
was significantly higher than during HCT alone (p
Influence of Sodium Intake on Hydrochlorothiazide-Induced Changes in Blood Pressure, Serum Electrolytes, Renin and Aldosterone in Essential Hypertension P. van Brummelen, M. Schalekamp and J. de Graeff From the Deparlment of Nephrology, University Hospital, Leiden, and the Department of Internal Medicine, Erasmus University, Rotterdam, The Netherlands
ABSTRACT. To determine the influence of dietary sodium intake on the effects of hydrochlorothiazide (HCT) on blood pressure (BP), serum electrolytes, renin and aldosterone, nine male patients with uncomplicated essential hypertension were studied during the following therapeutic regimes: 1) sodium restriction alone (50 mmol/day), 2) sodium restriction combined with HCT (50 mg twice daily), 3) HCT alone, and 4) sodium restriction combined with HCT. Low sodium diet alone and HCT alone lowered BP to the same extent. The combination of HCT and sodium restriction had no extra effect on supine BP, but elicited complaints of dizziness and weakness in each patient, and overt orthostatic hypotension in three cases. Sodium restriclon during HCT treatment caused hyponatraemia and aggravated hypokalaemia. Hyponatraemia could not be accounted for solely by changes in cumulative sodium balance. Plasma renin concentration rose markedly during the combined treatment. Plasma aldosterone was normal during HCT alone, but elevated when HCT was combined with sodium restriction. These results cast some doubt on the therapeutic value of prescribing a low sodlum diet to patients with essential hypertension treated with thiazide diuretics. Overactivity of the renin-angiotensin-aldosterone system during this regime might explain both the lack of a beneficial effect on BF and the adverse influence on serum potassium. Thiazide diuretics are widely used in the treatment of hypertension. Although most investigators agree that the antihypertensive effect of these drugs is somehow related to the urinary loss of sodium (7, 19,35,37), the efficacy of dietary sodium restriction during thiazide treatment has not been extensively studied and is subject to controversy (8, 21, 22.27). Moreover, pertinent data on the metabolic consequences of combined thiazide therapy and salt restriction are lacking. Therefore we studied the in-
fluence of sodium intake on BP, serum electrolytes and the plasma concentrations of renin and aldosterone in patients with uncomplicated essential hypertension treated with hydrochlorothiazide.
PATIENTS Nine patients (male, age 20-50 years) were studied, both under standardized conditions in a metabolic ward and as outpatients. A diagnosis of essential hypertension was made after a search for secondary causes, using investigations that included excretory urography ,radioisotope renography and urinary excretion of vanillylmandelic acid. Serum creatinine was normal in all patients (less than 120 pmol/l). Three cases showed ECG signs of left ventricular hyperthophy (SV1+RV,>3.5 mV). Eye ground changes were of grade I or 11.
STUDY PROTOCOL In the first study period, patients were seen weekly in the Outpatient Clinic for a period of four weeks. At each visit BP (supine and standing, pulse rate and body weight were measured and blood was drawn for determination of serum electrolytes. Patients had no medication and dietary sodium intake was not restricted. Urinary sodium excretion varied between 150 and 200 mmol/day. r9fter this period, patients were admitted to the metabolic ward and were put on a fixed diet containing 50 mmol of sodium and 90 mmol of potassium per day. Sodium excretion was measured daily. BP and pulse rate were measured daily at 11 a.m. and 4 p.m. Hydrochlorothiazide (HCT), 50 mg twice daily, was given after nine days for a period of eight days. On the day before HCT was started and after seven days of treatment, blood samples for determination of plasma renin concentration (PRC) and plasma aldsterone (PA) were taken at 9 a.m. after at least ten hours of recumbency. Blood for determination of serum electrolytes was taken at regular intervals. Abbreviations: HCT= hydrochlorothiazide, BP= blood pressure, PRC=plasma renin concentration, PA=plasma aldosterone. Acto Med Scand 204
152
P . van Brummelen et al.
Table I. Blood pressure (mmHg), pulse rate ( P R , beatslmin) and body weight (kg) before treatment, durini sodium restriction and during hydrochlorothiazide with and without sodium restriction sup= supine, st =standing
1 sup
3 4 5 6
During HCT (50 mg twice daily)
Sodium intake (mmol)
Sodium intake (mmol)
150-200
Case no.
2
Without HCT
St sup st sup st sup st sup st sup st
7 sup st 8" sup st 9 sup st Mean sup st
50
50
150-200
BP
PR
B.wt.
BP
PR
B.wt.
BP
PR
B.wt.
BP
PR
B.wt.
I681101 166111 1 1721112 1791113 1681116 1691117 1471102 15011I6 I40199 1391109 142195 1501105 137192 1541110 1741117 IWll38 1641122 1661130 1561106 16311I7
80 92 57 55 63 84 68 86 75 85 67 77 69 76 77 83 77 78 70 80
61 .O
1591104 161/109 132197 134189 1341% 117191 1461104 1531119 121191 1301109 133179 141199 127187 141I103 1701111 180/131 137195 1351103 1401% 1441106
81 95 61 74 69 1 I9 65 79 76 96 60 67 73 89 75 90 62 73 69 87
61.0
1591105 I20188 142191 150/98 124198 92/84 1421106 143111 I 103183 97/85 137192 122197 128190 140/105 163/109 I6 11134 137199 1 18/95 137197 127/100
89 116 75 102 85 138 72
59.7
1531103 1361101 149199 149199 136189 126192 138199 1441111 124191 1271106 137192 1421106 1361% 1481111 1631107 1701127 1421102 1431112 142198 1431107
84 100 66 75 75; Ill 72 87 81 105 67 78 69 81 73 85 75 88 74 90
60.1
75.0 77.9 74.8 82.7 80.3 84.7 106.7 85.6 77.7
74.0 74.9 74.5 82.1 80.8 83.0 104.1 83.8 76.8
72.5 72.3 70.8
%
84 127 70 92 70 98 80 102 75 105 77
79.3 78.4 81.9 101.2 80.5 74.4
108
73.7 78.6 75.6 83.2 82.4 83.2 88.1 83.9 77.6
" Body weight not used for calculating mean value because of deliberate weight loss.
During a subsequent period of four months, patients were seen biweekly in the Outpatient Clinic while HCT treatment was continued. Dietary sodium intake at that time was not restricted. Again, daily sodium excretion varied between 150 and 200 mmol. Halfway through this period, blood samples for determination of PRC and PA were taken at noon after three hours of recumbency. Finally the patients were readmitted to the metabolic ward for a period of nine days. Again a fixed diet containing 50 mmol of sodium and 90 mmol of potassium per day was given while HCT was continued. Measurements of BP, pulse rate, serum electrolytes, sodium excretion, PRC and PA were repeated.
METHODS BP was measured with a mercury sphygmomanometer after 10 min supine rest and 1 min standing. Pulse rate was recorded at the same time. Phase IV Korotkoff sounds were taken as diastolic BP. BP and pulse rate figures used for subsequent analysis were I) the mean of the values during the last two visits to the Outpatient Clinic, and 2 ) the mean of the values during the last two days of each study period in the metabolic ward. PRC was determined by radioimmunoassay (29, 32) after processing the plasma according to Skinner (30). PA Acru Med Sccrnd 204
was determined in the laboratory of M. Frolich by radioimmusoassay as described by Bayard et al. (2) and Friilich et al. (1 1) Student's I-test for paired observations was used to determine statistical signiftcance of differences. Values of pC0.05 were regarded as significant.
RESULTS BP, pulse rate and body weight
Individual data are summarized in Table I. Mean values +S.E.M. in each study period are shown in Fig. 1 and levels of significance for differences in Table 11. Admission to the metabolic ward with the institution of a low sodium diet lowered BP significantly. A similar fall in BP was observed after four months of treatment with HTC alone. Dietary sodium restriction during diuretic treatment caused a distinct fall in body weight but had little additional effect on supine BP. Standing BP was slightly but significantly reduced. This reduction in BP was most pro-
Sodium intake and hydrochlorothiazide treatment
153
was significantly higher than during HCT alone (p
