Abstract

Blacks demonstrate a higher response rate to diuretic therapy for hypertension than do whites. This study examined the pharmacokinetic (PK), pharmacodynamic, and neurohumoral effects of hydrochlorothiazide (HCTZ) administration in a matched group of 9 black and 9 white hypertensive patients (mean ± SD for black and white). After a 4-week washout period and 7-day control diet, subjects received a single dose of HCTZ (25 mg at 8 AM) with serial blood and urine collections for 36 hours. After HCTZ sodium excretion increased comparably in both groups (blacks: 122 ± 42 pre to 265 ± 49 mEq/24 hours post; whites: 117 ± 29 pre to 255 ± 39 mEq/24 hrs post). Potassium excretion tended to be higher at baseline and was significantly higher following HCTZ in whites (blacks: 45 ± 20 pre to 66 ± 13 mEq at 24 hours post; blacks: 57 ± 9 pre to 86 ± 14 mEq at 24 hours post) with most of the post-dosing difference being observed in the hours 0 to 12 after HCTZ. There were no between group PK differences for urinary HCTZ. Aldosterone excretion followed a normal circadian pattern in the whites but did not show this pattern in the blacks. Aldosterone excretion (0 to 12 hours) was generally lower post-dosing in blacks. In conclusion, whereas the PK and single-dose natriuretic response for HCTZ were not racially distinct, potassium excretion was notably less in blacks. Aldosterone excretion was also lower in blacks and without its normal circadian pattern which may, in part, explain their altered potassium excretion pattern.

Hypertension and its effective treatment remain major health care considerations in the United States. The Third National Health and Nutrition Examination Survey (1988-1991) estimated 43 million Americans (24% of the United States adult population) to be hypertensive.1 The age-adjusted prevalence of hypertension is ethnically distinct with hypertension being more commonly identified in blacks (32%) than in non-Hispanic whites (23%) or Hispanics (22%).1

The increased prevalence of hypertension in blacks has gathered considerable attention as relates to both etiology and treatment considerations. Though the causative factors of hypertension in blacks are incompletely elucidated, differential patterns of genetics, stress, salt sensitivity, and hormonal regulation have been implicated.2–5 The vasodepressor response to various antihypertensive medications has also proven racially dependent.6,7 In this regard, black hypertensives have typically proven more responsive to diuretics than white hypertensives.7–10 Despite consistent findings of a racial difference in the magnitude of the vasodepressor response to diuretic therapy, this phenomenon has yet to be specifically examined in the context of drug-related pharmacokinetics and pharmacodynamics. Thus, this study was designed to compare the pharmacokinetic and pharmacodynamic effects of acute hydrochlorothiazide (HCTZ) dosing in black and closely matched white hypertensive patients.

Methods

Eighteen patients with either Stage 1 or Stage 2 hypertension were studied with patient characteristics as those presented in Table 1. The groups were age, sex, and weight matched with all patients having a clearly documented history of hypertension. Patients with diabetes mellitus, secondary hypertension, renal insufficiency, or other active medical conditions were excluded from study participation. The utilization of concomitant medications was precluded during the study. Racial lineage was determined by patient designation and required both parents to be of the same race. The study was reviewed and approved by the Committee on the Conduct of Human Research of Virginia Commonwealth University prior to written informed consent being obtained from all study participants.

Table 1.

Patient Demographics

 Black White 
Subject number 
Male/female 2/7 2/7 
Age (yrs) 46 ± 7.6 42 ± 5.4 
Weight (kg) 92 ± 19 88 ± 18 
Inulin clearance (mL/min) 84 ± 17 87 ± 12 
Supine PRA post diet (ng/ml · hr) .96 ± .73 1.5 ± .9 
Supine Aldosterone post diet (ng/dl) 8.9 ± 5 11.9 ± 5.3 
 Black White 
Subject number 
Male/female 2/7 2/7 
Age (yrs) 46 ± 7.6 42 ± 5.4 
Weight (kg) 92 ± 19 88 ± 18 
Inulin clearance (mL/min) 84 ± 17 87 ± 12 
Supine PRA post diet (ng/ml · hr) .96 ± .73 1.5 ± .9 
Supine Aldosterone post diet (ng/dl) 8.9 ± 5 11.9 ± 5.3 

Mean ± SD.

Following a history screening, physical examination, laboratory studies, and an electrocardiogram, patients were withdrawn from all antihypertensive medications for a minimum of 3 weeks. During this washout phase patients were monitored on a weekly basis with a 24 hour urine obtained for determination of sodium and potassium excretion as well as creatinine clearance (baseline, 24 hour urine). The patients were then admitted to the General Clinical Research Center where they received a controlled diet, containing 150 mEq of sodium and 80 mEq of potassium. This diet was continued throughout the remainder of the study. On the sixth day of the study diet, another 24 hour urine was obtained for purposes of redetermining electrolyte excretion (diet, 24 hour urine).

On Day 7, glomerular filtration rate (GFR) was measured by performing an inulin clearance. As part of this study procedure a bolus amount of inulin (25 mg/kg) was followed by a sustaining infusion sufficient to maintain a plasma inulin level of 15 mg/dL. Following an equilibration period of 60 minutes, 3 precisely timed, 30-minute urine collections were obtained. Plasma sampling for inulin occurred at the beginning and end of each 30-minute clearance period. The inulin clearance reported for each patient was the average of these 3 consecutive inulin clearances.

At 8 AM on Day 8 each patient received a 25 mg tablet of HCTZ. Plasma samples for determination of plasma renin activity (PRA) and plasma aldosterone were serially collected at 0, 6, 12, 24, and 36 hours. At each time point plasma samples were obtained in both the supine and upright position after the patient had been in the respective position for a minimum of one hour. Urine collections were obtained over specific time intervals from 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, and 24 to 36 hours post-dose. Sodium, potassium, and aldosterone were measured in each urine collection. Individual time period concentrations for electrolytes and aldosterone and urine volume were calculated as the amount excreted during the 0 to 12, 12 to 24, and 24 to 36 hour time periods. A composite value for 0 to 24 hours was calculated from the 0 to 12 and 12 to 24 hour time periods. Blood pressure (BP) was measured with a Critikon Dinamapp® (Model 1846-SX: Johnson and Johnson, Tampa, FL) in both the supine and upright position at screening, 0 and 24 hours. Blood pressure measurements were obtained in triplicate in each position and the average value reported.

PRA was measured by a radioimmunoassay (RIA) method that measures the in vitro generation of angiotensin I. This assay employs a generation time of 90 minutes and a system pH of 6.0 (GammaCoat, Clinical Assays, Cambridge, MA). Random samples in normal ambulatory subjects on an ad libitum sodium intake average 1.67 ± 0.83 ng/ml · hr with this assay.11 Plasma and urinary aldosterone levels were determined by a solid phase RIA (Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA). Recumbent plasma aldosterone values on an ad libitum sodium intake vary between 1 and 16 ng/dl for this assay.11 Urinary HCTZ was measured using a recently developed HPLC method with a sensitivity of 2 μcg/mL and a detection limit of 1 μcg/mL.12

Time to maximal excretion rate in hours (Tmax) was determined for all urine parameters by visual inspection of the data set. Maximum urinary excretion rate (μcg/min) was also determined by visual inspection of the data set generated from a factoring of the excretion amount of each urine parameter per individual time period (minutes/collection interval). Time period excretion amounts were summed to obtain overall excretion and thereby percent dose recovered for HCTZ. Data are reported as mean ± SD. Paired t-tests and student t-tests were used for comparing data within groups and between groups, respectively. Bonferroni adjustments were used for all serial comparisons. Significance is reported at P ≤.05 following correction.

Results

Supine and upright blood pressure values are shown in Table 2. At baseline after a 3-week medication washout period and while on an ad lib diet, supine and upright mean arterial pressures (MAP) were similar in the black and white patients. Following 7 days on a sodium-controlled diet, upright MAP significantly decreased from baseline values in both groups (blacks: 116 ± 7 [baseline] v 106 ± 11 [sodium-controlled diet]; whites: 111 ± 3 v 97 ± 6 mm Hg) with supine MAP trending down but not reaching statistical significance. Supine MAP significantly decreased 24 hours after HCTZ dosing in the black patients (103 ± 9 [0 hour] v 96 ± 9 [24 hours post] mm Hg) and remained stable in the white patients (96 ± 8 [0 hour] v 96 ± 7 [24 hours post]). Upright MAP was not significantly changed 24 hours post-dose in either treatment group.

Table 2.

Blood Pressure Values

 Black White 
Baseline supine systolic 150 ± 12 144 ± 8 
Baseline supine diastolic 88 ± 5 86 ± 9 
BASELINE SUPINE MEAN 108 ± 7 105 ± 7 
Baseline upright systolic 162 ± 19 150 ± 9 
Baseline upright diastolic 96 ± 9 91 ± 6 
BASELINE UPRIGHT MEAN 116 ± 7 111 ± 3 
Diet supine systolic 141 ± 10* 128 ± 15* 
Diet supine diastolic 84 ± 9 79 ± 7 
DIET SUPINE MEAN 103 ± 9 96 ± 8 
Diet upright systolic 139 ± 11* 128 ± 10* 
Diet upright diastolic 89 ± 12 82 ± 6 
DIET UPRIGHT MEAN 106 ± 11* 97 ± 6* 
24 hour supine systolic 131 ± 11* 130 ± 9 
24 hour supine diastolic 78 ± 11 78 ± 8 
24 HOUR SUPINE MEAN 96 ± 9** 96 ± 7 
24 hour upright systolic 133 ± 15 134 ± 8 
24 hour upright diastolic 87 ± 8 86 ± 7 
24 HOUR UPRIGHT MEAN 102 ± 9 102 ± 6 
 Black White 
Baseline supine systolic 150 ± 12 144 ± 8 
Baseline supine diastolic 88 ± 5 86 ± 9 
BASELINE SUPINE MEAN 108 ± 7 105 ± 7 
Baseline upright systolic 162 ± 19 150 ± 9 
Baseline upright diastolic 96 ± 9 91 ± 6 
BASELINE UPRIGHT MEAN 116 ± 7 111 ± 3 
Diet supine systolic 141 ± 10* 128 ± 15* 
Diet supine diastolic 84 ± 9 79 ± 7 
DIET SUPINE MEAN 103 ± 9 96 ± 8 
Diet upright systolic 139 ± 11* 128 ± 10* 
Diet upright diastolic 89 ± 12 82 ± 6 
DIET UPRIGHT MEAN 106 ± 11* 97 ± 6* 
24 hour supine systolic 131 ± 11* 130 ± 9 
24 hour supine diastolic 78 ± 11 78 ± 8 
24 HOUR SUPINE MEAN 96 ± 9** 96 ± 7 
24 hour upright systolic 133 ± 15 134 ± 8 
24 hour upright diastolic 87 ± 8 86 ± 7 
24 HOUR UPRIGHT MEAN 102 ± 9 102 ± 6 

Blood pressure (mm Hg), mean ± SD.

*

P ≤ .05 compared to baseline.

**

P ≤ .05 compared to 0 hour.

The pharmacokinetics of HCTZ as assessed by urinary excretion are reported in Table 3. Urinary excretion rate, Tmax, and the % dose recovered in 36 hours was similar between the two groups. The time period during which urinary HCTZ was last detectable varied within each group: blacks: 8 hours (n = 1), 12 hours (n = 4), 24 hours (n = 3), 30 hours (n = 1); whites: 8 hours (n = 2), 12 hours (n = 2), 24 hours (n = 2), 30 hours (n = 3). This likely represented intragroup differences in HCTZ absorption.

Table 3.

Pharmacokinetics of Hydrochlorothiazide in Black and White Hypertensives

 Black White 
Tmax (hrs) 4 ± 2 3 ± 1 
Max exc rate (ucg/min) 46.3 ± 12 46.8 ± 18 
Dose recovered (%) 49.0 ± 16 55.0 ± 9 
 Black White 
Tmax (hrs) 4 ± 2 3 ± 1 
Max exc rate (ucg/min) 46.3 ± 12 46.8 ± 18 
Dose recovered (%) 49.0 ± 16 55.0 ± 9 

Mean ± SD. Max exc = maximum excretion rate.

Twenty-four-hour urinary excretion of sodium and potassium at baseline, following diet and post- HCTZ are shown in Figure 1. Sodium excretion (mEq/24 hours) tended to be lower in the blacks at baseline (blacks: 117 ± 51 mEq/24 hours, whites: 140 ± 50 mEq/24 hours). On the controlled diet sodium excretion was similar in the two groups (blacks: 122 ± 42 mEq/24 hours, whites: 117 ± 29 mEq/24 hours). Following HCTZ, 24-hour urine sodium excretion predictably increased in both groups with no between group differences (blacks: 265 ± 49 mEq/24 hours, whites: 255 ± 39 mEq/24 hours). Urinary potassium excretion at baseline (blacks: 43 ± 9 mEq/24 hours, whites: 53 ± 11 mEq/24 hours) and following diet (blacks: 45 ± 20 mEq/24 hours, whites: 57 ± 9 mEq/24 hours) was similar although lower in the blacks. The 24-hour potassium excretion following HCTZ significantly increased in both groups (P ≤ .05), (blacks: 66 ± 13 mEq/24 hours, whites: 86 ± 14 mEq/24 hours). Potassium excretion following HCTZ was significantly greater in the white than in the black cohort.

24 hour sodium and potassium excretion at baseline, after one week of diet, and following HCTZ dosing. Mean ± SD. *P ≤ .05 compared to baseline. # P ≤ .05 black versus white for the same time period.

Time-wise urinary sodium, potassium and aldosterone excretion are shown in Figure 2. The increased urinary sodium excretion following HCTZ occurred during the first 12 hours after dosing in both groups. Urinary potassium excretion also was highest in the first 12 hours following dosing. The 0 to 12 hour time period, post-dosing, also was the time period wherein the difference in kaliuresis between the two groups was primarily expressed. The greater kaliuretic response over the 0 to 12 hour time interval was associated with a significantly higher urinary aldosterone excretion in the white population. During the 12 to 24 hour period post-dosing (8 PM to 8 AM), urinary aldosterone excretion decreased significantly in the white group while remaining unchanged in the black cohort. During the 24 to 36 hour period (8 AM to 8 PM) post-dosing urinary aldosterone excretion again increased in the white patients and remained stable in the blacks.

Urinary excretion of sodium, potassium, and aldosterone following HCTZ dosing. *P ≤ .05 black versus white for the same time period. Mean ± SD. #P ≤ .05 12–24 hour compared to 0–12 hour in the white group.

Sodium (mEq)/HCTZ (μcg) excretion and potassium (mEq)/HCTZ (μcg) excretion, as surrogate measures of diuretic efficiency, were not statistically different between the two groups at any time period. Although the sodium/potassium excretion ratios following HCTZ significantly increased in both groups, the ratios for blacks were significantly higher in the 0 to 6 and 6 to 12 hour time periods compared to the whites. Supine and upright aldosterone and PRA values are shown in Figure 3. Supine PRA activity significantly increased in the black patients at 36 hours compared to pre-dose values and upright PRA increased during the same time period in the whites. Supine plasma aldosterone was significantly increased in the black patients only at 24 hours.

Plasma aldosterone and plasma renin activity at 0, 6, 12, 24, and 36 hours post HCTZ dosing. Mean ± SD. *P ≤ .05 compared to baseline.

Discussion

This study was designed as a single-dose study of the pharmacokinetic and pharmacodynamic effects of HCTZ in black and white hypertensive patients. Prior studies have suggested that hypertensive black subjects are more likely to achieve goal blood pressure when treated with diuretic therapy than is the case for white hypertensives.8–10 This observation may relate to the differing pathophysiologic mechanisms operative in black hypertensives wherein either absolute or relative plasma volume expansion commonly exists4,5,13; thus, the tendency for hypertension in blacks to be diuretic responsive. Despite the consistency with which studies have demonstrated diuretic responsiveness in this population there have been no studies which have specifically explored the relationship between the pharmacokinetics of HCTZ and its acute pharmacodynamic and neurohumoral effects.

A number of confounding variables typically exist in studies such as these including differences in gender distribution, age, body size, and level of renal function. In these studies the two groups were carefully matched for age (mean ± 5 years), sex, weight (mean ± 5 kg), and glomerular filtration rate as determined by inulin clearance (mean ± 5 ml/min). These goals were matched and exceeded in the final study population. In addition, the same racial lineage was required for both of the parents for each study group participant.

Only patients with Stage I or Stage II hypertension were included in these studies since a 3-week washout period was employed and there was concern about excessive blood pressure rise possibly occurring if more advanced stages of hypertension were submitted to study. In this regard, most of the study subjects had Stage I hypertension, as can be seen by the modest elevation in MAP at baseline. Accordingly, the decrease in MAP in response to the prescribed diet was sufficient to return BP values towards normal. The initial effect on BP during the diet phase was likely multifactorial since the prescribed diet did not alter urinary sodium excretion or body weight; thus, the early return of blood pressure towards normal could have represented adaptation to the study center and/or regression to the mean. Accordingly, the sought after pharmacodynamic differences to HCTZ based on racial considerations could only be determined from a near normal baseline BP. Blood pressure at baseline and following diet tended to be higher in the blacks. This trend resolved 24 hours after acute dosing with HCTZ. Because this was an acute dosing study, the blood pressure lowering effects of chronic HCTZ dosing were not evaluated.

A primary purpose of these studies was to define the pharmacokinetics and pharmacodynamics of HCTZ in black and white hypertensive patients. HCTZ is well-absorbed after oral administration (averaging 65% to 72 %) with peak plasma concentrations within 1.5 to 5.0 hours of its ingestion.14 HCTZ is largely renally eliminated without biotransformation thus its absorption can be estimated by cumulative urinary excretion.15 Williams et al demonstrated that the urinary pharmacokinetics of HCTZ predicted the time course of its pharmacodynamics as determined by increases in urine volume as well as sodium, and potassium excretion.16 In this study, the urinary kinetics of HCTZ were similar in both patient groups with the % dose excreted and the time course of excretion falling in the range seen in previous studies.13 In this study urinary excretion peaked within 3 to 4 hours and was generally undetectable after 24 hours, though the time to undetectable urinary levels showed marked intragroup variability. This study would suggest that single dose pharmacokinetic differences do not explain the previously reported racial differences in the blood pressure lowering response to HCTZ.8–10

At baseline sodium and potassium excretion tended to be lower in blacks. The low urinary excretion of potassium has been previously seen in larger cohorts of blacks.17,18 Following a controlled diet sodium excretion and potassium excretion remained relatively stable in the two groups. The diet was supplied on an outpatient basis to the patients, and they were instructed to ingest all of the food provided. All patients completed 7 days of the diet prior to HCTZ dosing. Patients were not required to meet arbitrary urinary sodium or potassium excretion rates prior to HCTZ dosing. The goal was to provide similar dietary intake prior to the HCTZ dosing rather than to establish a specific sodium or potassium balance state. In this regard, verifying potassium balance by urinary excretion has previously proven difficult. For example, following 10 weeks of oral potassium administration, Langford et al could show an increase in potassium excretion but only with considerable variability within treatment groups.19 Similarly, Morris et al were unable to show urinary potassium excretion to match intake in a potassium supplementation limb of a normotensive salt sensitivity study.20

As expected, sodium excretion increased following HCTZ dosing and the extent of natriuresis coincided with the rate of HCTZ excretion during the first 12 hours. Likewise, potassium excretion increased in both groups, again predominantly in the first 12 hours after HCTZ dosing. Although total potassium excretion following HCTZ increased in the black cohort, it occurred to a significantly less degree than was observed in the white group, with the majority of this difference occurring in the first 12 hours. As previously mentioned, there were no between group pharmacokinetic differences for HCTZ excretion which could serve as possible explanations for this pharmacodynamic difference. Furthermore, the mEq of either Na+ or K+/μcg of HCTZ excreted did not differ between the two groups. A number of explanations exist for the attenuated kaliuresis following HCTZ in the black patients including a pharmacodynamic difference in HCTZ action and thereby blunted potassium excretion or as a result of lower aldosterone excretion and/or activity during this time period. Of note, during the 24 to 36-hour period, when aldosterone excretion tended to be higher in whites, there was not a similar increase in potassium excretion. An additive interaction between HCTZ concentration and aldosterone excretion may offer the best explanation for the differences in kaliuresis.

The sampling time points for both PRA and aldosterone may have missed subtle differences in the hormonal response to HCTZ between the two groups. The timing of samples may also explain the increase in aldosterone in black patients, appearing to occur prior to an increase in PRA. The aldosterone excretion in the white patients follows the previously described circadian pattern with daytime excretion being higher and nocturnal elimination lower.21,22 Of note, this circadian pattern was not observed in the black patients, whose aldosterone excretion remained unchanged over the day-night-day periods. A racial variation in the circadian pattern of aldosterone excretion has not been previously described. The suggestion of a time-wise racial difference in aldosterone excretion shown in this study might reflect either a racially distinct response pattern to HCTZ or may represent differing baselines. Also, it has been previously shown that bed rest can dampen the aldosterone circadian pattern.18There were no obvious differences in patient activity between the two groups. Although this study was not designed as a circadian study, these observations suggest a need to further evaluate race-related circadian differences in aldosterone regulation.

In conclusion, the pharmacokinetics of HCTZ did not differ based on race; therefore, differing antihypertensive efficacy for HCTZ probably resides in a racially distinct pharmacodynamic pattern of response. The pharmacodynamic differences noted in these studies warrant additional mechanistic investigation, particularly as relate to chronic dosing with HCTZ.

References

1.
Burt
VL
,
Whelton
P
,
Roccella
EJ
et al
:
Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991
.
Hypertension
 
1995
;
25
:
305
313
.
2.
Jackson
FL
:
An evolutionary perspective on salt, hypertension, and human genetic variability
.
Hypertension
 
1991
;
17
(
suppl I
):
129
132
.
3.
Messerli
FH
,
DeCarvalho
JG
,
Christie
B
et al
:
Essential hypertension in black and white subjects. Hemodynamic findings and fluid volume state
.
Am J Med
 
1979
;
67
:
27
31
.
4.
Mitas
JA
,
Holle
R
,
Levy
SB
et al
:
Racial analysis of the volume-renin relationship in human hypertension
.
Arch Intern Med
 
1979
;
139
:
157
160
.
5.
Chrysant
SG
,
Danisa
K
,
Kem
DC
et al
:
Racial differences in pressure, volume and renin interrelationships in essential hypertension
.
Hypertension
 
1979
;
1
:
136
141
.
6.
Zhou
HH
,
Koshakji
RP
:
Racial differences in drug response
.
N Engl J Med
 
1989
;
320
:
565
570
.
7.
Weinberger
MH
:
Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mid-to-moderate hypertensive patients
.
J Cardiovasc Pharmacol
 
1985
;
7
(
suppl 1
):
S52
S55
.
8.
Veterans Administration Cooperative Study Group on Antihypertensive Agents
Comparison of Propranolol and Hydrochlorothiazide for the Initial Treatment of Hypertension
.
JAMA
 
1982
;
248
:
2004
2011
.
9.
Veteran Administration Cooperative Study Group on Antihypertensive Agents
Efficacy of nadolol alone and combined with bendroflumethiazide and hydralazine for systemic hypertension
.
Am J Cardiol
 
1983
;
52
:
1230
1237
.
10.
Moser
M
,
Lunn
J
:
Responses to captopril and hydrochlorothiazide in black patients with hypertension
.
Clin Pharmacol Ther
 
1982
;
32
:
307
312
.
11.
Gehr
TW
,
Sica
DA
,
Brater
C
et al
Furosemide pharmacokinetics and pharmacodynamics in renal transplantation
.
Clin Pharmacol Ther
 
1988
;
43
:
547
553
.
12.
Farthing
D
,
Fakhry
I
,
Ripley
EB
et al
:
Simple method for determination of hydrochlorothiazide in human urine by high performance liquid chromoatography utilizing narrowbore chromatography
.
J Pharm Biomed Anal
 
1998
;
17
:
1455
1459
.
13.
Lilley
JJ
,
Hsu
L
,
Stone
RA
:
Racial disparity of plasma volume in hypertensive man
.
Ann Intern Med
 
1976
;
84
:
707
708
.
14.
Beermann
B
,
Groschinsky-Grind
M
:
Pharmacokinetics of hydrochlorothiazide in man
.
Eur J Clin Pharmacol
 
1977
;
12
:
297
303
.
15.
Beerman
B
,
Groschinsky-Grind
,
Rosen
A
:
Absorption, metabolism, and excretion of hydrochlorothiazide
.
Clin Pharmacol Ther
 
1976
;
19
:
531
537
.
16.
Williams
RL
,
Davies
RO
,
Berman
RS
et al
:
Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin
.
J Clin Pharmacol
 
1982
;
22
:
32
41
.
17.
Pratt
JH
,
Manatunga
AK
,
Bloem
LJ
et al
:
Racial differences in aldosterone excretion: a longitudinal study in children
.
J Clin Endocrinol Metab
 
1993
;
77
:
1512
1515
.
18.
Veterans Administration Cooperative Study Group on Antihypertensive Agents
Urinary and serum electrolytes in untreated black and white hypertensives
.
J Chronic Dis
 
1987
;
40
:
839
847
.
19.
Langford
HG
,
Cushman
WC
,
Hsu
H
:
Chronic effect of KCl on black-white differences in plasma renin activity, aldosterone, and urinary electrolytes
.
Am J Hypertens
 
1991
;
4
:
399
403
.
20.
Morris
RC
Jr
,
Sebastian
A
,
Forman
A
et al
:
Normotensive salt sensitivity: effects of race and dietary potassium
.
Hypertension
 
1999
;
Jan
;
33
:
18
23
.
21.
Chiang
FT
,
Tseng
CD
,
Hsu
KL
et al
:
Circadian variations of atrial natriuretic peptide in normal people and its relationship to arterial blood pressure, plasma renin activity and aldosterone level
.
Int J Cardiol
 
1994
;
46
:
229
233
.
22.
Leppaluoto
J
,
Ruskoaho
H
:
Atrial natriuretic peptide, renin activity, aldosterone, urine volume and electrolytes during a 24-h sleep-wake cycle in man
.
Acta Physiol Scand
 
1990
;
139
:
47
53
.