AJH
1991;
4:399-403
Chronic Effect of KCl on Black-White Differences in Plasma Renin Activity, Aldosterone, and Urinary Electrolytes
In a 1 0 - w e e k t r i a l of t h e effect of 80 m E q K C l / d a y on b l o o d p r e s s u r e , t h e f o l l o w i n g b i o c h e m i c a l c h a n g e s w e r e n o t e d : p l a s m a r e n i n activity (PRA), o r i g i n a l l y significantly l o w e r i n b l a c k s t h a n w h i t e s , increased to t h e s a m e l e v e l as w h i t e s after Κ s u p plementation. A similar trend was noted with al d o s t e r o n e . KCl i n c r e a s e d c r e a t i n i n e excretion i n blacks a n d w h i t e s , a n d l o w e r e d Ca excretion i n
B
lacks in the United States h a v e lower plasma renin activity (PRA) t h a n w h i t e s . They also u s u ally ingest a n d excrete less potassium (K), a n d their blood pressures tend to be higher. The data reported here are from a study of the effect of KCl supplementation on blood pressure in hypertensive in dividuals attending the outpatient clinics of the Jackson, Miss., Veterans Affairs Medical Center. The blood pres sure data, w h i c h s h o w e d n o significant effect of KCl at 10 weeks, although a significant d r o p w a s present at 4 weeks in blacks, is to be reported elsewhere. In this report w e note that KCl supplementation raises PRA in blacks b u t n o t in whites, abolishing the blackwhite difference in PRA.
blacks. These results suggest that the low PRA f o u n d i n b l a c k s is d u e , at least i n p a r t , to l o w Κ i n t a k e , a n d n o t to g e n e t i c causes. A m J H y p e r t e n s 1991;4:399-403 KEY WORDS: P l a s m a r e n i n activity, p o t a s s i u m , chlo ride, blacks, whites.
METHODS
1
2
3
* Deceased. From the Departments of Medicine (HGL, WCC) and Preventive Medicine (Statistics) (HH), University of Mississippi Medical Center and Veteran's Administration Hospital (WCC), Jackson, Mississippi. This study w a s supported in part by grants from Robins Pharma ceuticals, w h o supplied the potassium supplements and matching placebos, and General Clinical Research Center (No. 2 M O I RR02303). Address correspondence and reprint requests to William C. Cush man, MD, VA Medical Center (111E5), 1030 Jefferson Avenue, M e m phis, TN 3 8 1 0 4 - 2 1 9 3 .
After giving informed consent, black a n d white m e n 18 to 69 (mean 53.9) years of age, with sitting diastolic blood pressures (BP) of 90 to 105 m m H g 2 to 8 weeks after w i t h d r a w a l of antihypertensive medications, were enrolled in the study if there w e r e n o exclusion criteria present, such as elevated creatinine, e n d organ disease, or important gastrointestinal disease. The m e a n blood pressure of the g r o u p w a s 1 5 0 / 9 5 m m Hg. There was n o significant difference b e t w e e n randomization groups or races. Patient treatment w a s initiated with single-blind placebo a n d followed every 2 weeks for 4 to 8 weeks. Before randomization, complete physical ex amination, electrocardiogram, serum electrolytes, 24 h urine for Na, K, Ca, Mg, a n d creatinine a n d plasma renin activity a n d serum aldosterone were measured. Blood for measuring plasma renin activity a n d aldosterone w a s d r a w n after 30 min sitting. The patients were t h e n r a n d o m i z e d to receive 80 m E q / d a y of KCl as Micro-K (A.H. Robins, Richmond, VA) or matching placebo, if the diastolic blood pressure was 90 to 105 m m H g a n d there were 80 to 110 percent compliance by pill count for t w o successive visits on placebo. N o special dietary instructions were given. Patients were seen every t w o weeks for ten weeks. At the e n d of the ten-week period,
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Herbert G. Langford* William G Cushman, and Henry Hsu
400
L A N G F O R D ET AL
RESULTS At baseline, the aldosterone of the blacks w a s signifi cantly lower t h a n that of the whites (blacks 7.61 ± 6.21 n g / d L , η = 3 1 , whites 11.16 ± 6 . 9 n g / d L ; Ρ = .046, η = 28). This difference h a d disappeared in the treated groups at 10 weeks (blacks 15.16 ± 13.19 n g / d L , η = 19, whites 16.18 ± 9.07 n g / d L , η = 14, Ρ = .810), (Fig ure 1). Blacks h a d lower PRA (0.96 ± 1.64 n g / m L / h , η = 31) t h a n whites (1.89 ± 1.78, η = 28) at baseline (P = .043). At 10 weeks, PRA in the treated blacks w a s significantly increased to 2.31 ± 2 . 9 1 n g / m L / h ; P = .045, η = 19, a n d w a s u n c h a n g e d in the treated whites, at 2.29 ± 1 . 4 1 n g / m L / h , η = 14, Ρ = .912. Plasma renin activity in the treated blacks w a s essentially iden tical to that of the treated whites (P = .980, Figure 2). Potassium excretion w a s lower ( Ρ = .059) in blacks at baseline (46 ± 27 m E q / d a y ) t h a n in whites (59 ± 24
FIGURE 1. Baseline and 10-week plasma aldosterone (ng/dL). Values were lower in blacks than in whites at baseline. The difference had dis appeared in the KCl treated group at 10 weeks.
1991-VOL
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m E q / d a y ) . (Table 1). Chloride excretion was not signifi cantly different at baseline b e t w e e n races or treatment groups, a n d it increased as anticipated in the treated individuals (Table 2). There w a s n o significant difference in sodium excre tion b e t w e e n races (Table 3). There w a s a n insignificant increase in sodium excretion in the treated groups and an insignificant decrease in the placebo groups. There w a s n o significant difference in baseline Mg excretion nor w a s there any significant difference be t w e e n races or treatment groups in response to therapy. However, there w a s a w e a k a n d insignificant increase (P = .108) in Mg excretion in the treated groups (Table 4). Creatinine excretion at baseline w a s significantly higher in blacks (1.76 ± 0.58 g / 2 4 h) t h a n in whites (1.38 ± 0.56 g / 2 4 h), (P = .013). By 10 weeks the dif ference b e t w e e n blacks a n d whites w a s n o longer signifi cant (blacks 1.77 ± 0 . 8 4 g / 2 4 h; whites 1.63 ± 0 . 9 2 g / 2 4 h; Ρ = .0557). It increased significantly more in the treated t h a n in the control groups (P = .038). There w a s n o significant difference in calcium excre tion b e t w e e n groups or races at baseline, although there w a s a significant g r o u p - r a c e interaction (P = .019) which is also present in extent of change from baseline to 10 weeks (P = .054), as well as a significant difference in the final calcium excretion with a rise in whites and a substantial fall in blacks (Table 5).
DISCUSSION The lower potassium excretion a n d lower P R A in blacks t h a n whites h a v e been described in numerous studies. The lower serum aldosterone in blacks was 2
1
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the above determinations were repeated. Electrolytes were m e a s u r e d by flame photometry. Aldosterone w a s m e a s u r e d using an i m m u n o a s s a y kit from Diagnostic Products Corporation. Plasma renin activity w a s m e a sured using a kit from Biotecx Laboratories. Creatinine w a s analyzed by a modified Jaffe m e t h o d (Sigma C h e m ical Co., St. Louis, MO). Calcium w a s determined by the cresolphthalein (Sigma) m e t h o d . Magnesium w a s de termined by the calmagite (Sigma) m e t h o d . The multivariate profile analysis w a s used to examine the effects of treatment a n d race on each variable while adjusting for the repeated n a t u r e of baseline a n d 10week data. A type I error probability of .05 w a s estab lished as the minimal level of significance. The correc tions for multiple comparisons within each variable were controlled by the technique of multivariate analysis.
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RACIAL DIFFERENCES IN THE E F F E C T OF KCl
401
r
5.0 4.5
• •
Placebo KCl
4.0 3.5
FIGURE 2. Plasma renin activity was significantly lower (P = .05) at baseline in blacks than in whites. The difference between blacks and whites disappeared in the KCl treated group.
3.0 2.5 2.0 1.5 1.0 0.5 Baseline
10-Weeks Black
Baseline
noted in a recent report. The special finding of this study is the increase of PRA in blacks treated with KCl, to the extent that the b l a c k - w h i t e difference in PRA was abolished. The rise in PRA found in the treated blacks is not w h a t would be predicted from some short-term studies. However, there are at least three w a y s that increased 3
4
10-Weeks White KCl could affect PRA: 1) KCl p r o d u c e d natriuresis, by leading to volume depletion, could increase P R A ; 2) The increased CI by a macula densa effect could de crease renin secretion ; a n d 3) The direct effect of Κ on the adrenal gland to increase aldosterone secretion could lead to s o d i u m retention, increased intravascular v o l u m e a n d decreased renin secretion. 5
6
7
TABLE 1. POTASSIUM EXCRETION AT BASELINE AND AT 10 WEEKS Black
White
Total
Baseline
10-week
Baseline
10-week
Baseline
10-week
Placebo
58.93 (36.90)
62.77 (19.26)
37.93 (14.82)
Total
46.06 (27.19)
65.09 (28.27) n = 14 129.82 (86.99) n = 14 96.25 (70.56)
61.00 (28.21)
Treated Group
36.29 (17.77) η = 12 101.66 (65.51) n = 19 72.35 (61.14)
51.80 (27.73) η = 26 113.10 (74.95) η = 33 85.62 (65.87)
Figures in parentheses are standard Units are mEq/day (SD).
55.03 (27.99) 59.04 (23.72)
44.87 (22.44) 52.10 (26.24)
deviations.
TABLE 2. CHLORIDE EXCRETION AT BASELINE AND AT 10 WEEKS Black
Placebo
Treated Group
Total Units are mEq/day (SD).
White
Total
Baseline
10-week
Baseline
10-week
Baseline
10-week
154.10 (41.92)
112.23 (54.68) n = 12 259.61 (177.42) n = 19 202.56 (159.08)
203.74 (117.43)
183.30 (73.74) n = 14 247.62 (135.40) n = 14 214.27 (110.69)
180.83 (92.63)
150.50 (73.81) η = 26 254.74 (159.40) η = 33 208.01 (137.63)
184.17 (119.03) 175.53 (96.77)
151.87 (84.00) 178.77 (104.16)
171.05 (105.91) 175.44 (99.44)
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0.0
402
LANGFORD ET AL
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PART 1
TABLE 3. SODIUM EXCRETION AT BASELINE AND AT 10 WEEKS Black
Placebo
Treated Group
10-week
Baseline
10-week
Baseline
10-week
159.70 (44.89)
128.25 (65.99) η = 12 212.97 (174.87) η = 19 180.18 (147.32)
194.11 (125.44)
187.14 (72.52) η = 14 158.52 (52.58) η = 14 173.36 (64.17)
178.23 (96.82)
159.96 (74.48) η = 26 190.85 (139.87) η = 33 177.00 (115.38)
182.08 (97.36)
Units are mEq/day
Total
Baseline
196.22 (118.41)
Total
White
140.42 (70.69) 168.26 (104.51)
173.55 (104.17) 175.65 (100.09)
(SD).
8
9
9
The significant rise in creatinine excretion found in KCl treated patients raises the question of w h e t h e r pro tein metabolism is affected by a change in Κ intake w h e n the basal intake is within the a m o u n t s usually consid ered normal. It is k n o w n that m a r k e d Κ deficiency inter feres with protein s y n t h e s i s . However, the baseline excretion of creatinine w a s greater in blacks t h a n in whites, although the black g r o u p h a d significantly lower baseline Κ excretion. Few other correlations reached significance, b u t a n u m b e r of t h e m are suggestive. The steady state sodium excretion rose in the KCl treated patients a n d fell slightly in the placebo treated patients, an effect n o t e d in previous studies of Κ s u p p l e m e n t a t i o n . Elevated PRA a n d elevated aldosterone should b o t h increase sodium a p p e t i t e . The increase in sodium intake should blunt the rise in PRA a n d aldosterone p r o d u c e d by Κ a n d also should blunt the effect of Κ to lower blood pressure. The calcium data, complicated by a significant g r o u p - r a c e interaction at baseline, is difficult to inter pret. The fall in Ca excretion in the KCl treated blacks could represent the following sequence: KCl produced initial natriuresis, t h e n intravascular v o l u m e contrac tion increased proximal tubular absorption of Ca, and i n d e p e n d e n t l y caused the previously n o t e d rise in PRA. Taken together, the data suggests that increasing KCl intake by 80 m E q / d a y produces a n u m b e r of changes: 10
11
12
TABLE 4. MAGNESIUM EXCRETION AT BASELINE AND AT 10 WEEKS Total
White
Black Baseline
10-week
Baseline
10-week
Baseline
10-week
Placebo
5.87 (2.36)
8.07 (2.98)
6.18 (3.91)
Total
6.06 (3.36)
7.39 (4.09) n = 14 6.70 (2.60) n = 14 7.06 (3.41)
7.05 (2.89)
Treated Group
5.67 (2.78) η = 12 6.93 (3.49) n = 19 6.44 (3.25)
6.60 (3.58) η = 26 6.84 (3.12) η = 33 6.73 (3.31)
Units are mEq/day
(SD).
5.47 (2.34) 6.81 (2.95)
5.89 (3.34) 6.41 (3.17)
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Which of these various effects p r e d o m i n a t e m a y d e p e n d in part on the baseline Κ intake. The very low Κ intake of the blacks m a y allow the PRA stimulant effect to predominate, while a higher Κ intake, or p e r h a p s a lower N a / K ratio, m a y allow the PRA depressant effects of KCl to p r e d o m i n a t e . These results, if confirmed, carry several implications: 1) The black-white difference in PRA m a y be d u e in large part to lower Κ c o n s u m p t i o n b y blacks. 2) Part of the increased susceptibility to h y p e r t e n sion of blacks, w h i c h w e a n d o t h e r s h a v e linked to their low Κ consumption, m a y b e b y t h e route of a low PRA. A low PRA (and aldosterone) w o u l d limit the h o meostatic response to increased N a intake: as it is al ready low on usual N a intake, it cannot go m u c h lower to blunt the effect of increased N a intake. Krishna h a s recently s h o w n that participants on a very low Κ intake h a v e significantly m o r e N a retention a n d blood pressure elevation t h a n the control g r o u p after a saline load, in keeping with the hypothesis n o t e d above. 3) The lower PRA found with hypertension a n d w i t h aging m a y b e in part a consequence of low Κ intake. The frequent correlation of N a / K ratio a n d h y p e r t e n sion m a y h a v e a low PRA as a usual component; the elevated blood pressure of aging also should b e studied for its correlation with low Κ intake.
AJH-MAY
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R A C I A L DIFFERENCES I N THE EFFECT OF KCl
403
TABLE 5. CALCIUM EXCRETION AT BASELINE AND AT 10 WEEKS Black 10-week
Baseline
10-week
Baseline
10-week
114.72 (56.10)
111.86 (59.75) η = 12 144.50 (99.18) η = 19 131.86 (86.44)
194.18 (97.27)
180.28 (83.37) η = 14 196.65 (72.52) η =14 188.16 (77.26)
157.53 (89.09)
148.70 (79.97) η = 26 165.69 (91.79) η = 33 158.07 (86.37)
Treated Group
175.20 (101.48)
Total
151.78 (90.72)
140.63 (81.34) 168.40 (92.35)
4.
Langford HG, Langford FPJ, Tyler M: Dietary profile of sodium, potassium, and calcium in U.S. blacks, in Hall DW, Saunders E, Shulman NB (eds): Hypertension in Blacks: Epidemiology, Pathophysiology and Treatment. Chicago, Year Book Medical Publishers, Inc., 1985, pp 49-57. Prineas RJ and Gillum R: U.S. epidemiology of hyper tension in blacks, in Hall DW, Saunders E, Shulman NB (eds): Hypertension in Blacks: Epidemiology, Pathophys iology and Treatment. Chicago, Year Book Medical Pub lishers Inc., 1985, pp 17-36. Cushman WC and Langford HG: Randomized con trolled trial of potassium chloride versus placebo in mildly hypertensive blacks and whites (abst). Circula tion 1988,11-370. Brunner HR, Baer L, Sealey JE, et al: The influence of potassium administration and of potassium deprivation on plasma renin in normal hypertensive subjects. J Clin Invest 1970;49(11):2128-2138.
Smith SJ, Markander ND, Sagneller GA, Poston L, et al: Does potassium lower blood pressure by increasing so dium excretion? J Hypertens 1983;l(Suppl 2):27-30.
6. Julian BA, Galla JH, Guthrie GP, Kotchen TA: Renin and aldosterone responses to short-term NaCl or NaHC03 loading in man. J Lab Clin Med 1982;100(2):261-268. 7.
Davis JO, Urquhart J, Higgins JT, Jr., et al: The effect of alterations of plasma sodium and potassium concentra tion on aldosterone secretion. J Clin Invest 1963,42:597609.
8.
Langford HG: Can the black/white differences in blood pressure and hypertensive mortality in the U.S. be ex plained by differences in potassium intake? in Whelton PK, Whelton H, Walker WG (eds): Potassium in Cardio vascular and Renal Medicine. New York-Basel, Marcell Dekker, 1986.
9.
Krishna G, Miller E, Kapoor S: Increased blood pressure during potassium depletion in normotensive men. Ν Engl J Med 1989;320:1177-1182.
10.
Rudman D, Millikan WJ, Richardson RJ, et al: Elemental balances during intravenous hyperalimentation of un derweight adult subjects. J Clin Invest 1975;55:94-104.
11.
Matlou CM, Isler CG, Higep A, et al: Potassium supple mentation in blacks with mild to moderate essential hy pertension. J Hypertens 1988;4:61-64.
12.
Dalhouse AD, Langford HG, Walsh D, Barnes T: Brief communication, angiotensin and salt appetite: physiolog ical amounts of angiotensin given peripherally increased salt appetite in the rat. Behavioral Neuroscience 1986;100:597-602.
13.
Lawton WJ, Fitz AE, Anderson EA, et al: Effect of dietary potassium on blood pressure, renal function, muscle sympathetic nerve activity, and forearm vascular resist ance and flow in normotensive and borderline hyperten sive humans. Circulation 1990;Vol 81:173-184.
REFERENCES
3.
159.52 (91.05)
Downloaded from http://ajh.oxfordjournals.org/ at New York University on July 12, 2015
5.
13
2.
161.94 (94.01)
(SD).
PRA increases in blacks but not in whites, a n d aldoster o n e increases in b o t h races, but more in blacks. Calcium excretion increases in whites a n d falls in blacks, creati nine excretion increases, a n d there is a n (insignificant) increase in sodium excretion. The data is compatible with the interpretation that KCl h a s p r o d u c e d an initial natriuresis a n d steady-state volume contraction. More over, it suggests that the low PRA of blacks is d u e at least in part to low Κ intake, a n d not genetic origin. The data presented here are complementary to the results of Lawton et al, w h o d e m o n s t r a t e d that PRA w a s significantly lower in individuals given a low K, high N a diet t h a n those participants given a high K, high N a diet. They also d e m o n s t r a t e d that Ca excretion w a s greater on the low K + d i e t .
1.
Total
Baseline Placebo
Units are mEq/day
White
1991;
4:399-403
Chronic Effect of KCl on Black-White Differences in Plasma Renin Activity, Aldosterone, and Urinary Electrolytes
In a 1 0 - w e e k t r i a l of t h e effect of 80 m E q K C l / d a y on b l o o d p r e s s u r e , t h e f o l l o w i n g b i o c h e m i c a l c h a n g e s w e r e n o t e d : p l a s m a r e n i n activity (PRA), o r i g i n a l l y significantly l o w e r i n b l a c k s t h a n w h i t e s , increased to t h e s a m e l e v e l as w h i t e s after Κ s u p plementation. A similar trend was noted with al d o s t e r o n e . KCl i n c r e a s e d c r e a t i n i n e excretion i n blacks a n d w h i t e s , a n d l o w e r e d Ca excretion i n
B
lacks in the United States h a v e lower plasma renin activity (PRA) t h a n w h i t e s . They also u s u ally ingest a n d excrete less potassium (K), a n d their blood pressures tend to be higher. The data reported here are from a study of the effect of KCl supplementation on blood pressure in hypertensive in dividuals attending the outpatient clinics of the Jackson, Miss., Veterans Affairs Medical Center. The blood pres sure data, w h i c h s h o w e d n o significant effect of KCl at 10 weeks, although a significant d r o p w a s present at 4 weeks in blacks, is to be reported elsewhere. In this report w e note that KCl supplementation raises PRA in blacks b u t n o t in whites, abolishing the blackwhite difference in PRA.
blacks. These results suggest that the low PRA f o u n d i n b l a c k s is d u e , at least i n p a r t , to l o w Κ i n t a k e , a n d n o t to g e n e t i c causes. A m J H y p e r t e n s 1991;4:399-403 KEY WORDS: P l a s m a r e n i n activity, p o t a s s i u m , chlo ride, blacks, whites.
METHODS
1
2
3
* Deceased. From the Departments of Medicine (HGL, WCC) and Preventive Medicine (Statistics) (HH), University of Mississippi Medical Center and Veteran's Administration Hospital (WCC), Jackson, Mississippi. This study w a s supported in part by grants from Robins Pharma ceuticals, w h o supplied the potassium supplements and matching placebos, and General Clinical Research Center (No. 2 M O I RR02303). Address correspondence and reprint requests to William C. Cush man, MD, VA Medical Center (111E5), 1030 Jefferson Avenue, M e m phis, TN 3 8 1 0 4 - 2 1 9 3 .
After giving informed consent, black a n d white m e n 18 to 69 (mean 53.9) years of age, with sitting diastolic blood pressures (BP) of 90 to 105 m m H g 2 to 8 weeks after w i t h d r a w a l of antihypertensive medications, were enrolled in the study if there w e r e n o exclusion criteria present, such as elevated creatinine, e n d organ disease, or important gastrointestinal disease. The m e a n blood pressure of the g r o u p w a s 1 5 0 / 9 5 m m Hg. There was n o significant difference b e t w e e n randomization groups or races. Patient treatment w a s initiated with single-blind placebo a n d followed every 2 weeks for 4 to 8 weeks. Before randomization, complete physical ex amination, electrocardiogram, serum electrolytes, 24 h urine for Na, K, Ca, Mg, a n d creatinine a n d plasma renin activity a n d serum aldosterone were measured. Blood for measuring plasma renin activity a n d aldosterone w a s d r a w n after 30 min sitting. The patients were t h e n r a n d o m i z e d to receive 80 m E q / d a y of KCl as Micro-K (A.H. Robins, Richmond, VA) or matching placebo, if the diastolic blood pressure was 90 to 105 m m H g a n d there were 80 to 110 percent compliance by pill count for t w o successive visits on placebo. N o special dietary instructions were given. Patients were seen every t w o weeks for ten weeks. At the e n d of the ten-week period,
Downloaded from http://ajh.oxfordjournals.org/ at New York University on July 12, 2015
Herbert G. Langford* William G Cushman, and Henry Hsu
400
L A N G F O R D ET AL
RESULTS At baseline, the aldosterone of the blacks w a s signifi cantly lower t h a n that of the whites (blacks 7.61 ± 6.21 n g / d L , η = 3 1 , whites 11.16 ± 6 . 9 n g / d L ; Ρ = .046, η = 28). This difference h a d disappeared in the treated groups at 10 weeks (blacks 15.16 ± 13.19 n g / d L , η = 19, whites 16.18 ± 9.07 n g / d L , η = 14, Ρ = .810), (Fig ure 1). Blacks h a d lower PRA (0.96 ± 1.64 n g / m L / h , η = 31) t h a n whites (1.89 ± 1.78, η = 28) at baseline (P = .043). At 10 weeks, PRA in the treated blacks w a s significantly increased to 2.31 ± 2 . 9 1 n g / m L / h ; P = .045, η = 19, a n d w a s u n c h a n g e d in the treated whites, at 2.29 ± 1 . 4 1 n g / m L / h , η = 14, Ρ = .912. Plasma renin activity in the treated blacks w a s essentially iden tical to that of the treated whites (P = .980, Figure 2). Potassium excretion w a s lower ( Ρ = .059) in blacks at baseline (46 ± 27 m E q / d a y ) t h a n in whites (59 ± 24
FIGURE 1. Baseline and 10-week plasma aldosterone (ng/dL). Values were lower in blacks than in whites at baseline. The difference had dis appeared in the KCl treated group at 10 weeks.
1991-VOL
4, NO. 5, PART 1
m E q / d a y ) . (Table 1). Chloride excretion was not signifi cantly different at baseline b e t w e e n races or treatment groups, a n d it increased as anticipated in the treated individuals (Table 2). There w a s n o significant difference in sodium excre tion b e t w e e n races (Table 3). There w a s a n insignificant increase in sodium excretion in the treated groups and an insignificant decrease in the placebo groups. There w a s n o significant difference in baseline Mg excretion nor w a s there any significant difference be t w e e n races or treatment groups in response to therapy. However, there w a s a w e a k a n d insignificant increase (P = .108) in Mg excretion in the treated groups (Table 4). Creatinine excretion at baseline w a s significantly higher in blacks (1.76 ± 0.58 g / 2 4 h) t h a n in whites (1.38 ± 0.56 g / 2 4 h), (P = .013). By 10 weeks the dif ference b e t w e e n blacks a n d whites w a s n o longer signifi cant (blacks 1.77 ± 0 . 8 4 g / 2 4 h; whites 1.63 ± 0 . 9 2 g / 2 4 h; Ρ = .0557). It increased significantly more in the treated t h a n in the control groups (P = .038). There w a s n o significant difference in calcium excre tion b e t w e e n groups or races at baseline, although there w a s a significant g r o u p - r a c e interaction (P = .019) which is also present in extent of change from baseline to 10 weeks (P = .054), as well as a significant difference in the final calcium excretion with a rise in whites and a substantial fall in blacks (Table 5).
DISCUSSION The lower potassium excretion a n d lower P R A in blacks t h a n whites h a v e been described in numerous studies. The lower serum aldosterone in blacks was 2
1
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the above determinations were repeated. Electrolytes were m e a s u r e d by flame photometry. Aldosterone w a s m e a s u r e d using an i m m u n o a s s a y kit from Diagnostic Products Corporation. Plasma renin activity w a s m e a sured using a kit from Biotecx Laboratories. Creatinine w a s analyzed by a modified Jaffe m e t h o d (Sigma C h e m ical Co., St. Louis, MO). Calcium w a s determined by the cresolphthalein (Sigma) m e t h o d . Magnesium w a s de termined by the calmagite (Sigma) m e t h o d . The multivariate profile analysis w a s used to examine the effects of treatment a n d race on each variable while adjusting for the repeated n a t u r e of baseline a n d 10week data. A type I error probability of .05 w a s estab lished as the minimal level of significance. The correc tions for multiple comparisons within each variable were controlled by the technique of multivariate analysis.
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r
5.0 4.5
• •
Placebo KCl
4.0 3.5
FIGURE 2. Plasma renin activity was significantly lower (P = .05) at baseline in blacks than in whites. The difference between blacks and whites disappeared in the KCl treated group.
3.0 2.5 2.0 1.5 1.0 0.5 Baseline
10-Weeks Black
Baseline
noted in a recent report. The special finding of this study is the increase of PRA in blacks treated with KCl, to the extent that the b l a c k - w h i t e difference in PRA was abolished. The rise in PRA found in the treated blacks is not w h a t would be predicted from some short-term studies. However, there are at least three w a y s that increased 3
4
10-Weeks White KCl could affect PRA: 1) KCl p r o d u c e d natriuresis, by leading to volume depletion, could increase P R A ; 2) The increased CI by a macula densa effect could de crease renin secretion ; a n d 3) The direct effect of Κ on the adrenal gland to increase aldosterone secretion could lead to s o d i u m retention, increased intravascular v o l u m e a n d decreased renin secretion. 5
6
7
TABLE 1. POTASSIUM EXCRETION AT BASELINE AND AT 10 WEEKS Black
White
Total
Baseline
10-week
Baseline
10-week
Baseline
10-week
Placebo
58.93 (36.90)
62.77 (19.26)
37.93 (14.82)
Total
46.06 (27.19)
65.09 (28.27) n = 14 129.82 (86.99) n = 14 96.25 (70.56)
61.00 (28.21)
Treated Group
36.29 (17.77) η = 12 101.66 (65.51) n = 19 72.35 (61.14)
51.80 (27.73) η = 26 113.10 (74.95) η = 33 85.62 (65.87)
Figures in parentheses are standard Units are mEq/day (SD).
55.03 (27.99) 59.04 (23.72)
44.87 (22.44) 52.10 (26.24)
deviations.
TABLE 2. CHLORIDE EXCRETION AT BASELINE AND AT 10 WEEKS Black
Placebo
Treated Group
Total Units are mEq/day (SD).
White
Total
Baseline
10-week
Baseline
10-week
Baseline
10-week
154.10 (41.92)
112.23 (54.68) n = 12 259.61 (177.42) n = 19 202.56 (159.08)
203.74 (117.43)
183.30 (73.74) n = 14 247.62 (135.40) n = 14 214.27 (110.69)
180.83 (92.63)
150.50 (73.81) η = 26 254.74 (159.40) η = 33 208.01 (137.63)
184.17 (119.03) 175.53 (96.77)
151.87 (84.00) 178.77 (104.16)
171.05 (105.91) 175.44 (99.44)
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0.0
402
LANGFORD ET AL
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TABLE 3. SODIUM EXCRETION AT BASELINE AND AT 10 WEEKS Black
Placebo
Treated Group
10-week
Baseline
10-week
Baseline
10-week
159.70 (44.89)
128.25 (65.99) η = 12 212.97 (174.87) η = 19 180.18 (147.32)
194.11 (125.44)
187.14 (72.52) η = 14 158.52 (52.58) η = 14 173.36 (64.17)
178.23 (96.82)
159.96 (74.48) η = 26 190.85 (139.87) η = 33 177.00 (115.38)
182.08 (97.36)
Units are mEq/day
Total
Baseline
196.22 (118.41)
Total
White
140.42 (70.69) 168.26 (104.51)
173.55 (104.17) 175.65 (100.09)
(SD).
8
9
9
The significant rise in creatinine excretion found in KCl treated patients raises the question of w h e t h e r pro tein metabolism is affected by a change in Κ intake w h e n the basal intake is within the a m o u n t s usually consid ered normal. It is k n o w n that m a r k e d Κ deficiency inter feres with protein s y n t h e s i s . However, the baseline excretion of creatinine w a s greater in blacks t h a n in whites, although the black g r o u p h a d significantly lower baseline Κ excretion. Few other correlations reached significance, b u t a n u m b e r of t h e m are suggestive. The steady state sodium excretion rose in the KCl treated patients a n d fell slightly in the placebo treated patients, an effect n o t e d in previous studies of Κ s u p p l e m e n t a t i o n . Elevated PRA a n d elevated aldosterone should b o t h increase sodium a p p e t i t e . The increase in sodium intake should blunt the rise in PRA a n d aldosterone p r o d u c e d by Κ a n d also should blunt the effect of Κ to lower blood pressure. The calcium data, complicated by a significant g r o u p - r a c e interaction at baseline, is difficult to inter pret. The fall in Ca excretion in the KCl treated blacks could represent the following sequence: KCl produced initial natriuresis, t h e n intravascular v o l u m e contrac tion increased proximal tubular absorption of Ca, and i n d e p e n d e n t l y caused the previously n o t e d rise in PRA. Taken together, the data suggests that increasing KCl intake by 80 m E q / d a y produces a n u m b e r of changes: 10
11
12
TABLE 4. MAGNESIUM EXCRETION AT BASELINE AND AT 10 WEEKS Total
White
Black Baseline
10-week
Baseline
10-week
Baseline
10-week
Placebo
5.87 (2.36)
8.07 (2.98)
6.18 (3.91)
Total
6.06 (3.36)
7.39 (4.09) n = 14 6.70 (2.60) n = 14 7.06 (3.41)
7.05 (2.89)
Treated Group
5.67 (2.78) η = 12 6.93 (3.49) n = 19 6.44 (3.25)
6.60 (3.58) η = 26 6.84 (3.12) η = 33 6.73 (3.31)
Units are mEq/day
(SD).
5.47 (2.34) 6.81 (2.95)
5.89 (3.34) 6.41 (3.17)
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Which of these various effects p r e d o m i n a t e m a y d e p e n d in part on the baseline Κ intake. The very low Κ intake of the blacks m a y allow the PRA stimulant effect to predominate, while a higher Κ intake, or p e r h a p s a lower N a / K ratio, m a y allow the PRA depressant effects of KCl to p r e d o m i n a t e . These results, if confirmed, carry several implications: 1) The black-white difference in PRA m a y be d u e in large part to lower Κ c o n s u m p t i o n b y blacks. 2) Part of the increased susceptibility to h y p e r t e n sion of blacks, w h i c h w e a n d o t h e r s h a v e linked to their low Κ consumption, m a y b e b y t h e route of a low PRA. A low PRA (and aldosterone) w o u l d limit the h o meostatic response to increased N a intake: as it is al ready low on usual N a intake, it cannot go m u c h lower to blunt the effect of increased N a intake. Krishna h a s recently s h o w n that participants on a very low Κ intake h a v e significantly m o r e N a retention a n d blood pressure elevation t h a n the control g r o u p after a saline load, in keeping with the hypothesis n o t e d above. 3) The lower PRA found with hypertension a n d w i t h aging m a y b e in part a consequence of low Κ intake. The frequent correlation of N a / K ratio a n d h y p e r t e n sion m a y h a v e a low PRA as a usual component; the elevated blood pressure of aging also should b e studied for its correlation with low Κ intake.
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TABLE 5. CALCIUM EXCRETION AT BASELINE AND AT 10 WEEKS Black 10-week
Baseline
10-week
Baseline
10-week
114.72 (56.10)
111.86 (59.75) η = 12 144.50 (99.18) η = 19 131.86 (86.44)
194.18 (97.27)
180.28 (83.37) η = 14 196.65 (72.52) η =14 188.16 (77.26)
157.53 (89.09)
148.70 (79.97) η = 26 165.69 (91.79) η = 33 158.07 (86.37)
Treated Group
175.20 (101.48)
Total
151.78 (90.72)
140.63 (81.34) 168.40 (92.35)
4.
Langford HG, Langford FPJ, Tyler M: Dietary profile of sodium, potassium, and calcium in U.S. blacks, in Hall DW, Saunders E, Shulman NB (eds): Hypertension in Blacks: Epidemiology, Pathophysiology and Treatment. Chicago, Year Book Medical Publishers, Inc., 1985, pp 49-57. Prineas RJ and Gillum R: U.S. epidemiology of hyper tension in blacks, in Hall DW, Saunders E, Shulman NB (eds): Hypertension in Blacks: Epidemiology, Pathophys iology and Treatment. Chicago, Year Book Medical Pub lishers Inc., 1985, pp 17-36. Cushman WC and Langford HG: Randomized con trolled trial of potassium chloride versus placebo in mildly hypertensive blacks and whites (abst). Circula tion 1988,11-370. Brunner HR, Baer L, Sealey JE, et al: The influence of potassium administration and of potassium deprivation on plasma renin in normal hypertensive subjects. J Clin Invest 1970;49(11):2128-2138.
Smith SJ, Markander ND, Sagneller GA, Poston L, et al: Does potassium lower blood pressure by increasing so dium excretion? J Hypertens 1983;l(Suppl 2):27-30.
6. Julian BA, Galla JH, Guthrie GP, Kotchen TA: Renin and aldosterone responses to short-term NaCl or NaHC03 loading in man. J Lab Clin Med 1982;100(2):261-268. 7.
Davis JO, Urquhart J, Higgins JT, Jr., et al: The effect of alterations of plasma sodium and potassium concentra tion on aldosterone secretion. J Clin Invest 1963,42:597609.
8.
Langford HG: Can the black/white differences in blood pressure and hypertensive mortality in the U.S. be ex plained by differences in potassium intake? in Whelton PK, Whelton H, Walker WG (eds): Potassium in Cardio vascular and Renal Medicine. New York-Basel, Marcell Dekker, 1986.
9.
Krishna G, Miller E, Kapoor S: Increased blood pressure during potassium depletion in normotensive men. Ν Engl J Med 1989;320:1177-1182.
10.
Rudman D, Millikan WJ, Richardson RJ, et al: Elemental balances during intravenous hyperalimentation of un derweight adult subjects. J Clin Invest 1975;55:94-104.
11.
Matlou CM, Isler CG, Higep A, et al: Potassium supple mentation in blacks with mild to moderate essential hy pertension. J Hypertens 1988;4:61-64.
12.
Dalhouse AD, Langford HG, Walsh D, Barnes T: Brief communication, angiotensin and salt appetite: physiolog ical amounts of angiotensin given peripherally increased salt appetite in the rat. Behavioral Neuroscience 1986;100:597-602.
13.
Lawton WJ, Fitz AE, Anderson EA, et al: Effect of dietary potassium on blood pressure, renal function, muscle sympathetic nerve activity, and forearm vascular resist ance and flow in normotensive and borderline hyperten sive humans. Circulation 1990;Vol 81:173-184.
REFERENCES
3.
159.52 (91.05)
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5.
13
2.
161.94 (94.01)
(SD).
PRA increases in blacks but not in whites, a n d aldoster o n e increases in b o t h races, but more in blacks. Calcium excretion increases in whites a n d falls in blacks, creati nine excretion increases, a n d there is a n (insignificant) increase in sodium excretion. The data is compatible with the interpretation that KCl h a s p r o d u c e d an initial natriuresis a n d steady-state volume contraction. More over, it suggests that the low PRA of blacks is d u e at least in part to low Κ intake, a n d not genetic origin. The data presented here are complementary to the results of Lawton et al, w h o d e m o n s t r a t e d that PRA w a s significantly lower in individuals given a low K, high N a diet t h a n those participants given a high K, high N a diet. They also d e m o n s t r a t e d that Ca excretion w a s greater on the low K + d i e t .
1.
Total
Baseline Placebo
Units are mEq/day
White
