Urinary Kallikrein and Plasma Renin Activity as Determinants of Renal Blood Flow THE INFLUENCE OF RACE AND DIETARY SODIUM INTAKE

STEVEN B. LEVY, JOHN J. LILLEY, RONALD P. FRIGON, and RICHARD A. STONE From the Division of Nephrology, Departments of Medicine, University of California, San Diego, School of Medicine, and Veterans Administration Hospital, San Diego, California 92161

A B S T R A C T We investigated the relationship of the support the concept that the kallikrein-kinin system kallikrein-kinin system and the renin-angiotensin sys- and the renin-angiotensin system contribute to the tem in the regulation of blood pressure, salt and water regulation of renal blood flow and may account for excretion, and renal blood flow. Normotensive and racial differences in renal vascular resistance. hypertensive black and white men were studied during unrestricted sodium intake as well as on a 10INTRODUCTION meq/day sodium intake; potassium intake was held Kallikrein is an enzyme that catalyzes the formation constant throughout the study (80 meq/day). During unrestricted sodium intake, urinary kalli- of the vasodilator hormones, lysyl-bradykinin (kallikrein activity was greater in white normotensives din) and bradykinin, from a plasma alpha-2 globulin than white hypertensives or black normotensives. substrate, kininogen (1). Urinary kallikrein appears to There was no difference (P > 0.05) between white be derived from the kidney and differs from the enzyme and black hypertensives or between black normoten- that circulates in plasma (2). It has been proposed sives and black hypertensives. All groups had greater that kallikrein exists in the renal cortex and may occupy urinary kallikrein activity on low sodium vs. unre- a location that is juxtaposed to the enzyme renin (3). stricted sodium intake, but the increase in black hyper- Although a physiologic function for lysyl-bradytensives was small, and they excreted significantly less kinin, the enzymatic product, has not been estabkallikrein than the other groups on the low sodium lished, pharmacologic infusion studies have shown that diet. Plasma renin activity showed similar increments the peptide is a natriuretic and vasodilatory comafter sodium restriction in all groups. Urinary kalli- pound (4). A number of studies in humans and experimental krein activity correlated with renal blood flow in all groups except the black normotensives on low sodium animals have attempted to determine the relationship intake. Renal blood flow could be correlated uni- between urinary kallikrein activity and blood pressure formly with log (urinary kallikrein activity/supine regulation (5-9). Although most investigators feel that plasma renin activity) in all groups on either diet. kallikreins could influence blood pressure, the meanUrinary sodium and potassium excretion and urine ing of these findings is controversial. Based on provocavolume were not different among the groups. We con- tive preliminary observations (10) and the aforemencluide: (a) important racial differences exist in urinary tioned studies, it seemed appropriate to examine the kallikrein activity that are uinrelated to sodium or simultaneous influence of race and blood pressture on potassium excretion or urine volume; (b) dietary urinary kallikrein activity. In addition, we have exsodiuim restriction further delineates racial differences amined the association between kallikrein in uirine and suiggests alternative pathophysiologic mechanisms and factors that have been related to blood pressure for human hypertension; (c) urinary kallikrein activity regulation including urinary volume, soditum excrecorrelates with renal blood flow; and (d) our data tion, plasma renin activity, and renal blood flow. These latter studies were designed to determine a Received for publication 22 November 1976 and in re- possible physiologic role for the kallikrein-kinin sysvisedform 7 February 1977. tem in blood pressure control. The Journal of Clinical Investigation Volume 60 July 1977 *129-138 129

METHODS Patients. Four groups of men (38 white and 21 black) with differing blood pressure patterns were studied at the Diagnostic and Treatment Unit of the San Diego Veterans Administration Hospital. The subjects included 25 hypertensive patients (18 white, 7 black) and 34 apparently healthy men (20 white, 14 black). All subjects were screened several times before hospitalization, and all hypertensive patients were required to exhibit the arbitrary criteria consisting of a supine mean arterial pressure (diastolic blood pressure plus one-third pulse pressure) that was at least 110 mm Hg on each determination. Apparently healthy normotensive men were paid volunteers who fulfilled the arbitrary criteria of a supine mean arterial pressure that was consistently less than 95 mm Hg during at least three separate measurements. Every subject gave his informed written consent, and the Committee on Human Experimentation of the University of California, San Diego, approved the protocol. Each subject was admitted to the hospital and the evaluation consisted of a complete history and physical examination; multiple determinations of blood pressure (vide infra); routine blood chemical studies including determinations of the blood urea nitrogen concentration and the serum concentrations of sodium, potassium, chloride, bicarbonate, magnesium, calcium, and creatinine; a hemogram, a complete urinalysis including microscope examination of the urinary sediment and urine culture, a roentgenogram of the chest, and an electrocardiogram. While ingesting a diet with defined quantities of sodium and potassium (vide infra), each subject provided urine for two consecutive 12-h measurements of kallikrein activity, creatinine, sodium and potassium concentrations. In addition, samples of peripheral venous blood were obtained for the determination of plasma renin activity (PRA).' Patients who met our arbitrary criteria for hypertension were evaluated further for known secondary causes of blood pressure elevation. These studies included an intravenous urogram, selective renal angiography with measurements of PRA in the renal venous effluent from the two kidneys, and the 24-h urinary excretion of 17-hydroxycorticosteroids, catecholamines, and vanillylmandelic acid. Only two patients had received previous therapy for hypertension, and in both instances medication was omitted for 3 wk before enrollment in the study.

Procedures Each hypertensive patient was studied during two separate balance periods of dietary salt ingestion. During the initial phase (5 days) of hospitalization, subjects were fed a diet without restriction of sodium content (>100 meq/24 h) and which contained approximately 80 meq/24 h of potassium. Repeat urinary investigations were performed on the 11th hospital day after 5 days of restricted sodium ingestion ( 0.10) from black hypertensives who averaged 41.4±4.7 yr (range 28-57 yr). In addition, hypertensive patients did not differ in age from any group of normotensive subjects (P > 0.10). Analysis of automated blood pressure patterns revealed the expected differences between those subjects previously and arbitrarily classified as hypertensive and those defined as normotensive (Table I). The average automated mean arterial pressure of white hypertensive men was 114.5 ±1.4 mm Hg (range 108-126 mm Hg) and was similar (P >0.10) to black hypertensive men (mean 121.6 ±3.6 mm Hg, range 113-141 mm Hg). Regardless of race or dietary salt intake, all normotensive subjects exhibited blood pressures that were similar to each other (P > 0.10) but differed (P < 0.01) from all hypertensive men. Serum sodium and potassium concentrations were similar (P > 0.10) in all groups of subjects, and all exhibited normal renal function by the criteria of serum creatinine concentrations (Table I) and urinary examination. Results of all other diagnostic procedures were within the normal range for all hypertensive patients, and thus they were considered to have primary (essential) hypertension. Dietary salt intake or race did not influence these results in any group (Table I). Urinary sodium excretion is summarized in Table II. There were no differences between sodium excretion on the day before urinary kallikrein measurement and the 24-h period during

Urinary Kallikrein and Renin

131

TABLE II Summary of Urinary Sodium Excretion 24-h UN,+Vt

Before kallikrein determination

During kallikrein determination

meq

meq

Normotensives UnNa+ Whlite White

161±12 16±4

149±11

UnNa+

176±26

178±20

Hypertensives UnNa+ White White

~~LNa+

168±21 15±3

177±20 19±2

UnNa+

159±15

165±16

Experimental group

Diet*

~~LNa+

Black

15±4

LNa+

Black

19±4

LNa+

18±5

13±3

19±3

* Diet: UnNa+, unrestricted sodium intake; LNa+, low sodium intake. t UN.+V, 24-h urinary sodium excretion.

which kallikrein was measured in any of the four groups. Additionally, every subject had decreased his urinary sodium excretion to less than 40 meq/24 h by the 4th day of the low sodium phase and in no instance was this value more than 5 meq greater than the 5th day, documenting that stable sodium balance was attained.

Urinary kallikrein activity differed among groups according to race and blood pressure pattern, and these differences showed distinct changes after dietary salt restriction (Tables III and IV). During unrestricted dietary sodium intake, 24-h urinary kallikrein activity (the sum of the two 12-h collections) was 18.7+3.1 EU in white normotensives and differed (P < 0.025) from that of white hypertensive men who averaged 9.2+2.3. Black normotensives excreted 3.8+0.9 EU, not significantly different from black hypertensives (3.0+ 1.1 EU) at this amount of dietary salt intake. The difference between black and white normotensives is significant (P < 0.01), while black hypertensives do not differ (P > 0.1) from the white hypertensive group (Fig. 1). After dietary salt restriction (Table IV, Fig. 1) there was a significant increment (P < 0.05) of urinary kallikrein activity in all groups. White normotensive men excreted 38.8±12.1 EU and did not differ (P > 0.05) from white men with hypertension (30.3+6.8 EU) or healthy black subjects who averaged 20.9+5.7 EU. Black hypertensive men exhibited urinary kallikrein activity which averaged 4.9+1.9 EU and was significantly less (P < 0.01) than all other groups on low sodium diets. The aforementioned differences among subjects were observed despite similar (P > 0.05) urinary volumes and urinary sodium and potassium excretions among all groups (Tables III and IV). Urine was collected in two 12-h aliquots (8:00 a.m. to 8:00 p.m. and 8:00 p.m. to 8:00 a.m.) as an index

TABLE III Summary of Urinary Kallikrein Activity, UNaV, UV, Renal Blood Flow, and Supine and Stimulated PRA on Unrestricted Sodium Intake (Mean ±SEM) PRA

UKa

UV

UN.V Experimental 8 a.m.-8 p.m.

group

8 p.m.-8 a.m.

8 a.m.-8 p.m.

8 p.m.-8 a.m.

EUI12 h

RBF/BSA

Supine

Stimulated

ml/minim2

ng A,lml/h

84±9

65±5

878±130

818±113

10.6±2.1

8.1±1.4

*570±13

1.6±0.3 6.2±0.9

100±19

82±12

951±154

683± 87

2.2±0.8

1.6±0.5

582±12

0.8±0.3 4.3±1.0

110±14

67±10

1,025+108

747±88

5.9±1.6

3.3±0.7

*499±17

2.8±1.1 4.6±2.0

87±9

78±8

686±64

691±83

1.3±0.5

1.7±0.6

470±39

0.7±0.2 1.0±0.4

(n = 13) Black (n = 8) Hypertensives White (n = 18) Black (n = 7)

8 p.m.-8 a.m.

ml/12 h

meql12 h

Normotensives White

8 a.m.-8 p.m.

UNBV, urinary sodium excretion; UV, urinary volume; PRA, plasma renin activity; UKa, urinary kallikrein activity; RBF/BSA, renal blood flow/body surface area. Supplemental material for Tables III and IV has been deposited with the National Auxiliary Publications Service (NAPS) as NAPS document 03007. This information may be ordered from ASIS/NAPS. c/o Microfiche Publications, 305 East 46th Street, New York 10017. Remit with order for each NAPS document number $1.50 for microfiche or $5.00 for photocopies for up to 30 pages. Checks should be made payable to Microfiche Publications. * n = 12 for this determination.

132

S. B. Levy, J. J. Lilley, R. P. Frigon, and R. A. Stone

TABLE IV Summary of Urinary Kallikrein Activity, UNGV, UV, Renal Blood Flow, and Supine and Stimulated PRA on Low Sodium Intake (Mean+±SEM) UNaV

UKa

UV

PRA

Experimental group

8 a.m.-8 p.m.

8 p.m.-8 a.m.

8 a.m.-8 p.m.

meqll2 h

Normotensives White

8 p.m.-8 a.m.

8 a.m.-8 p.m.

mil/12 h

8 p.m.-8 a.m.

Supine

RBF/BSA

EUI12 h

Stimtulated

ml/minim2

ng A,/ml/hz

12+4

6+2

783+222

656±181

19.4+4.4

19.4+10.4

518+19

3.7+0.6 10.2+0.9

7+3

6+2

402+96

432+78

10.6+4.6

10.3+2.8

509+15

1.9+0.7

11+2

8+1

815+63

896±126

17.3+3.6

13.0±3.5

*449+23

9±1

9±2

577±123

601±108

2.7±1.0

2.1±0.9

360±35

(n = 7) Black (n = 6) Hypertensives White (n = 18) Black

7.1±+1.3

8.2+1.4 13.4+3.1 6.9±2.1

10.7±3.8

(n = 7) UNaV, urinary sodium excretion; UV, urinary volume; PRA, plasma renin activity; UKa, urinary kallikrein activity; RBF/BSA, renal blood flow/body surface area. For supplemental material, see legend of Table III. * n = 12 for this determination.

of day-night variation of urinary kallikrein excretion (Tables III and IV). White hypertensive patients exhibited significantly higher (P < 0.05) urinary kallikrein activity during the day, and this was accompanied by a parallel variation of urinary volume and urinary sodium concentration. We observed these differences among white hypertensive men irrespective of sodium intake, but we could not observe this phenomenon in any other group during either dietary manipulation. Determinations of PRA during unrestricted sodium intake and supine posture averaged 2.8±1.1 ng AVml per h among white hypertensives and was similar (P > 0.05) to black hypertensives and white normotensives, who exhibited measurements of 0.7+0.2 and 1.6+0.3 ng AVml per h, respectively (Tables IIIV). However, stimulated PRA on unrestricted sodium diet for black hypertensive men (mean, 1.0+0.4 ng AVml per h) was significantly less (P < 0.025) than that of apparently healthy black men who averaged 4.3 ±1.0 ng A/ml per h. There were no other differences (P > 0.10) among the compared groups during unlimited salt intake. A comparison of groups on restricted sodium intake indicated that there were no significant differences (P > 0.05) among subjects irrespective of race or blood pressure pattern (Table V). We also contrasted supine vs. stimulated PRA at both extremes of salt intake (Tables III-V). It is noteworthy that black hypertensive men alone did not exhibit an increase of PRA (P > 0.05) after our standard stimulation during either dietary manipulation. All other groups on either diet increased PRA consistently after the stimuli of furosemide and ambulation. However, dietary salt restriction resulted in a significant

increment (P < 0.05) of PRA in all groups regardless of position (Table V). Renal blood flow was determined from the formuila: renal blood flow = p-aminohippurate clearance/(1hematocrit). Data for renal blood flow are expressed as square meters of body surface area (Tables III and IV). On unrestricted sodium intake white normotensives had a renal blood flow of 570+13 ml/min per m2, Na+ INTAKE

=

Unrestricted EJ 10 meq /24 h 'z

X

50

11-1 =3

t

40

30 -cl LLJ

cr .e

20 h

+

-i -i .e

10

crm cc =o

[

hFh

nI

v

WHITE

BLACK

LHYPERTENSIVESJ

F'] WHITE

BLACK

LNORMOTENSIVESI

FIGURE 1 Urinary kallikrein response to sodium restriction. On unrestricted sodium intake white normotensives have greater urinary kallikrein activity than white hypertensives or black normotensives. There is no difference between white and black hypertensives or between black normotensives and black hypertensives. All groups had greater urinary kallikrein activity on low sodium vs. high sodium intake, with black hypertensives excreting less kallikrein than the other compared groups.

Urinary Kallikrein and Renin

133

TABLE V Summary of 24-H UNaV, UW, UKa, UKV, and Supine and Stimulated PRA PRA

Experimental

UN.V

UKV

UKa

m1l24 h

meq/24 h

meqI24 h

EU

UnNa+ LNa+

1,701±206 1,499+-363

149±11 18-+-5

70+5 66-+-4

38.8+±12.0

3.7±0.6

10.2±0.9

UnNa+

1,633±173

LNa+

833±168

178±20 13±3

64±5 68±4

3.8±0.9 20.9±5.7

0.8±0.3 1.9±0.7

4.3±1.0 7.1±1.3

White

UnNa+ LNa+

1,768±183 1,710±157

177±20 19±2

63±3 68±5

30.3±6.8

9.2±2.3

8.2±1.4

2.8±1.1

4.6±2.0 13.4±3.1

Black

UnNa+

1,377±144

165±16

65±6

3.0±1.1

0.7±0.2 6.9±2.1

1.0±0.4 10.7±3.8

group

Diet

Normotensives White Black

UV

18.7+3.1

Supine

Stimulated

ng A,/mlIh

1.6+0.3

6.2±0.9

Hypertensives

LNa+

1,181±227

19±3

71±4

4.9±1.9

UNaV, urinary sodium excretion; UV, urinary volume; UKa, urinary kallikrein; PRA, plasma renin activity; UnNa+, unrestricted sodium intake; LNa+, low sodium intake; UKV, urinary potassium excretion.

not different from black normotensives who averaged 582±12 ml/min per i2. At this level of sodium intake, white and black hypertensives had similar renal blood flow, 499±17 and 470±39 ml/min per m2, respectively. For both racial groups normotensives had greater renal blood flow than hypertensives (P < 0.025). Renal blood was significantly (P

Urinary kallikrein and plasma renin activity as determinants of renal blood flow. The influence of race and dietary sodium intake.

Urinary Kallikrein and Plasma Renin Activity as Determinants of Renal Blood Flow THE INFLUENCE OF RACE AND DIETARY SODIUM INTAKE STEVEN B. LEVY, JOHN...
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