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(Hypertension. 1999;33:633-639.)
© 1999 American Heart Association, Inc.
Scientific Contribution |
NaCl-Induced Renal Vasoconstriction in Salt-Sensitive African Americans
Antipressor and Hemodynamic Effects of Potassium Bicarbonate
From the Department of Medicine, General Clinical Research Center, University of California, San Francisco, Calif.
Correspondence to Dr R. Curtis Morris, Jr, General Clinical Research Center, University of California, San Francisco, 1202 Moffitt Hospital, San Francisco, CA 94143-0126. Email cmorris{at}gcrcmail.ucsf.edu
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Abstract |
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Abstract—In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9±3.5 (mean±SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K+) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K+ was supplemented to 170 mmol/d (KHCO3). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (
MAP
>+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR
subjects, RBF (mL/min/1.73 m2) decreased from 920±75 to
828±46 (P<0.05); filtration fraction (FF, %)
increased from 19.4± to 21.4 (P<0.001); and renal
vascular resistance (RVR) (103xmm Hg/[mL/min])
increased from 101±8 to 131±10 (P<0.001). In all
subjects combined, MAP varied inversely with RBF
(r =-0.57, P=0.02) and directly with
RVR (r = 0.65, P=0.006) and FF
(r = 0.59, P=0.03), but not with MAP
before NaCl loading. When supplemental KHCO3 abolished the
pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and
FF decreased. The results show that in marginally
K+-deficient blacks (1) NaCl-induced renal
vasoconstrictive dysfunction attends salt sensitivity;
(2) the dysfunction varies in extent directly with the NaCl-induced
increase in blood pressure (BP); and (3) is complexly affected by
supplemented KHCO3, GFR and FF decreasing but RBF not
changing. In blacks, NaCl-induced renal vasoconstriction may be a
pathogenetic event in salt sensitivity.
Key Words: race • normotension • kidney • sodium chloride, dietary • potassium
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Introduction |
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Blood pressure (BP) can be judged to be salt sensitive (SS) when it varies directly and substantially with the dietary intake of NaCl.1 2 3 Given that the occurrence of normotensive salt sensitivity increases the likelihood of later hypertension,2 4 5 the same mechanism may mediate salt sensitivity in both conditions and that mechanism may be critical to the pathogenesis of SS hypertension. In patients with essential hypertension, the mechanism of salt sensitivity may involve a dysfunctional renal hemodynamic response to increased dietary NaCl: With NaCl loading, renal blood flow (RBF) may either fail to increase6 7 8 9 or may decrease10 11 such that both renal vascular resistance (RVR)8 9 10 11 and filtration fraction (FF)7 9 11 increase, with glomerular filtration rate (GFR) persisting unchanged10 11 or increasing.7 12 13 In African Americans (blacks) with SS hypertension, administration of nifedipine that corrected an NaCl-induced increase in BP also corrected an attending NaCl-induced reduction in RBF and the consequent increase in FF.10 If such an NaCl-induced renal vasoconstrictive dysfunction is a critical mediator of salt sensitivity in many hypertensive blacks, and normotensive and hypertensive salt sensitivity in many cases reflects different stages of the same disorder, NaCl-induced renal vasoconstrictive dysfunction may be a critical mediator of salt sensitivity in many blacks regardless of their basal level of BP. This possibility seems not to have been investigated.
When dietary potassium (K+) was controlled at a marginally deficient intake of 30 mmol/d, not uncommon in many blacks,14 15 16 17 we recently observed that salt sensitivity occurred in the great majority of normotensive blacks but in relatively few normotensive whites and on average was more severe in blacks.18 In both, increasing dietary K+ attenuated salt sensitivity. In the current study of black men and women in whom the values of BP before dietary intervention ranged from normal to mildly increased and in whom dietary intake of K+ was initially set at a marginally deficient intake, we asked these questions: (1) In those who are SS, does dietary salt loading induce a renal vasoconstrictive dysfunction? (2) If so, does its severity vary either with the level of BP before NaCl loading or the NaCl-induced increase in BP? (3) Is the dysfunction affected by supplemental dietary K+ that abolishes salt sensitivity?
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Methods |
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Participants
Participants were recruited through advertisement/flyers and through word-of-mouth referral. Selection criteria included self-identification as black, age
25 and 
60 years, body weight (BW)
within 30% of ideal, no history of acute or chronic diseases, in
particular renal disease, ischemic heart disease, stroke, or
diabetes, and no regular medication. Participants were admitted to the
General Clinical Research Center (GCRC) at the University of California
at San Francisco (UCSF) for 21 days. The study was approved by and
conducted according to the guidelines of the Committee on Human
Research at UCSF. Participants gave written informed consent.
Diets
Throughout the study, participants ate a diet that provided an
amount of energy calculated to keep their BW constant, with total
calories derived from protein 10%, carbohydrates 45%, and fat 45%.
Per 70 kg of BW, the basal diet provided 15 mmol
Na+, 30 mmol K+, and
14 mmol Ca2+. Ingredients for all meals,
preparation of meals, and the time of meal provision were kept constant
throughout the study. Participants received 25 to 30 g/kg BW/d of
deionized water during the low NaCl phase and 40 g/kg BW/d during the
high NaCl phase, respectively.
The study consisted of one 6-day and two 7-day periods: (1) low NaCl, low K+ (LL) during which the basal diet was provided without supplements; (2) high NaCl, low K+ (HL) during which NaCl was increased to a total of 250 mmol/70 kg BW/d by adding 115 mmol NaCl to the food and by providing 120 mmol/70 kg/d as gelatin capsules (6 mmol/capsule) with meals; and (3) high NaCl, high K+ (HH) during which 140 mmol/70 kg BW KHCO3 was supplemented as a combination of gelatin capsules (10 mmol/capsule) and cherry-flavored syrup (1 mol/L) equally distributed between meals. Throughout the study, each participant received the same number of identically appearing capsules without being informed about their content.
BP and BW
We measured BP every 4 hours after 15 minutes of rest in the
supine position using an automated oscillometric device (Dinamap,
Critikon Inc) programmed to obtain 5 readings within 5 minutes, and
average daily pressures were calculated. BW was measured daily at 6
AM before breakfast. Average BPs and BWs of the last 2 days
of each study period before renal hemodynamic measurements are
reported.
Renal Hemodynamics
On the last day of each study period, 2 hours after breakfast
and after an oral water load of 1 L administered over an hour,
participants received an intravenous bolus of 5% inulin
and 5% PAH dissolved in 5% glucose, followed by inulin and PAH
continuous infusions. Doses were calculated to achieve steady-state
inulin and PAH plasma concentrations of 15 to 20 mg/L and 1.5 to 2
mg/L, respectively. Deionized water was administered orally at 200 to
250 mL/20 min throughout the renal hemodynamics
measurements. Participants remained in supine position except for
urination, during which they stood up for 1 to 2 minutes. After a
1-hour equilibration period, three 20-minute timed urine samples and
midtime blood samples were obtained. BP was measured at 5-minute
intervals.
Laboratory Measurements
Spontaneously voided urine was collected daily over 24-hour
periods except on the day of renal hemodynamics
measurements. PAH, inulin, and electrolyte concentrations and
hematocrits were determined in blood and urine samples at the GCRC Core
Laboratory by use of standard techniques.
Data Analysis
Effective renal plasma flow (ERPF), RBF, and GFR were calculated
from urine and plasma PAH and inulin concentrations and hematocrit
values. We calculated FF by GFR/ERPFx100 and RVR by
MAP/RBFx103 (using MAP measured during renal
hemodynamics studies). Intrarenal resistances and
glomerular capillary pressure were estimated for the LL and
HL periods by use of the renal function curves.19 Colloid
osmotic pressure was estimated from plasma protein
concentrations.20 The effect of diets on 24-hour BP, BW,
electrolytes, and renal hemodynamic
parameters was assessed by repeated measure ANOVA and
contrast analysis. Differences between groups at baseline and
differences in diet-induced changes were analyzed by unpaired
and paired t test, respectively. Stepwise linear regression
analysis was performed to assess the effect of independent
variables on renal hemodynamics. Data are expressed
as mean±SEM. The null hypothesis was rejected at
P<0.05.
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Results |
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As judged by an increase in MAP of >5%2 on high (250 mmol/d) compared with low (15 mmol/d) NaCl intake, 10 (9 men, 1 woman) of 16 participants were classified as SS and 6 (5 men, 1 woman) as salt resistant (SR),
MAP% 13.2±1.8 versus
2.5±0.9, respectively, P<0.001. Baseline characteristics
(Table 1) were not different
between the 2 groups although SR subjects tended to be heavier. Three
of 10 SS and 2 of 6 SR subjects were mildly hypertensive on admission.
Throughout the course of the study, urine volumes, daily and cumulative
urinary Na+ and K+
excretion, Na+ balance, and serum electrolytes
were not different between groups, except that serum
Cl- increased with NaCl loading in SS subjects
and serum K+ was slightly but significantly lower
in SR subjects at the end of LL. K+ repletion
with KHCO3 increased serum
K+ levels significantly in both groups (Table 2).
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Effect of NaCl Loading on BP, Renal Hemodynamics,
BW, and Electrolytes
In SS versus SR subjects, respectively, NaCl loading
increased systolic BP (SBP) (mm Hg) 17.3±1.7 versus 5.5±1.9,
P<0.001; diastolic BP (DBP) (mm Hg) 9.7±1.8
versus 0.8±1.0, P<0.01; and MAP (mm Hg) 12.2±1.9 versus
2.3±0.9, P<0.001 (Figure 1A). Only in SS subjects did NaCl loading
increase DBP and MAP significantly. With NaCl loading, BW (kilograms)
increased (2.4±0.2 versus 2.8±0.6) and hematocrit decreased
(-0.037±0.005 versus -0.039±0.01) significantly and to a similar
degree in both groups (Table 2). In SS versus SR subjects, NaCl loading
had opposite effects on RBF (mL/min/1.73 m2)
(-93±35 versus 50±47, P<0.05) (Figure 1B), FF (%)
(2.0±0.6 versus -1.4±0.8, P<0.01) (Figure 1C), RVR
(103xmm Hg/[mL/min]) (29±7 versus -3±6,
P<0.01) (Figure 1D), afferent renal arteriolar resistance
(Ra), efferent renal arteriolar resistance (Re), and
glomerular capillary pressure (PGC)
(Table 4), respectively. NaCl loading (HL) compared with low NaCl (LL)
induced significant changes in RBF, FF, RVR, Ra, Re, and
PGC in SS subjects only (Tables 3 and 4).
GFR did not change significantly with NaCl loading in either group but
trended upward in SS subjects.
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When the renal effects of NaCl loading were analyzed separately
in those 7 SS subjects with baseline BPs in the normal range, results
were not different from those of all SS subjects combined (RBF
[HL-LL] -104±35 mL/min/1.72 m2,
P<0.01; GFR 6±6 mL/min/1.73 m2,
P=NS; FF 2.6±0.7%, P<0.01; RVR
34±8 mm Hg/[mL/min], P<0.01) (Figure 2).
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In all subjects combined, stepwise linear regression analysis
revealed that the NaCl-induced change in MAP strongly predicts the
changes in RBF, FF, and RVR (Figure 3)
but not GFR. Age, MAP before NaCl loading, and
Na+ balance were not predictive of NaCl-induced
changes in renal hemodynamics. The severity of salt
sensitivity was not related to the BP level before NaCl loading (MAP
during LL versus MAP [HL-LL]: r=0.134,
P=NS).
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Effect of K+ Supplementation on BP, Renal
Hemodynamics, BW, and Electrolytes
In SS subjects, dietary K+ supplementation
abolished the NaCl-induced increases in BP. In SR subjects,
K+ repletion decreased DBP and MAP but not SBP to
a level significantly lower than that occurring during LL (Table 2). In
SS subjects, SBP decreased by -18.5±2.4, in SR -11.0±4.7
mm Hg, P=NS; DBP -9.0±1.8 versus -5.7±2.0 mm Hg,
P=NS; MAP -12.2±1.9 versus -7.5±2.9 mm Hg,
P=NS. K+ supplementation reversed
the NaCl-induced increases in RVR and FF observed in SS subjects but it
did not change RBF (Table 3). GFR and FF decreased significantly with
K+ supplementation in SS subjects. In SR
subjects, K+ supplementation induced a small, not
statistically significant decrease in GFR. Changes in renal
hemodynamics were not predicted by the change in MAP
induced by KHCO3. Pressor and renal
hemodynamic effects induced by
KHCO3 were not significantly different between SS
and SR subjects with 1 exception: FF=-2.8±0.5 in SS subjects
versus 0.4±1 in SR subjects, P<0.01. With
K+ supplementation, weekly cumulative
Na+ excretion and changes in BW, hematocrit,
serum Na+, Cl- and
K+ were similar in SS and SR subjects (Table 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this study show that in SS blacks with either normal or mildly elevated BP, NaCl loading induced a renal vasoconstrictive dysfunction in which RBF decreased, RVR and FF increased, and GFR trended upward. In those normotensive and hypertensive subjects who were not SS, renal dysfunction was not observed when NaCl was loaded. In all subjects combined, neither the extent of NaCl-induced increase in BP nor that of the NaCl-induced renal dysfunction was related to the level of BP measured immediately before NaCl loading. However, the increase in BP induced by NaCl loading varied directly with the extent of renal dysfunction so induced. Specifically, the changes in MAP induced by dietary NaCl varied inversely with those induced in RBF and directly with those in RVR and FF.
A similar pressor-renal hemodynamic relationship with NaCl loading was observed by van Paassen et al21 in a group of predominantly white male patients selected only for hypertension. These investigators proposed that in hypertensive patients, "a rise in blood pressure in response to a high Na+ intake appears to partially be the result of insufficient renal vasodilation" and a consequent impaired capacity to excrete NaCl. Such a dysfunctional renal hemodynamic response to NaCl loading was earlier formulated by Hollenberg and Williams22 to mediate salt sensitivity in patients selected for "nonmodulating" essential hypertension. In support of these formulations, in both black and white patients with hypertension, pharmacological agents that ameliorated an NaCl-induced rise in BP also ameliorated an attending renal hemodynamic dysfunction.10 21 22 We propose that in normotensive as well as hypertensive blacks, NaCl-induced renal vasoconstrictive dysfunction can be a critical mediator of salt sensitivity. Since occurrence of normotensive salt sensitivity reportedly increases the likelihood that SS hypertension will occur within a decade,2 4 5 both conditions in blacks could reflect different stages of a single disorder in which NaCl-induced renal vasoconstriction is a critical pathogenetic component.
The NaCl-induced renal vasoconstrictive dysfunction currently observed in SS blacks is similar to that previously described in hypertensive black,10 white,11 and Japanese23 subjects selected for salt sensitivity. In these studies, however, as in those of SS patients with nonmodulating essential hypertension,22 the renal hemodynamic dysfunction that occurred with NaCl loading was not reported to vary in extent with that of the increase in BP induced by NaCl loading. Further, in these studies as in those of van Paassen et al,21 preexisting hypertension and "fixed vascular changes in the hypertensive kidney" may have been necessary pathogenetic components of both the NaCl-induced rise in BP and the attending renal hemodynamic dysfunction. By contrast, in most of the currently studied blacks with salt sensitivity, the NaCl-induced reduction in RBF occurred unassociated with hypertensive levels of BP and persisted after supplemental dietary K+ abolished the NaCl-induced increase in BP. Hence, the renal vasoconstriction induced by dietary NaCl did not depend on either the concomitance of hypertension or rise in BP (or a marginal dietary intake of K+) and, thus, could of itself have mediated salt sensitivity, ie, in the absence of "fixed vascular changes." However, over time, such a renal vasoconstrictive dysfunction in blacks could contribute to the pathogenesis of renal disease expressed as SS hypertension (vide infra).
Although Na+ retention and volume expansion are considered critical events in the pathogenesis of SS hypertension,24 Na+ balance does not necessarily predict changes in BP responses in normotensive or in hypertensive subjects.10 25 26 27 28 In studies of the Dahl rat, NaCl loading increased plasma volume and cardiac output equally in SS rats (DS) and SR rats (DR), but total peripheral vascular resistance decreased only in DR.29 When volume expansion was prevented in NaCl-loaded DS, BP did not rise.29 The investigators concluded that in the DS, the plasma volume expansion induced by NaCl loading was necessary but not sufficient to induce hypertension. They proposed that an impaired cardiovascular response to that expansion was also necessary. In SS and SR subjects in the current study, NaCl loading induced a similarly positive Na+ balance and seemed to induce a similar expansion of plasma volume, as judged by the occurrence in both groups of similar decreases in hematocrit and increases in BW. This would suggest that plasma volume expansion is not sufficient to effect salt sensitivity. However, the fact that supplemental dietary K+ that abolished salt sensitivity also natriuretically contracted the apparently expanded plasma volume suggests that expansion was necessary for the expression of that salt sensitivity. The fact that the NaCl-induced reduction in RBF persisted unchanged when K+ supplementation abolished the NaCl-induced increase in BP shows that this NaCl-induced renal hemodynamic dysfunction is not of itself sufficient to mediate salt sensitivity. Thus, given the direct relationship between the increase in BP and the decrease in RBF observed with NaCl loading in the blacks currently studied, both this dysfunction and plasma volume expansion may have been necessary, yet possibly not sufficient, for the NaCl-induced pressor effect.
Like Guyton,30 31 most investigators assume that a sustained increase in BP induced by NaCl– salt sensitivity–is a consequence of an impaired capacity of the kidney to excrete salt at a lower BP, pressure natriuresis being required to overcome that impairment and to restore the capacity of the kidney to maintain NaCl and water balance. According to one formulation,32 hypertension becomes SS when either the renal ultrafiltration coefficient (Kf) is reduced or the renal tubular reabsorption of NaCl is increased or both. In both instances, an increased PGC is believed to occur and to mediate pressure natriuresis. An NaCl-induced increase in GFR has been reported in SS normotensive white men,33 in a racially mixed group of SS hypertensive subjects,7 and in black hypertensive subjects12 and is inferred to reflect an increase in Re that increases PGC, thereby facilitating pressure natriuresis, if over time causing renal damage in trade-off.10 11 As reported previously in SS hypertensive subjects,7 10 11 in the current study, NaCl loading induced in SS but not in SR blacks an increase in FF, PGC, and Re. In the current study, these increases varied directly with those in MAP.
In the current study, supplementing dietary K+ with KHCO3 not only abolished the NaCl-induced increase in BP and FF without affecting RBF but also induced a large decrease in GFR. The decrease in GFR may be in part a consequence of natriuretic contraction of plasma volume32 induced by supplemental K+ by its direct reduction of renal tubular reabsorption of Na+.34 However, it also seems likely that the decrease in GFR induced by KHCO3 reflects a decrease in an otherwise increased PGC and Re. Such decreases may be clinically relevant. In hypertensive patients, it has been observed that a prompt decrease in GFR and FF induced by the initiation of antihypertensive therapy is associated with a decreased rate of loss of renal function during continued treatment,35 possibly by decreasing intraglomerular pressure.
In NaCl-loaded SS blacks, it remains to be determined whether supplementing dietary K+ with KHCO3 has antipressor and GFR- and FF-reducing effects not shared by KCl. In SS human hypertension, the pressor effect of NaCl requires its Cl- component36 ; NaHCO3 has attenuated hypertension.37 In experimental animals, dietary Cl- can have its own pressor38 39 and renal vasoconstrictive effect,40 which may involve both efferent and afferent arterioles.41 In the SS, stroke-prone spontaneously hypertensive rat fed a normal NaCl diet, supplemental KHCO3 attenuated hypertension whereas supplemental KCl exacerbated it.39 Such selective Cl- sensitivity is likely to be mediated in part by renal vasoconstrictive dysfunction.39 In NaCl-loaded SS blacks, KCl may then have a lesser antipressor effect than KHCO3 and induce a lesser decrease in GFR and FF. Also, in SS blacks, Cl- may contribute to the pressor effect of dietary NaCl, not only by complementing Na+ in the expansion of plasma volume caused by salt36 but also by inducing renal vasoconstriction that both restricts the riddance of that expansion and directly participates in increasing peripheral vascular resistance.
In summary, in SS blacks, we find that dietary NaCl loading induced renal vasoconstriction whose extent varied directly with that of the attending pressor effect of NaCl. Supplemental KHCO3 abolished the pressor effect of NaCl without affecting the NaCl-induced reduction of RBF. However, supplemental KHCO3 reversed an NaCl-induced increase in FF and induced a substantial decrease in GFR that could reflect abolishment of an NaCl-induced increase in intraglomerular pressure.
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Acknowledgments |
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These studies were carried out in the General Clinical Research Center (GCRC), the University of California at San Francisco (NIH NCRR Grant M01 00079), California. This research was supported in addition by National Institutes of Health Grant HL47943 and by gifts from Church & Dwight Co, Inc, and the Emil Mosbacher, Jr, Foundation. The authors thank Deanna Sheeley, RN, and the nursing staff of the GCRC; Joan Ottaway and the laboratory staff; Karen Todd, RD, and the dietary kitchen staff; and Andrea Marcellano for their excellent assistance in conducting these studies and preparing the manuscript.
Received August 3, 1998; first decision August 24, 1998; accepted September 29, 1998.
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