Clinical Nephrology

Enhanced Responses of Blood Pressure, Renal Function, and Aldosterone to Angiotensin I in the DD Genotype Are Blunted by Low Sodium Intake

Frank G. H. van der Kleij, Paul E. de Jong, Rob H. Henning, Dick de Zeeuw and Gerjan Navis
JASN April 2002, 13 (4) 1025-1033;

Abstract

ABSTRACT. Angiotensin-converting enzyme (ACE) activity is increased in the DD genotype, but the functional significance for renal function is unknown. Blunted responses of BP and proteinuria to ACE inhibition among DD renal patients during periods of high sodium intake were reported. It was therefore hypothesized that sodium status affects the phenotype in the ACE I/D polymorphism. The effects of angiotensin I (AngI) and AngII among 27 healthy subjects, with both low (50 mmol sodium/d) and liberal (200 mmol sodium/d) sodium intakes, were studied. Baseline mean arterial pressure (MAP) values, renal hemodynamic parameters, and renin-angiotensin system parameters were similar for all genotypes with either sodium intake level. With liberal sodium intake, the increases in MAP, renal vascular resistance, and aldosterone levels during AngI infusion (8 ng/kg per min) were significantly higher for the DD genotype, compared with the ID and II genotypes (all parameters presented as percent changes ± 95% confidence intervals), with mean MAP increases of 22 ± 2% (DD genotype), 13 ± 5% (ID genotype), and 12 ± 6% (II genotype) (P < 0.05), mean increases in renal vascular resistance of 100.1 ± 19.7% (DD genotype), 73.0 ± 16.3% (ID genotype), and 63.2 ± 16.9% (II genotype) (P < 0.05), and increases in aldosterone levels of 650 ± 189% (DD genotype), 343 ± 71% (ID genotype), and 254 ± 99% (II genotype) (P < 0.05). Also, the decrease in GFR was more pronounced for the DD genotype, with mean decreases of 17.9 ± 4.7% (DD genotype), 8.8 ± 3.4% (ID genotype), and 6.4 ± 5.9% (II genotype) (P < 0.05). The effective renal plasma flow, plasma AngII concentration, and plasma renin activity values were similar for the genotypes. In contrast, with low sodium intake, the responses to AngI were similar for all genotypes. The responses to AngII were also similar for all genotypes, with either sodium intake level. In conclusion, the responses of MAP, renal hemodynamic parameters, and aldosterone concentrations to AngI are enhanced for the DD genotype with liberal but not low sodium intake. These results support the presence of gene-environment interactions between ACE genotypes and dietary sodium intake.

The renin-angiotensin system (RAS) plays an important role in the regulation of BP, volume homeostasis, and cardiovascular and renal pathophysiologic processes. Angiotensin-converting enzyme (ACE) is an important enzyme of the RAS, because it converts angiotensin I (AngI) into AngII. The gene coding for ACE is subject to an insertion/deletion polymorphism that is a main determinant of plasma (1) and tissue (2–4) ACE levels. ACE levels are highest with the DD genotype, lowest with the II genotype, and intermediate for heterozygotes (1).

Many studies have addressed the role of the ACE gene as a candidate gene for cardiovascular and renal organ damage. Although many studies support a role for the D allele as a risk factor for cardiovascular or renal target organ damage (5–13), other studies have provided conflicting results (14–16). Data on the responses to ACE inhibition are also conflicting (17–20). Increased conversion of AngI to AngII has been suggested as a mechanism underlying cardiovascular and renal differences among subjects with different ACE genotypes. An increased pressor response to AngI has been reported for the DD genotype, but other studies have provided conflicting findings (21–23). To date, no data are available on the effects of ACE genotype on the renal responses to AngI. In this study, therefore, we studied the effects of ACE genotype on the responses of renal hemodynamics, as well as BP and RAS hormones, to AngI in healthy volunteers.

We previously reported blunted BP and proteinuria responses to ACE inhibition among renal patients with the DD genotype, compared with the II and ID genotypes, for subjects with a high sodium intake but not subjects with a low sodium intake (24). This led us to hypothesize a gene-environment interaction between dietary sodium intake and ACE I/D polymorphism. To test this hypothesis, all subjects were studied twice, i.e., in balance with liberal and low sodium intakes.

Materials and Methods

Subjects

Twenty-seven healthy Caucasian volunteers (age, 18 to 35 yr) were included (Table 1). The study was approved by the local medical ethics committee, and all participants gave written informed consent. All had medical histories without significant disease, and physical examination results were unremarkable. Blood counts, serum creatinine levels, electrolyte levels, and liver enzyme values were normal. All subjects exhibited a mean systolic BP of <140 mmHg and a diastolic BP of <85 mmHg. None of the subjects used medications, including oral contraceptives.

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Table 1.

Baseline characteristics of volunteers with low- and liberal-sodium dieta

Study Design

Subjects were studied on two separate occasions, i.e., with a low-sodium diet (50 mmol/d) and a liberal-sodium diet (200 mmol/d). For each study day, subjects were instructed to maintain the prescribed sodium diet during the 7 d preceding the study day. The diet period was set at 7 d. Sodium restriction induces RAS activation within 3 d, with concurrent sodium balance (25). A period of 7 d has been demonstrated to be sufficient for stabilization of circulatory hormones (26). The diets were prescribed in randomized order. Potassium intake was standardized at 100 mmol/d for both periods. For assessment of dietary compliance, 24-h urine samples were collected on days 5 and 7 after the start of the diet. No differences in sodium excretion or body weight were observed between day 5 and day 7, indicating a stable sodium balance at the time of the experiment. The 24-h urinary excretion at day 7 is presented in Table 1. Female subjects were tested in the midluteal phase of their menstrual cycles. Having abstained from food, alcohol, fluids, and strenuous exercise for 12 h, subjects reported to the research unit at 8:00 a.m. One intravenous cannula were inserted into each forearm, for infusions and drawing of blood samples. Throughout the study, subjects remained in a semirecumbent position. All subjects were given 250 ml of orally administered fluids every 1 h and a meal of similar caloric content every 2 h. Sodium intake during the study day was adjusted according to the prescribed diet. To ensure sufficient urine output, glucose (5%, 250 ml/h) was administered in the right antecubital vein. The ensuing water loading is not expected to suppress RAS parameters to a relevant extent, in contrast to water and salt loading (27,28). Blood samples were drawn at 8:00 a.m., at 10:00 a.m., and each hour thereafter until 6:00 p.m. From 12:00 p.m. to 2:00 p.m., AngI (CLINALFA AG, Laufeifingen, Switzerland) was administered in the left antecubital vein, at dosages of 4 ng/kg per min in the first 1 h and 8 ng/kg per min in the second 1 h. This administration was followed by a washout period from 2:00 p.m. to 4:00 p.m. For investigation of whether possible differences in AngI responses might be attributable to differences in sensitivity to AngII, AngII (CLINALFA) was administered from 4:00 p.m. to 6:00 p.m., at dosages of 4 ng/kg per min in the first 1 h and 8 ng/kg per min in the second 1 h.

Test Procedures

BP, expressed as mean arterial pressure (MAP), was measured with an automated device (Dynamap; GE Medical Systems, Milwaukee, WI) at 15-min intervals, except during AngI and AngII infusion, when BP was measured every 5 min. Serum electrolyte, creatinine, and liver enzyme levels were determined with an automated multianalyzer (SMA-C; Technicon, Tarrytown, NY). Effective renal plasma flow (ERPF) and GFR were measured according to a previously described method, using constant infusions of [125I]iothalamate and 131I-hippurate, respectively (29). The coefficients of variation for GFR and ERPF were 2.2 and 5.0%, respectively. The clearances were calculated by using the formulae U × V/P and I × V/P, respectively. U × V represents the urinary excretion of the tracer, I × V represents the infusion rate of the tracer, and P represents the plasma tracer level at the end of each clearance period. Errors in the estimation of GFR attributable to incomplete bladder emptying and dead space were corrected by multiplying the clearance of [125I]iothalamate using the following formula: clearance of 131I-hippuran (I × V/P)/clearance of 131I-hippurate (U × V/P). The filtration fraction was calculated as the GFR/ERPF ratio. Renal vascular resistance (RVR) was defined as the MAP/ERPF ratio. Urine collection was performed immediately after blood samples were obtained.

Assay Methods

All blood samples were drawn in prechilled tubes and centrifuged at 4°C. Plasma was stored at −20°C until analysis. Tubes for AngII sample collection contained ethylenediaminetetraacetate, enalaprilat, and 1,10-phenanthroline, to prevent in vitro formation and degeneration of AngII. Plasma samples for AngII determinations were stored at −80°C. Serum ACE activity was determined with an HPLC-assisted assay (30). AngII levels were determined with a RIA (Nicols Institute, San Juan Capistrano, CA). The cross-reactivity of the anti-AngII antibody with AngI was 0.1%. Plasma renin activity (PRA) was assessed by quantification of generated AngI with a RIA (Rianen AngI RIA kit; Dupont, Wilmington, DE). Aldosterone levels were determined with a RIA (31). ACE genotypes were determined by using PCR, as described previously (32). To prevent mistyping of heterozygotes, intron-specific primers were used. Blood specimens were collected in ethylenediaminetetraacetate-containing tubes, after which DNA could be extracted from peripheral leukocytes. Genomic DNA was amplified by PCR, and the amplified genes were separated by agarose gel electrophoresis.

Statistical Analyses

All data are expressed as means ± 95% confidence intervals. Baseline values are expressed as absolute values. The responses to AngI and AngII are expressed as percent changes, compared with baseline values. For hormonal values, the averages of values measured at 10:00 a.m. and 12:00 p.m. were used as baseline values. The BP values measured from 10:00 a.m. to 12:00 p.m. (at 15-min intervals) were used as baseline BP values. The percent change in MAP during a given infusion step was analyzed as the average of all MAP values measured during the 1-h infusion period (at 5-min intervals). For renal hemodynamics, the average values for the clearance periods from 10:00 a.m. to 11:00 a.m. and from 11:00 a.m. to 12:00 p.m. were used as baseline values. Differences between means were compared by using the Wilcoxon test for paired data (comparing liberal- and low-sodium values, within one genotype) or the unpaired Mann-Whitney nonparametric test (comparing the three genotypes separately), as appropriate. The responses to AngI and AngII infusions (percent changes) among the three genotypes were also compared by using ANOVA for repeated measurements, with post hoc Bonferroni comparisons. A two-sided P value of <0.05 was considered significant.

Results

Baseline characteristics measured during periods of low and liberal sodium intake are presented in Tables 1 to 3. Plasma ACE activity was higher among DD subjects at both sodium intake levels. The 24-h values for sodium and potassium excretion demonstrated dietary compliance, without significant differences among the genotypes. Slightly greater body weights were observed during liberal sodium intake, which reached statistical significance for DD subjects only. Liberal sodium intake suppressed PRA and aldosterone levels, without significant differences among the genotypes. For the ID and II genotypes but not the DD genotype, AngII levels were also significantly suppressed by liberal sodium intake. This change was associated with a nonsignificant reduction in plasma potassium levels (−0.17 ± 0.31 mM) with liberal sodium intake among DD subjects, in contrast to slight increases among ID (0.25 ± 0.32 mM) and II (0.12 ± 0.40 mM) subjects. The change in plasma potassium levels with liberal sodium intake for the DD genotype was significantly different, compared with findings for the ID and II genotypes (P < 0.05).

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Table 2.

Baseline characteristics, response parameters during Angl infusion, and recovery data with a low sodium dieta

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Table 3.

Baseline characteristics, response parameters during AngI infusion, and recovery data with a liberal sodium dieta

The absolute values for BP, renal hemodynamic parameters, and hormonal parameters recorded before, during, and after (recovery data recorded after 2 h of washout, at 4:00 p.m.) AngI infusion are presented in Tables 2 and 3. The percent changes from baseline values are presented in Figures 1 and 2. With low sodium intake, the changes from baseline values with both doses of AngI were similar for the genotypes, with comparable increases in MAP, ERPF, RVR, AngII levels, and aldosterone levels. The reductions in GFR and PRA were also similar for the genotypes. However, with liberal sodium intake, a significant difference in the responses to AngI (8 ng/kg per min) was apparent among the genotypes (all presented as percent changes ± 95% confidence intervals). The increase in MAP was significantly higher for the DD genotype (P = 0.002, by repeated-measures ANOVA), with a mean increase of 22 ± 2% (DD genotype), compared with 13 ± 5% (ID genotype) and 12 ± 6% (II genotype). The renal hemodynamic responses to AngI were significantly different, with a decrease in GFR of 17.9 ± 4.7% (DD genotype), compared with 8.8 ± 3.4% (ID genotype) and 6.4 ± 5.9% (II genotype) (P < 0.05), and a mean increase in RVR of 100.1 ± 19.7% (DD genotype), compared with 73.0 ± 16.3% (ID genotype) and 63.2 ± 16.9% (II genotype) (P < 0.05). Also, the increase in aldosterone levels during AngI infusion was significantly greater for the DD genotype, with an increase of 650 ± 189% (DD genotype), compared with 343 ± 71% (ID genotype) (P < 0.05) and 254 ± 99% (II genotype) (P = <0.0001). In contrast, the decreases in ERPF and PRA and the increases in AngII levels were comparable among the genotypes. All responses to AngII were similar for the genotypes during infusion of AngII, with both the low-sodium and liberal-sodium diets (Figures 1 and 2).

Figure1

Figure 1. Mean arterial pressure (MAP), renal vascular resistance (RVR), GFR, and effective renal plasma flow (ERPF) responses (mean percent changes ± 95% confidence intervals) to infusions of angiotensin I (AngI) and AngII (4 and 8 ng/kg per min), with a low-sodium (□) and liberal-sodium (▪) diet. *P < 0.05.

Figure2

Figure 2. Aldosterone concentration, AngII concentration, and plasma renin activity (PRA) responses (mean percent changes ± 95% confidence intervals) to infusions of AngI and AngII (4 and 8 ng/kg per min), with a low-sodium (□) and liberal-sodium (▪) diet. *P < 0.05.

Discussion

This study is the first to provide data on the effects of ACE genotypes on renal responses to AngI among healthy subjects. With liberal sodium intake, the responses of GFR and RVR, as well as the responses of BP and aldosterone levels, to AngI were enhanced for the DD genotype. Dietary sodium restriction, which was studied in the same individuals, eliminated the differences among the genotypes, suggesting gene-environment interactions between sodium status and ACE genotype.

To date, data on ACE genotypes and renal hemodynamics have been reported only for diabetic subjects (33,34). Data for patients with early diabetes mellitus suggested that ACE genotypes might be relevant to renal hemodynamics (33,34). Because glycemic status interacts with the effects of ACE genotypes on renal hemodynamics (35), however, the significance of those findings for nondiabetic subjects was unclear. For our healthy volunteers, renal hemodynamic parameters did not differ among the genotypes with either sodium intake level. With liberal sodium intake, ERPF responses did not differ among the genotypes but, because of the larger increase in MAP, the increase in RVR was significantly more pronounced for DD subjects. Remarkably, despite the higher BP, the decrease in GFR was also larger. This finding suggests that the differences among the genotype groups are attributable to differences in afferent arteriolar (or mesangial) responses to AngI.

The enhanced aldosterone response to AngI that we observed for the DD subjects with liberal sodium intake has not been previously observed (21–23,36). Previous studies did not standardize dietary sodium intake, however, and the reported 24-h sodium excretion was lower than that under our liberal sodium conditions, ranging from 100 to 150 mmol/d. Because our data suggest that liberal sodium intake is a prerequisite for differences in AngI responses among the genotypes, the lower sodium intake may partly explain the discrepancy with our findings. However, previous studies also did not standardize potassium intake (which affects aldosterone responsiveness) (37,38), which hampers direct comparisons with our data. Recent data for patients with heart failure, demonstrating an association between the DD genotype and aldosterone escape during ACE inhibition (39), can be considered in line with our data and indicate the possible clinical relevance of our findings. PRA was expected to be more downregulated in the DD genotype during AngI infusion. There was a distinct trend toward such a difference, with PRA being suppressed to approximately one-half of its baseline value for the II and ID genotypes but to one-third of its baseline value for the DD genotype. However, with our protocol, PRA suppression was not a sensitive parameter for detection of differences in AngI-elicited responses, because PRA values during AngI infusion were near the lower limit of detection for several patients in the II/ID groups as well. That condition hampered the detection of statistical differences in PRA downregulation among the genotype groups.

Therefore, with liberal sodium intake, responses to AngI of three unrelated parameters, namely BP, GFR, and aldosterone levels, were enhanced among DD subjects. Increased AngI responses could reflect enhanced conversion of AngI or increased responsiveness to AngII. In accordance with previous studies, we observed no differences in AngII responses among the genotypes (21,40,41). It could be argued that our study design does not exclude carryover from the AngI infusion. However, after withdrawal of AngI, BP and renal hemodynamic parameters quickly returned to baseline values and remained stable during the 2-h washout period. Taken together with findings from previous studies, these data render it unlikely that differences in AngII sensitivity account for the differences in AngI responses.

As anticipated, plasma ACE levels were highest for the DD genotype. It would be logical to assume that this finding could account for increased AngI responses, with the generation of more AngII from a given dose of AngI. However, plasma AngII levels during infusion of AngI were similar for the genotypes. Ueda et al. (21,36) and Brown et al. (42) reported higher plasma AngII levels during AngI infusion among DD subjects but only with the use of higher doses of AngI, compared with this study. During the infusion of doses comparable to ours, the pressor response to AngI was enhanced among DD subjects (21,36), without differences in plasma AngII levels. Apparently, the pressor response to AngI can be enhanced without detectable differences in plasma AngII levels. It has been pointed out, however, that the value of plasma AngII levels as an index of the conversion of AngI to AngII is relatively limited without an index of AngII clearance (43).

Increased tissue AngI conversion should also be considered. It is usually assumed that renin, and not ACE activity, is rate-limiting for the generation of AngII. However, recent data suggest that elevated ACE activity can have pathophysiologic consequences. Transfection of vascular smooth muscle cells with human ACE has been demonstrated to result in an increased wall/lumen AngII concentration ratio, indicating that overexpression of tissue ACE is associated with biologic effects (44). Other authors reported similar findings (45). Also, among human subjects with myocardial infarctions and increased cardiac ACE expression, de novo cardiac AngI production and the fractional conversion to AngII are both increased (46). Other evidence for the biologic relevance of differences in ACE activity was presented in a recent study by Gainer et al. (47). The absence of differences in plasma ACE activity among ACE genotypes, as observed for black subjects, was associated with diminished differences in vasodilator responses to bradykinin among the different ACE genotypes. In contrast, white subjects with the DD genotype do exhibit higher ACE activity; in that group, the response to bradykinin was clearly attenuated among DD subjects.

Among human subjects, infusion of equimolar doses of AngI and AngII elicited similar MAP and aldosterone responses, despite lower AngII levels during AngI infusion, suggesting that AngII formation at the tissue level contributes to the responses to AngI (48). For the DD genotype, enhanced vasoconstrictor responses to AngI were observed in isolated human blood vessels (40) and in forearm blood flow measurements (41), in the absence of differences in AngII responses and without significant differences in plasma AngI levels (41). These studies suggest that differences in the vascular conversion of AngI can account for the increased systemic and renal vascular responses to AngI in the DD genotype.

Interestingly, the differences in AngI responses among the genotypes were abolished with low sodium intake. This was observed for parameters for which low sodium intake is known to blunt the angiotensin response, i.e., BP and GFR, as well as for aldosterone levels, for which low sodium intake is known to enhance the response to angiotensin. It could be argued that our study had insufficient power to substantiate the null finding with low sodium intake. However, the observations with low versus liberal sodium intake were recorded among the same individuals, and the confidence intervals of the responses were comparable for low and liberal sodium intakes. Consequently, the power to detect differences among the genotypes was similar for the two sodium intake levels. Taken together with the concordance of the effects of sodium on three independent parameters, we consider it likely that the blunting of the differences among the genotypes with low sodium intake is genuine. We cannot exclude the possibility, however, that a much larger study could detect small differences among the genotypes with low sodium intake.

The effects of sodium on the phenotype in ACE I/D polymorphism are in line with our findings for proteinuric patients, for whom a poor response to ACE inhibition for DD homozygotes was observed only among subjects ingesting excess sodium (24). Therefore, liberal sodium intake may be a prerequisite for expression of the unfavorable phenotype not only among healthy subjects but also among patients with relevant clinical conditions. In this study, we did not specifically investigate the mechanism of the interaction of sodium status with genotype, but some clues can be derived from the literature. Ueda et al. (21,36) observed greater pressor responses to AngI among DD homozygotes ingesting approximately 150 mmol sodium/d. Lachurié et al. (22), however, observed no differences in AngI responses among subjects pretreated with renin inhibition, to eliminate the effects of differences in background RAS activity. Taken together with our finding that sodium intake (which modifies background RAS activity) is a determinant of differences among the genotypes, those findings suggest that sodium-dependent differences in background RAS activity are relevant to differences in AngI responses among the genotypes.

What differences in background RAS activity or function could be involved? In accord with other studies, preinfusion values of plasma RAS hormone levels were not different among the genotypes. However, a comparison of low and liberal sodium intake data suggests that ACE genotypes might exert effects on the response of the RAS to altered sodium intake. The shift from low to liberal sodium intake did not alter plasma AngII levels for the DD genotype alone. If this finding indicates facilitated generation (or reduced breakdown) of AngII with liberal sodium intake or hampered AngII generation (or enhanced breakdown) with low sodium intake, then this would be consistent with enhanced responses to AngI with liberal but not low sodium intake. This finding may seem to be at variance with the lack of differences in plasma AngII concentration increases during AngI infusion but, as noted above, interpretation of plasma AngII levels during AngI infusion is difficult. Plasma aldosterone levels were adequately suppressed during liberal sodium intake irrespective of genotype, which may seem to be at variance with the relatively fixed plasma AngII levels among DD subjects. However, liberal sodium intake elicited a small but significant decrease in plasma potassium levels for the DD genotype alone. Lower plasma potassium levels decrease aldosterone concentrations (37,38), and this may have accounted for the adequate net suppression of aldosterone levels in the DD genotype with liberal sodium intake, despite inadequate AngII suppression. An effect of genotype on the adaptation to altered sodium intake is also suggested by the higher body weights during liberal sodium intake among DD subjects, indicating excess sodium retention among these subjects. However, further study, including assessments of sodium and potassium balances during the shift in sodium intake, would be needed to support these assumptions.

Plasma ACE activity was not affected by sodium status in any genotype. Whether sodium status could affect tissue ACE activity among human subjects, with possible differences among genotypes, is unknown. Interestingly, Boddi et al. (49) recently observed that fractional AngI conversion in the peripheral vascular bed among human subjects was higher during liberal sodium intake than during low sodium intake, which could be of relevance to our findings, but the effect of ACE genotype was not evaluated in their study. Finally, it has long been known (and is confirmed by the data presented here) that low sodium intake blunts the systemic and renal vascular responsiveness to angiotensin, with a reciprocal increase in the adrenal responsiveness (37). In view of the opposing effects of sodium intake on hemodynamic and adrenal sensitivity to angiotensin, it seems unlikely that sodium-induced alterations in the responsiveness to angiotensin account for the effects of low sodium intake on the differences among the genotypes, because those effects were observed for both hemodynamic and adrenal responses.

In conclusion, with a sodium intake that is approximately normal for a western industrialized society, the responses of BP and renal function, as well as aldosterone levels, to a pharmacologic dose of exogenous AngI were enhanced for the DD genotype. This suggests that the elevated ACE levels in the DD genotype could have functional significance under specific conditions. Dietary sodium restriction blunts the differences among the genotypes. Further studies are needed to investigate whether sodium status also modifies clinical phenotypic characteristics of ACE genotypes and to determine whether sodium restriction could be used as an intervention strategy to modify unfavorable phenotypic characteristics of the DD genotype.

Acknowledgments

We are indebted to Aly Drent-Bremer, Marja van Kammen, Alex Kluppel, Floris Wachters, Jan Wouter Brunings, and Robert Kalksma for skillful technical assistance and to Berta Beusekamp for dietary advice. This study was supported by a study grant from the Jan Kornelis de Cock Foundation (Project 97-27).

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Enhanced Responses of Blood Pressure, Renal Function, and Aldosterone to Angiotensin I in the DD Genotype Are Blunted by Low Sodium Intake
Frank G. H. van der Kleij, Paul E. de Jong, Rob H. Henning, Dick de Zeeuw, Gerjan Navis
JASN Apr 2002, 13 (4) 1025-1033;
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