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(Hypertension. 2000;36:411.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Angiotensin II Sensitivity Is Associated With the Angiotensin II Type 1 Receptor A¹¹⁶⁶C Polymorphism in Essential Hypertensives on a High Sodium Diet

Wilko Spiering; Abraham A. Kroon; Monique M. J. J. Fuss-Lejeune; Mat J. A. P. Daemen; Peter W. de Leeuw

From the Departments of Internal Medicine (W.S., A.A.K., M.M.J.J.F-L., P.W. de L.) and Pathology (M.J.A.P.D.), Cardiovascular Research Institute Maastricht, Maastricht University and University Hospital Maastricht, Netherlands.

Correspondence to Peter W. de Leeuw, University Hospital Maastricht, Department of Internal Medicine, PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail P.deleeuw{at}intmed.unimaas.nl

	Abstract

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Abstract—Several investigations have shown heterogeneity in the functional responses to angiotensin II (Ang II) in patients with essential hypertension. The present study was initiated to evaluate whether the A¹¹⁶⁶C polymorphism of the Ang II type 1 receptor (AT₁R) gene contributes to this variability in Ang II responses. After 7 days of a high-sodium diet (220 mmol Na⁺ per day), we measured in 42 essential hypertensive patients blood pressure, heart rate, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), active plasma renin concentration, aldosterone, and atrial natriuretic peptide (ANP) before and during Ang II infusion (increasing doses of 0.3, 1.0, and 3.0 ng/kg per minute). Calculated variables were filtration fraction and renal vascular resistance (RVR). Patients in the 3 genotype groups (AA: n=14; AC: n=17; CC: n=11) were matched for gender, age, and body mass index. At baseline, CC patients had decreased GFR (P=0.06) and aldosterone (P<0.05) and increased ANP (P<0.05) compared with AA patients. Moreover, responses of ERPF, GFR, and RVR to the lowest concentration of Ang II (0.3 ng/kg per minute) were more pronounced in CC patients than in AA patients (ERPF/GFR: P<0.05; RVR: P=0.07), whereas maximal responses were all comparable between the groups. Heart rate was decreased at all levels of Ang II infusion in CC patients, while it did not change in AA or AC patients. There were no differences in responses of active plasma renin concentration, aldosterone, and ANP to Ang II between the 3 groups. From these data, we conclude that the C allele of the AT₁R A¹¹⁶⁶C polymorphism is associated with increased sensitivity but not reactivity to Ang II. An augmented response to Ang II may well be responsible for the increased incidence of cardiovascular abnormalities found in patients with 1 or 2 C alleles.

Key Words: angiotensin II • receptors, angiotensin II • polymorphism

	Introduction

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One of the striking features of essential hypertension is the heterogeneity of patients’ responses to angiotensin II (Ang II).¹ This is apparent not only in situations in which the formation or action of endogenous Ang II is blocked but also when exogenous Ang II is administered. In addition to interindividual differences in responses to Ang II, there is marked variability in tissue sensitivity to this peptide. For instance, we and others have shown that the kidney is more sensitive to Ang II than the systemic vasculature and that an enhanced responsiveness cannot be explained satisfactorily from differences in plasma levels of Ang II.^{2 3} Ultimately, however, it is the Ang II type 1 receptor (AT₁R) that translates angiotensin stimulation into a (patho)physiological response. Recently, it was found that the A¹¹⁶⁶C polymorphism of the AT₁R gene is associated with essential hypertension⁴ and myocardial infarction.⁵ The C allele of this polymorphism even shows a synergistic interaction with the D allele of the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism with respect to the risk of myocardial infarction.⁶ In addition, the C allele seems to be an independent determinant of aortic stiffness.⁷ Although these studies suggest that the A¹¹⁶⁶C AT₁R polymorphism contributes to cardiovascular disease, the exact role of this polymorphism in the pathophysiology of hypertension is as yet unclear. Moreover, no unequivocal data exist to show that this polymorphism may account for (part of) the variability in responsiveness to exogenous Ang II, especially with regard to renal hemodynamics. Therefore, we conducted a study in which we investigated the possible influence of the A¹¹⁶⁶C polymorphism of the AT₁R on the reactivity to Ang II in hypertensive patients. To this end, we measured systemic and renal hemodynamic responses as well as humoral changes during infusion of graded doses of Ang II. Studies were performed under conditions of high salt intake, because this augments the responsiveness to exogenous Ang II.^{8 9} Because patients with the CC genotype run an increased risk of cardiovascular complications, we hypothesized that C allele carriers exhibit an increased responsiveness to Ang II.

	Methods

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Patients
A genetic database of hypertensive patients was screened for those with the relatively rare CC genotype of the AT₁R A¹¹⁶⁶C polymorphism. Eleven patients with this genotype were selected. Subsequently, the database was searched for patients with the AA and AC genotype to match with the selected CC patients for age, gender, and body mass index. Secondary hypertension was excluded on the basis of clinical and laboratory evaluation, as well as renal angiography if necessary. All 42 selected patients (14 AA, 17 AC, 11 CC) gave written informed consent to participate in the study. The study was approved by the Medical Ethics Committee of the University Hospital Maastricht.

Genetic Analysis
DNA was extracted from whole blood with the use of the QIAamp Blood Kit (Qiagen Inc). We adopted the mutagenically separated polymerase chain reaction (PCR) technique¹⁰ to determine the genotype of the AT₁R A¹¹⁶⁶C mutation. Briefly, 2 allele-specific primers and their nonselective complementary strand primer were mixed and used for the PCR amplification in a single reaction. In addition to the base substitution, deliberate differences were introduced into the allele-specific primers. In that way we were able to drastically reduce cross-reactions between 2 allelic PCRs in a mixed reaction. The following primers were used: •FP1166A, 5'-CTC TGC AGC ACT TCA CTA CCA AAT GAT CA-3' •FP1166C, 5'-GAA GGA GCA AGA GAA CAT TCG ACT GCA GCA CTT CAC TAC CAA ATG AGA C-3' •RP1166, 5'-TGC CGA CGA GCT TCT TGT TAC AGT CTT T-3' (deliberated differences and base substitutions are underlined). The sizes of PCR products were 190 and 210 bp for the ¹¹⁶⁶A and ¹¹⁶⁶C alleles, respectively. These products were resolved on a 3% agarose gel.

Ang II Infusion Protocol
Patients were investigated after 7 days of high-salt diet (220 mmol Na⁺ per day), with a fixed potassium intake of 80 mmol/d. Compliance with the diet was checked by measuring sodium, potassium, and creatinine output in 24-hour urine collections obtained during the last day of the dietary period. Antihypertensive medication had been stopped 2 weeks before the start of dietary intervention. Patients refrained from nicotine, alcohol, caffeine, and caffeinelike substances from 8 PM the evening before the measurements. Experiments started at 8:30 AM after an overnight fast, and patients remained supine during the entire session. In both arms an antecubital vein was cannulated with a 20-gauge cannula. The cannula in the right arm was connected to a 3-way tap for the infusion of Ang II and para-aminohippurate (PAH)/inulin (for measuring renal hemodynamics), whereas the cannula in the left arm was used for blood sampling. To ensure diuresis, subjects consumed 200 mL of water every hour until the last blood samples had been drawn. After a 2-hour equilibration period, necessary to reach steady state plasma concentrations of PAH and inulin, stepwise increasing doses (0.3, 1.0, and 3.0 ng/kg per minute) of human Ang II (Clinalpha AG) were administered. Each infusion step was continued for 30 minutes to allow renal clearances to reach a new steady state. Blood pressure and heart rate (HR) were measured at 3-minute time intervals, and after each infusion period blood samples were drawn for measurement of PAH, inulin, hematocrit, and plasma levels of Ang II, active plasma renin concentration (APRC), aldosterone, and atrial natriuretic peptide (ANP). Blood samples for measurement of ACE were drawn only at baseline. All samples were stored at -80°C until assay. For each determination, all samples from the same individual were assayed in a single run.

Hemodynamic Methods
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR were measured by a semiautomatic oscillometric device (Dinamap Vital Signs Monitor 1846, Critikon). Renal hemodynamics, ie, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR), were measured as the clearance of PAH (Merck Sharp & Dohme) and inulin (Inutest, Laevosan Gesellschaft), respectively, with the continuous infusion method.¹¹ Both variables were corrected for body surface area and expressed as mL/(min · 1.73 m²). Effective renal blood flow (ERBF) was calculated by the following formula: ERPF/(1-hematocrit). Filtration fraction (FF) was calculated as GFR/ERPF. Renal vascular resistance (RVR) was calculated according to the following formula: (MAP/ERBF)x80.000 and expressed in dyne · s/cm⁵.

Assay Methods
Active plasma renin concentration was measured by a 2-site direct immunoassay (Nichols Institute Diagnostics).¹² For measuring Ang II, blood samples were collected in tubes containing an inhibitor solution to prevent in vitro generation and degradation of this peptide¹³ and spun immediately in a cooled centrifuge. Subsequently, the plasma was quickly frozen in liquid nitrogen. Hereafter, Ang II was determined by ¹²⁵I radioimmunoassay following ethanol extraction (Nichols Institute Diagnostics). Aldosterone was assayed by means of a solid-phase protein binding radioimmunoassay (Diagnostic Products Corporation).¹⁴ ANP was measured by a ¹²⁵I radioimmunoassay (DiaSorin Inc). ACE, PAH, and inulin levels were measured by means of a spectrophotometer.^{11 15} Intracoefficients and intercoefficients of variation of all assays were <10%. All samples from the same individual were assayed in a single run.

Statistical Analysis
Sample size was estimated by use of power calculations on the basis of variances derived from earlier studies. Of all measurements, the assessment of the ERPF has been shown to be the one with the highest SD, in our experience 6.4% in carefully gender- and age-matched subjects. A difference in ERPF >10% can be detected in this study with a power of 0.8. Results are expressed as median±interquartile (25% and 75%) ranges. Because of small samples sizes (n<20), nonparametric tests were used. To compare data between groups (AA, AC, and CC), a 2-step approach was used. First, overall differences between groups were evaluated by means of Kruskal-Wallis ANOVA. When these analyses revealed a significant effect of genotype, data were further tested by pairwise comparisons with the Mann-Whitney U test. To compare the effect of Ang II infusion within groups, data were analyzed by the Friedman test. Furthermore, results were analyzed according to a recessive C allele model (AA/AC patients versus CC patients) and to a dominant C allele model (AA patients versus AC/CC patients). A P value of <0.05 was considered statistically significant. Statistical analyses were performed with SPSS 9.0 for Windows (SPSS Inc).

	Results

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Baseline Characteristics
The baseline characteristics of the 3 genotype groups are summarized in Table 1 and Figure 1. There were no significant differences in age, body mass index, and 24-hour urinary sodium excretion (U_NaV) between the groups. SBP was higher in AC patients than in AA patients (P<0.05). HR was lower in CC patients than in AA patients (P<0.05). GFR in CC patients was slightly lower than in AA patients (P=0.06). In addition, plasma aldosterone was lower in CC patients than in either AA or AC patients (P<0.05, Figure 1, top). Plasma ANP was significantly higher in CC patients than in AA patients (P<0.05, Figure 1, bottom). RVR, ERPF, ERBF, FF, APRC, Ang II, and ACE were comparable in the 3 groups.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Essential Hypertensives on a High-Sodium Diet Genotyped for the AT1R A1166C Polymorphism

View larger version (29K): [in this window] [in a new window]   Figure 1. Top, Baseline plasma aldosterone (median with interquartile ranges). Bottom, Baseline plasma ANP (median with interquartile ranges).

Responses to Ang II
Plasma Ang II levels were comparable for all genotype groups during the different infusion doses of Ang II (Figure 2). The responses of SBP, DBP, HR, ERPF, GFR, and RVR to increasing doses of Ang II are summarized in Table 2. A significant increase during Ang II infusion within all groups was found for SBP, DBP, RVR, Ang II, aldosterone, and ANP, whereas a significant decrease during Ang II infusion within all groups was found for ERPF, ERBF, and APRC. No differences were found between the genotype groups for both SBP and DBP at any dose of Ang II. During infusion of all doses of Ang II, HR showed a decrease in CC patients, while it did not change in AA and AC patients (Figure 3). Borderline significant differences in HR were found between AC and CC patients at 0.3 and 1.0 ng/(kg · min) and between AA and CC at 0.3 and 3.0 ng/(kg · min). At the lowest dose of Ang II, GFR showed a small increase in AA patients, in contrast to a small decrease in CC patients (P<0.05, Figure 4). No differences between the genotype groups were found at the higher doses. ERPF in AA and AC patients did not change at the lowest dose, whereas CC patients showed a marked decrease that was significantly different from the response in AA patients (P<0.05, Figure 5). No differences between the genotype groups were found at the higher doses. The increase in RVR during the lowest dose was more pronounced in CC patients than in AA patients, although not significantly (P=0.07). Again, no differences between the genotype groups were found at the higher doses. There were no differences between the genotype groups with respect to changes in FF, APRC, aldosterone, and ANP during the 3 doses of Ang II.

View larger version (18K): [in this window] [in a new window]   Figure 2. Plasma Ang II (AII) levels during infusion of increasing doses of continuously infused Ang II (median with interquartile ranges).

View this table: [in this window] [in a new window]   Table 2. Responses to Increasing Doses of Ang II in Essential Hypertensives on a High-Sodium Diet Genotyped for the AT1R A1166C Polymorphism

View larger version (18K): [in this window] [in a new window]   Figure 3. Responses of HR to increasing doses of continuously infused Ang II (AII) (median with interquartile ranges).

View larger version (15K): [in this window] [in a new window]   Figure 4. Responses of GFR to increasing doses of continuously infused Ang II (AII) (median with interquartile ranges).

View larger version (21K): [in this window] [in a new window]   Figure 5. Responses of ERPF to increasing doses of continuously infused Ang II (AII) (median with interquartile ranges).

Genetic Model
Comparison of a recessive C allele model (AA/AC patients versus CC patients) with a dominant C allele model (AA patients versus AC/CC patients) showed that the differences described above remained significant only in the recessive model.

	Discussion

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This study investigated the potential role of the AT₁R A¹¹⁶⁶C polymorphism in the renal hemodynamic and humoral responses to Ang II in essential hypertensive patients during a high-sodium diet. Our data show that patients with the CC genotype display an exaggerated response of GFR, ERPF, and RVR to Ang II at a low dose of 0.3 ng/(kg · min) but not at the higher doses used. In addition, we found that CC patients, in contrast to the others, respond to Ang II with an overall decrease in HR. Thus, except for the changes in HR, phenotypic differences between the groups were observed only at the lowest dose when plasma levels of Ang II remain within the physiological range. Because responses to Ang II during the supraphysiological doses of 1.0 and 3.0 ng/(kg · min) were comparable between the genotype groups, our data indicate that sensitivity, but not reactivity to Ang II, is increased in CC patients. These findings are in agreement with observations by others showing increased vascular responsiveness of coronary and internal mammary arteries to different stimuli in patients carrying the C allele.^{16 17}

We did not find any differences between the genotype groups with respect to their humoral responses to Ang II. This is in agreement with the data of Giacche et al,¹⁸ who measured the aldosterone response to Ang II in white hypertensives after a low-salt diet and found no differences between the genotype groups. Unfortunately, they only infused 3.0 ng/(kg · min) and they did not study their patients after a high-salt diet, when the effects of exogenous Ang II are likely to be more pronounced.^{8 9}

Recently, after we had completed our investigation, a study like ours was published in which no differences in response to Ang II between the 3 genotypes were found.¹⁹ However, the authors of that study used a higher initial dose of Ang II: 0.5 ng/(kg · min). This dose may already be too high to find the increased sensitivity to Ang II. Furthermore, the data they presented were based on 15-minute infusions, which could be too short to attain a steady state effect of Ang II. Finally, the heterogeneous population of normotensive and hypertensive subjects in that study could also explain the discrepancies with the results we found.

Although it is not readily apparent why CC patients exhibit an exaggerated renal hemodynamic response to a low dose of Ang II, it may be related to an altered renal sodium handling. Normally, when an individual switches from a low to a high sodium diet, (renal) vascular responsiveness to Ang II increases, with a concurrent decline in adrenal responsiveness.^{8 9} In our study all patients adhered to the same diet, yet CC patients seemed to respond as though they were more salt repleted than the others. In this respect it is striking that already at baseline, patients with the CC genotype had lower plasma aldosterone and higher plasma ANP levels than patients with the AA genotype. Although we did not measure body fluid volumes, the latter combination strongly suggests that, at least after 1 week of high sodium intake, CC patients are relatively hypervolemic. Because we did not study our patients at a low salt intake, we do not know whether this relative hypervolemia is an intrinsic abnormality of CC patients or whether it becomes evident only at a high salt intake. Whatever the case may be, we can only speculate why CC patients apparently fail to adjust their (circulating) volume in response to a high-salt diet. Because tubular reabsorption of sodium is partly regulated by Ang II, it is possible that the responses of renal tubular cells to Ang II are enhanced as well in patients with the CC genotype. Indeed, the fact that CC patients had Ang II levels comparable to those in the other genotype groups but tended to have a lower GFR and ERPF and a higher RVR even before the Ang II infusion was started suggests that these patients may also be hyperresponsive to endogenous Ang II.

A remarkable finding in our data concerns HR, which not only was significantly lower in CC patients than in AA patients before the infusion but also slowed down at all levels of Ang II infusion in CC patients, while it did not change appreciably in the others. All these differences occurred in the face of comparable blood pressures. Therefore, it seems that baroreceptor sensitivity is enhanced in CC patients, which would be in agreement with our "hypervolemia hypothesis." Indeed, if we assume that circulating volume is increased in CC patients, then a baroreceptor-mediated decline in HR would be one mechanism to prevent too much of a rise in blood pressure.

Although several of our data suggest an "allele dose effect," further analysis in which combinations of genotypes were compared (AA versus AC/CC and AA/AC versus CC) points toward a recessive effect of the C allele. This indicates that it is highly probable that the significant results found in CC patients have to be explained by the genotype of the AT₁R A¹¹⁶⁶C polymorphism rather than by chance. It remains elusive, however, why the C allele of this polymorphism is associated with increased sensitivity to Ang II and in the end an increased incidence of cardiovascular disease.^{4 5 6 7 20 21 22 23 24 25 26} Because this polymorphism is located in the uncoding 3' region of the AT₁R gene, it is likely to be in linkage disequilibrium with a mutation nearby, which may affect AT₁R mRNA stability, protein structure and/or function of the AT₁R, number of AT₁Rs, and/or the process of receptor internalization. Poirier et al²⁷ recently performed a rescanning of the AT₁R gene but did not find new variants that could affect the regulation of the gene in response to Ang II.

In conclusion, we have found that the genotype of the AT₁R A¹¹⁶⁶C polymorphism is yet another factor that needs to be taken into account when the effects of Ang II on the kidney are assessed. Increased sensitivity to Ang II may well be associated with a tendency for volume expansion and hence volume-dependent hypertension.

Received January 3, 2000; first decision January 18, 2000; accepted March 10, 2000.

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