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(Hypertension. 1995;25:1266-1269.)
© 1995 American Heart Association, Inc.

Articles

Enhanced Pressor Response to Angiotensin I in Normotensive Men With the Deletion Genotype (DD) for Angiotensin-Converting Enzyme

Shinichiro Ueda; Henry L. Elliott; James J. Morton; John M. C. Connell

From the University Department of Medicine and Therapeutics (S.U., H.L.E.) and MRC Blood Pressure Unit (J.J.M., J.M.C.C.), Western Infirmary, Glasgow, Scotland.

	Abstract

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Abstract The insertion (I)/deletion (D) polymorphism of the human angiotensin-converting enzyme gene has emerged as a genetic risk factor for ischemic heart disease. However, the functional consequences of this polymorphism in humans are not known. Ten normotensive men with the DD genotype and 10 with the II genotype participated in a study in which pressor responses to stepwise infusions of incremental doses of angiotensin I (Ang I) and Ang II and Ang II production during Ang I infusion were measured. Pressor responses were expressed as PD₂₀, which reflects the angiotensin dose required to raise mean blood pressure by 20 mm Hg. The PD₂₀ for Ang I in subjects with the DD genotype was significantly lower than that in II genotype subjects (8.8 versus 14.8 ng/kg per minute, P=.0091), whereas the PD₂₀ for Ang II between the two groups did not differ significantly. The ratio of PD₂₀ for Ang I and Ang II in DD subjects was significantly lower than that in II subjects (0.85 versus 0.96, P=.0452), and the venous levels of Ang II during Ang I infusion in DD subjects were significantly higher than those in II subjects (P<.01). Our study has shown increased pressor responsiveness to Ang I, probably as a consequence of the generation of increased Ang II levels, in subjects homozygous for the DD allele of the angiotensin-converting enzyme gene. This result may be relevant to the reported adverse cardiovascular risk conferred by the D allele, as it provides a mechanistic rationale for the association between this polymorphism and cardiovascular disease.

Key Words: angiotensin-converting enzyme • alleles • angiotensin I • angiotensin II

	Introduction

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It has long been recognized that genetic factors contribute significantly to the development of ischemic heart disease. In particular, there is recent evidence in humans of associations between the insertion/deletion (I/D) polymorphism of the gene encoding human angiotensin-converting enzyme (ACE) and the development, progression, and outcome not only of ischemic heart disease^{1 2 3 4} but also of left ventricular hypertrophy, which is an independent risk factor for ischemic heart disease.⁵ Furthermore, there is evidence that the risk of premature death in hypertensive patients is increased by the presence of the DD genotype.⁶ While genotype may in part control serum ACE activity in humans,^{7 8} there is little information about the functional consequences of the ACE gene polymorphism. Although it might be reasonable to assume that higher levels of ACE activity will lead to higher angiotensin II (Ang II) levels, and the predictable hemodynamic consequences, no data have been published showing that the ACE gene polymorphism is related to either a predisposition to hypertension or higher circulating Ang II concentrations.^{9 10} It is possible, however, that increased Ang II production and enhanced Ang II–mediated effects manifest only when the renin-angiotensin system is activated and plasma Ang I levels are increased. Accordingly, in this study we investigated Ang II generation and systemic pressor response to intravenous administration of Ang I in normotensive men with contrasting ACE genotypes.

	Methods

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Subjects
More than 100 healthy normotensive men who had previously taken part as volunteers in research studies (12 to 18 months before) gave additional written informed consent for blood sampling to allow determination of their ACE genotypes. The ACE gene polymorphism was detected by the polymerase chain reaction (PCR) according to the method of Rigat et al.¹¹ From the subjects who were homozygous for II and DD genotypes, two groups of 10 subjects were identified and matched for age and family history of hypertension. These 20 subjects participated in the angiotensin infusion study after giving further informed consent. The study was approved by the West Ethics Committee of the Greater Glasgow Health Board.

Angiotensin Infusion Study
All subjects were instructed to maintain a normal sodium diet (approximately 150 mmol/d) for 3 days before the study day. After an overnight fast and avoidance of alcohol and caffeine-containing beverages, subjects reported to the clinical investigation and research unit at 8 AM. After insertion of an intravenous cannula into each forearm and a period of not less than 30 minutes of recumbent rest, each subject received stepwise incremental doses of Ang I (CLINALFA AG) and Ang II (CIBA-Geigy) (each administered as 1, 2.5, 5, 10, and 20 ng/kg per minute, 8 minutes for each dose) by intravenous infusion (Braun Infusion Syringe Driver). There was a 1-hour washout period between infusions, and infusion order was randomized. Blood pressure and heart rate were measured each minute by a semiautomated sphygmomanometer (Critikon, Johnson & Johnson Professional Products Ltd), and the increase in blood pressure (from baseline) was calculated for each dose step as the mean of the final five readings. From the dose-response curve of each subject, pressor responses were then characterized by calculation of PD₂₀, ie, the angiotensin dose that increased mean blood pressure by 20 mm Hg. The detailed methodology for the analysis of pressor response studies has been described previously.¹² Blood samples were obtained from the opposite arm before and after each incremental infusion for measurement of ACE activity, Ang II, and aldosterone.

PCR Method
Genomic DNA was extracted from peripheral blood leukocytes by standard methods.^{13 14} The template DNA was amplified by PCR with 10 pmol of each primer (sense, 5'-CAGGAGACCACTCCCATCCTTTCT, and anti-sense, 5'-GATGTGGCCATCACATTCGTCAGAT), 3 mmol/L MgCl₂, commercial PCR buffer without MgCl₂, 0.5 mmol/L of each dNTP, and 1 U Taq polymerase (Ang II reagents from Promega) for 30 cycles at 94°C for 1 minute, 58°C for 1 minute, and 72°C for 2 minutes. The PCR product was visualized after electrophoresis on 1.5% agarose gels with ethidium bromide staining. Reanalysis of genotype with 5% dimethyl sulfoxide added to the reaction confirmed the original assignment.

Analysis of Blood Samples
Plasma Ang II concentrations were measured by radioimmunoassay after extraction with Sep-Pak C18 cartridges.¹⁵ Ang I was also measured to check for cross-reaction in the Ang II assay, although this was less than 0.6%. Ang I levels did not significantly interfere in the Ang II assay, but we took account of any such small interference. Plasma aldosterone concentration was measured by radioimmunoassay.¹⁶ Plasma active renin concentration was measured by radioimmunoassay with the use of an antibody trapping method.¹⁷ Serum ACE activity was measured by high-performance liquid chromatography with the use of an artificial substrate (Hip-His-Leu).¹⁸ Coefficients of variation of assays were all less than 10%.

Statistical Analysis
Data are shown as median and range unless otherwise indicated. Comparison of the two groups was by Mann-Whitney U test with 95% confidence intervals (CI); comparison of the differences in the Ang II and aldosterone levels during Ang I infusion was by repeated-measures ANOVA with 95% CI and Bonferroni correction.

	Results

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Table 1 summarizes the demographic data for the two matched groups of subjects in whom there were no significant differences in smoking habit, body mass index, baseline blood pressure, or urinary sodium excretion.

View this table: [in this window] [in a new window]   Table 1. Demographic Data of Subjects

Activity of the Renin-Angiotensin System at Baseline
Table 2 shows baseline activities and concentrations for the different components of the renin-angiotensin system. ACE activity in the subjects with the DD genotype was significantly higher than in those with the II genotype, whereas baseline aldosterone and active renin concentrations did not differ significantly. Although not attaining conventional statistical significance, basal Ang II levels in the DD subjects tended to be higher than those in the II subjects (with the lower limit of the 95% CI at almost zero). Basal Ang II levels and active renin concentrations were significantly correlated in each group (r²=.589, P<.012 for DD group; r²=.810, P=.000 for II group), with a tendency for the linear regression line of the relationship between renin and Ang II to be steeper in DD subjects than in II subjects (y=0.490x-1.6 versus y=0.236x+0.54). There was no significant correlation between basal ACE activity and Ang II level.

View this table: [in this window] [in a new window]   Table 2. Baseline Renin-Angiotensin System

Pressor Responses to Ang I and Ang II
Fig 1 shows PD₂₀ values for the pressor responses to Ang I and Ang II and also the ratio for the PD₂₀ values for Ang I and Ang II. PD₂₀ for Ang I was significantly lower in DD subjects than in II subjects (8.8 versus 14.8 ng/kg per minute; P=.0091; 95% CI, 1.3-8.7), whereas PD₂₀ for Ang II did not differ significantly between the two groups (15.3 versus 16.5 ng/kg per minute; P=NS; 95% CI, -8.2-4.8). The ratio of Ang I and Ang II PD₂₀ (which represents the PD₂₀ for Ang I adjusted for the pressor response to Ang II) was also lower in the DD subjects than in the II subjects (0.85 versus 0.96; P=.0452; 95% CI, 0.005-0.57).

View larger version (13K): [in this window] [in a new window]   Figure 1. Plots show pressor responses to angiotensin I (a), angiotensin II (b), and the ratio of PD20 for angiotensin I and II (c) in subjects with II () and DD () angiotensin-converting enzyme (ACE) genotypes. Horizontal lines indicate medians. *P=.0091, **P=.0452.

Plasma Ang II Concentrations During Ang I Infusion
Fig 2 shows plasma Ang II concentrations during the incremental Ang I infusion. Ang I infusion significantly increased plasma Ang II concentrations in both groups, but across the dose range, the levels produced in the DD subjects were consistently significantly higher than those in the II subjects (P<.01 by ANOVA). This difference was most apparent at the highest dose of 20 ng/kg per minute (95% CI, 58-118 mol/L).

View larger version (14K): [in this window] [in a new window]   Figure 2. Line graph shows plasma angiotensin II concentrations during angiotensin I infusion in subjects with II () and DD () angiotensin-converting enzyme genotypes. Data are shown as mean and SD. *P<.01 by ANOVA; 95% CI, 58-118 mol/L.

Relationship Between Changes in Plasma Ang II Levels and Mean Blood Pressure
Fig 3 shows the relationship between the changes in plasma Ang II levels and mean blood pressure. In both groups, the change in Ang II levels and the change in blood pressure were significantly correlated (r²=.790, P=.000 for DD; r²=.613, P=.000 for II), with closely similar linear regression equations (y=0.101x+4.2 for DD, y=0.098x+3.6 for II).

View larger version (17K): [in this window] [in a new window]   Figure 3. Scatterplot shows relationships between changes in mean blood pressure and plasma angiotensin II concentration during angiotensin I infusion in subjects with II () and DD () angiotensin-converting enzyme genotypes.

Aldosterone, Active Renin, and ACE Activity
Increases in plasma aldosterone during the Ang I and Ang II infusions did not differ, and serum ACE activity did not change significantly. Plasma active renin concentrations in both groups were significantly reduced after Ang I and Ang II infusions, but there were no significant differences between the two groups.

	Discussion

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The D allele of the ACE gene has been linked with an increased incidence of myocardial infarction and increased mortality.^{1 2 3} However, the pathophysiological mechanisms underlying this association have not been extensively investigated. We have now documented that pressor responses to Ang I were enhanced and higher plasma levels of Ang II were generated in normotensive men with the DD genotype for ACE, suggesting that the DD genotype is associated with higher ACE activity in vivo as well as in vitro. Although plasma renin activity has generally been used as an index for the activity of the renin-angiotensin system, these results indicate that it may be possible for ACE activity to regulate Ang II production, particularly when Ang I levels are high. The reason why the deletion in the 16th intron of the ACE gene is associated with increased ACE activity remains to be determined, and it seems likely that this is in linkage disequilibrium with a causal mutation, possibly in the 5' promoter region, which results in greater ACE expression in tissues.

Our method for the assessment of the systemic effects of Ang I and of in vivo ACE activity is analogous to that used for testing of the effectiveness and duration of action of an ACE inhibitor drug by its ability to attenuate the pressor response to Ang I in humans.¹⁹ Factors other than circulating ACE activity will obviously affect the pressor response to Ang I, but our study design allows us to exclude the potential influence of a differential tissue sensitivity to the generated Ang II; thus, the PD₂₀ for Ang I was adjusted for the PD₂₀ for Ang II to show that the differential response to Ang I was not an indirect reflection of a differential sensitivity to Ang II that might arise because of differences between the two groups in their basal Ang II levels or, for example, by other unknown genetic tissue factors. Additionally, the likelihood of any potential effect of sodium intake on the pressor and aldosterone responses was minimized by prior adherence to a normal sodium diet confirmed by 24-hour urinary Na⁺ excretion before the study. Furthermore, it seems unlikely that the basal activity of the renin-angiotensin system would affect the pressor response to Ang I because the achieved Ang II level during the Ang I infusion was 100 times higher than the basal level. The significantly higher circulating Ang II levels in the course of the Ang I infusion probably explain the enhanced pressor response to Ang I in DD subjects, particularly as the relationships in the two groups between the changes in mean blood pressure and the changes in plasma Ang II levels during Ang I infusion were similar. However, enhanced tissue production of Ang II in the DD subjects²⁰ after local uptake of Ang I obviously could not be estimated in this study, and it is possible that increased local generation of Ang II may explain the increased pressor effect in this group. The increases in Ang II during Ang I infusion achieved a significant treatment-time difference across the entire dose range, but with only the highest dose level studied achieving independent statistical significance. It is possible, therefore, that differences attributable to in vivo ACE activity are most evident when the renin-angiotensin system is activated and that there are relatively high circulating or tissue levels of Ang I.

Although basal Ang II levels in the two groups did not differ significantly, they tended to be higher in the DD subjects. This trend has been previously reported,⁷ although not in all such studies,⁹ and it is consistent with the concept of a greater regulatory contribution of ACE activity to Ang II generation (relative to renin activity) when the renin-angiotensin system is stimulated.

Despite higher plasma levels of Ang II in DD subjects, aldosterone concentrations during Ang I infusion did not differ significantly between the two groups. However, we designed the study principally to assess pressor responses, and the duration of each dose of Ang I was probably insufficient to achieve a steady-state aldosterone response to the generated Ang II.

In conclusion, our study has shown increased pressor responsiveness to Ang I, probably as a consequence of the generation of increased levels of Ang II, in normotensive men with the DD type of the ACE gene. This result may be relevant to the reported adverse cardiovascular risk conferred by the D allele as it provides a mechanistic rationale for the association between the ACE gene polymorphism and cardiovascular disease. Further studies focusing on pharmacological and physiological consequences of the ACE gene polymorphism (including possible differences in kinin metabolism and the responses to ACE inhibitor drugs) will be required to establish whether prevention and treatment of ischemic heart disease can be targeted to those patients.

	Footnotes

 
Reprint requests to Dr H.L. Elliott, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, G11 6NT, Scotland. E-mail h.elliott@udcf.gla.ac.uk.

Received November 15, 1994; first decision December 16, 1994; accepted February 16, 1995.

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