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(Hypertension. 1999;34:171-175.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Angiotensin-Converting Enzyme Inhibition Modifies Angiotensin but Not Kinin Peptide Levels in Human Atrial Tissue

Duncan J. Campbell; Ann-Maree Duncan; Athena Kladis

From St Vincent's Institute of Medical Research, Victoria, Australia.

Correspondence to Dr DJ Campbell, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail j.campbell{at}medicine.unimelb.edu.au

	Abstract

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Abstract—Angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) to angiotensin II (Ang II) and metabolizes bradykinin and kallidin peptides. Decreased Ang II levels and increased kinin peptide levels are implicated in the mediation of the therapeutic effects of ACE inhibition. However, alternative non-ACE pathways of Ang II formation have been proposed to predominate in human heart. We investigated the effects of ACE inhibition on cardiac tissue levels of angiotensin and kinin peptides. High-performance liquid chromatography–based radioimmunoassays were used to measure angiotensin peptides and hydroxylated and nonhydroxylated bradykinin and kallidin peptides in right atrial appendages of subjects who had been prepared for cardiopulmonary bypass. Peptide levels in subjects who received ACE inhibitor therapy were compared with those who did not receive ACE inhibitor therapy. ACE inhibition reduced Ang II levels, which was associated with an 80% reduction in the Ang II/Ang I ratio. ACE inhibition did not modify either bradykinin or kallidin peptide levels or the bradykinin-(1-7)/bradykinin-(1-9) ratio. The 80% reduction in the Ang II/Ang I ratio by ACE inhibition indicated a primary role for ACE in the conversion of Ang I to Ang II in atrial tissue. These data support a role for reduced Ang II levels but do not support a role for increased kinin peptide levels in mediating the direct cardiac effects of ACE inhibition.

Key Words: angiotensin • bradykinin • kallidin • angiotensin-converting enzyme • heart

	Introduction

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Inhibitors of angiotensin-converting enzyme (EC 3.4.15.1, ACE) are valuable therapy for cardiac failure because they can attenuate ventricular remodeling and reduce mortality in heart failure patients. Although some of these benefits may be due to systemic actions, ACE inhibitors also have direct cardiac and vascular effects. Intracoronary administration of ACE inhibitors increases coronary flow and improves diastolic function, although there may be a negative inotropic effect in some patients.^{1 2} In experimental models, ACE inhibitors reduce cardiac hypertrophy and induce myocardial capillary proliferation in situations in which afterload is not reduced.^{3 4}

ACE converts the inactive angiotensin I (Ang I) to angiotensin II (Ang II) and metabolizes kinins. Decreased Ang II levels and increased kinin levels have been implicated in mediating the therapeutic effects of ACE inhibition. However, controversy exists over the role of ACE in Ang II formation in the human heart, and the effect of ACE inhibition on local cardiac Ang II levels remains unknown. On the basis of in vitro studies, Urata et al^{5 6} proposed that ACE mediates only 11% of Ang II formation in human heart and that human heart chymase, an enzyme resistant to inhibition by ACE inhibitors, is primarily responsible for cardiac Ang II formation. If the chymase were the major pathway of Ang II formation in the heart, then ACE inhibition would not decrease cardiac Ang II levels and might even increase cardiac Ang II levels because of chymase-mediated conversion of the increased plasma Ang I levels that accompany ACE inhibition.⁷ In contrast to the studies of Urata et al,^{5 6} Zisman et al⁸ reported that ACE accounts for 89% of Ang I conversion to Ang II across the coronary vascular bed.

The effect of ACE inhibition on local cardiac kinin levels is also unknown. Current understanding of kinin peptide formation in humans is that tissue kallikrein forms kallidin [Lys⁰-BK-(1-9), KBK-(1-9)] from low-molecular-weight kininogens (LMWKs) and high-molecular-weight kininogens (HMWKs), whereas plasma kallikrein forms bradykinin [BK-(1-9)] from HMWKs. ⁹ Moreover, a proportion of HMWKs is hydroxylated on proline³ [Hyp³ of the BK-(1-9) sequence],¹⁰ and both hydroxylated and nonhydroxylated kinins are derived from HMWKs. The kininase I metabolites of BK-(1-9) and KBK-(1-9) are BK-(1-8) and KBK-(1-8), which are also bioactive, whereas the ACE metabolites BK-(1-7) and KBK-(1-7) are inactive.

In the present study, we investigated the effects of ACE inhibition on angiotensin and kinin peptide levels in the right atrial appendage of patients undergoing preparation for cardiopulmonary bypass procedures. We used high-performance liquid chromatography (HPLC)–based radioimmunoassays (RIAs) to measure Ang II, Ang I, angiotensin-(1-7) [Ang- (1-7)], angiotensin-(1-9) [Ang-(1-9)], and hydroxylated and nonhydroxylated BK-(1-9) and KBK-(1-9) and their metabolites. In addition to measurement of absolute peptide levels, we also calculated the Ang II/Ang I ratio, an index of Ang I conversion to Ang II, and the BK-(1-7)/BK-(1-9) and KBK-(1-7)/KBK-(1-9) ratios, which are indices of BK-(1-9) and KBK-(1-9) metabolism to BK-(1-7) and KBK-(1-7), respectively.

	Methods

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Subjects
Right atrial appendages were obtained from 49 subjects, 42 men and 7 women, undergoing elective procedures that required cardiopulmonary bypass. The mean age of subjects was 64 years (range, 33 to 84 years). Forty subjects had coronary artery grafts performed for ischemic heart disease, 5 subjects had both coronary artery grafts and aortic or mitral valve surgery, and 4 subjects had only aortic or mitral valve surgery. None of the subjects had undergone previous cardiac surgery. Twenty subjects were receiving ACE inhibitor therapy before their admission to hospital. For 13 subjects, the ACE inhibitor was administered on the morning of surgery, 4 to 8 hours before surgery; for the other 7 subjects, the ACE inhibitor was administered on the morning of the day before surgery, 26 to 30 hours before surgery. Subjects received enalapril (12 subjects, 2.5 to 20 mg/d), lisinopril (3 subjects, 2.5 to 5 mg/d), ramipril (2 subjects, 2.5 to 5 mg/d), captopril (1 subject, 25 mg/d), fosinopril (1 subject, 20 mg/d), and trandolapril (1 subject, 1 mg/d). This study was approved by the Human Research Ethics Committee of St Vincent's Hospital (Victoria, Australia).

Extraction and HPLC of Angiotensin and Kinin Peptides
At the time this study was performed, it was routine procedure for the tip of the right atrial appendage to be excised and discarded before insertion of the venous lines for cardiopulmonary bypass. In the present study, a clamp was placed across the tip of the appendage, which was rapidly excised with scissors, briefly but thoroughly rinsed in ice-cold 0.15 mol/L sodium chloride to remove blood, and immediately dropped into liquid nitrogen. Appendages were stored at -80°C. The mean weight of appendages was 0.5 g (range, 0.2 to 1.4 g). The frozen appendages were pulverized in dry ice, then homogenized in 4 mol/L guanidine thiocyanate/1% trifluoroacetic acid (GTC/TFA), and extracted with Sep-Pak C₁₈ cartridges (Waters Chromatography Division).¹¹ Particular precaution was taken to prevent thawing of the tissue before homogenization. We have previously shown that this methodology prevents artifactual generation or degradation of peptides during sample processing.¹² Tissue extracts were extracted with diethyl ether before acetylation and piperidine treatment, and HPLC was performed as described elsewhere.¹¹ Most tissues were processed within 3 weeks of collection; no differences existed in the duration of storage at -80°C between tissues collected from subjects who received ACE inhibitor therapy and those who did not receive ACE inhibitor therapy. Moreover, there was no relationship between the duration of storage and peptide levels.

Peptide RIA
Angiotensin, bradykinin, and kallidin peptides were measured with N-terminal–directed RIA. Angiotensin and bradykinin peptides were measured as described previously with antibodies A41 and B24, respectively.¹¹ The cross-reactivities, recoveries, and minimum detectable amounts are shown in Table 1. Antibody B24 cross-reacted with Hyp³-bradykinin peptides, which allowed the measurement of both hydroxylated and nonhydroxylated bradykinin peptides (Table 1). Kallidin peptides were measured with antibody K10, which was raised in a rabbit immunized with ,-acetyl-Lys⁰-Hyp³-Lys⁹–BK-(1-9) conjugated by the C-terminal lysine residue to bovine thyroglobulin with glutaraldehyde. Tracer for this RIA was ¹²⁵I-labeled acetyl-Lys⁰-Hyp³-Tyr⁸–BK-(1-9). The K10 RIA had a sensitivity of 0.2 fmol/tube. Full details of the development and validation of this RIA will be reported elsewhere (A.M. Duncan, A. Kladis, G.L. Jennings, A.M. Dart, M. Esler, D.J. Campbell, unpublished data, 1999). Antibody K10 had similar cross-reactivities for kallidin and Hyp³-kallidin peptides (Table 1). Data were corrected for antibody cross-reactivity and peptide recovery.

View this table: [in this window] [in a new window]   Table 1. Cross-Reactivities, Recoveries, and Minimum Detectable Amounts for RIA of Angiotensin and Kinin Peptides in HPLC Fractions

Angiotensin peptide recoveries shown in Table 1 are from Reference 13. Recoveries were determined by adding standard peptides to extracts of rat hearts as described elsewhere^{11 13} and represent recoveries through the whole assay procedure, including Sep-Pak extraction, ether extraction, acetylation, piperidine treatment, and HPLC.

Statistical Methods
For angiotensin data, comparisons between subjects without ACE inhibition and those who received ACE inhibitor 4 to 8 hours or 26 to 30 hours before surgery were by ANOVA, with the Dunnett test for multiple comparisons with the control. For bradykinin and kallidin data, comparisons between subjects with and without ACE inhibitor therapy were by unpaired t test. When more than half of the samples that composed a mean had values below the minimum detectable, the sample mean is shown as less than the minimum detectable. When values were below the minimum detectable, they were set at half the minimum detectable for statistical calculations. Logarithmic transformation of the data was performed when required to obtain similar variances among groups. All tests were 2-tailed. Differences were considered significant at P<0.05. Statistical analyses were performed with SuperANOVA (Abacus Concepts).

	Results

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The elution positions of acetylated angiotensin, bradykinin, and kallidin peptides from HPLC of representative atrial extracts are shown in Figure 1.

View larger version (22K): [in this window] [in a new window]   Figure 1. Line graphs show HPLC elution positions of acetylated angiotensin, bradykinin, and kallidin peptides in representative atrial extracts.

Angiotensin Peptides
Angiotensin peptides were measured in atrial appendages from 25 subjects, 11 of whom received ACE inhibitor therapy. ACE inhibitor subjects received enalapril (5 subjects), lisinopril (3 subjects), or captopril, fosinopril, or ramipril (1 subject for each drug). Ang II and Ang I were readily identified in atrial appendage extracts (Figures 1 and 2), but Ang-(1-7) and Ang-(1-9) levels were below the minimum detectable (<8 and<7 fmol/g, respectively). ACE inhibition reduced Ang II levels in subjects who received ACE inhibitor therapy 4 to 8 hours before surgery, but the reduction in Ang II levels was not statistically significant when ACE inhibitor administration was 26 to 30 hours before surgery. However, there were similar, statistically significant reductions of 80% in the Ang II/Ang I ratio at both times after an ACE inhibitor was administered (Figure 2).

View larger version (12K): [in this window] [in a new window]   Figure 2. Bar graphs show levels of Ang II, Ang I, and the Ang II/Ang I ratio in extracts of right atrial appendage from control subjects (n=14) and subjects who received ACE inhibitor therapy either 4 to 8 hours (A, n=6) or 26 to 30 hours (B, n=5) before surgery. Data shown as mean±SEM. *P<0.05; **P<0.01 vs control values as determined by the Dunnett test.

Bradykinin Peptides
Bradykinin peptides were measured in atrial appendages from 10 subjects, 4 of whom received enalapril 4 to 8 hours before surgery. Although the levels were low, both nonhydroxylated and Hyp³-bradykinin peptides were detected in atrial appendage extracts (Figure 1). ACE inhibition did not modify bradykinin peptide levels or the BK-(1-7)/BK-(1-9) ratio (Table 2).

View this table: [in this window] [in a new window]   Table 2. Kinin Peptide Levels in Human Right Atrial Appendage

Kallidin Peptides
Kallidin peptides were measured in atrial appendages from 19 subjects, 5 of whom received ACE inhibitor therapy. ACE inhibitor subjects received enalapril (3 subjects), ramipril (1 subject), or trandolapril (1 subject). ACE inhibitor was administered 4 to 8 hours before surgery in 3 subjects and 26 to 30 hours before surgery in 2 subjects. Given that a similar inhibition of ACE, as indicated by the Ang II/Ang I ratio, was seen when ACE inhibitors were administered 4 to 8 hours and 26 to 30 hours before surgery, kallidin peptide data were pooled for the 5 subjects who received ACE inhibitor therapy. Kallidin peptide levels were close to or below the minimum detectable and Hyp³-kallidin peptides were below the minimum detectable (Figure 1, Table 2). ACE inhibition did not modify kallidin peptide levels (Table 2).

	Discussion

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This is the first report of angiotensin and kinin peptide levels in human cardiac tissue. Our finding that ACE inhibition reduced atrial tissue Ang II levels and the Ang II/Ang I ratio indicates that ACE is the main pathway of Ang I conversion to Ang II in this tissue and supports a role for reduced cardiac Ang II levels in mediating the therapeutic effects of ACE inhibition. Moreover, we found no effect of ACE inhibition on kinin peptide levels, which suggests that the therapeutic effects of ACE inhibition are not mediated by alteration of kinin peptide levels in cardiac tissue.

We chose to study the right atrial appendage because it could be rapidly removed with a minimum of dissection and trauma to the tissue. This is of importance because tissue trauma can activate kallikrein, which leads to artifactual generation of kinin peptides. Moreover, delay in tissue removal can lead to alteration of tissue peptide levels as a result of peptide generation and metabolism. Subjects were fully anticoagulated, which further reduced the potential for activation of plasma kallikrein. In addition, tissue was rapidly rinsed in ice-cold 0.15 mol/L sodium chloride to remove contaminating blood before it was frozen in liquid nitrogen, and frozen tissue was not allowed to thaw before extraction with GTC/TFA. Our methodologies have been extensively validated in previous studies of angiotensin and bradykinin peptide levels in rat tissues.^{11 12 14}

We previously showed that the Ang II/Ang I ratio was a sensitive indicator of the effects of ACE inhibition on angiotensin peptide metabolism.¹⁴ Our finding that ACE inhibition produced an 80% decrease in the atrial Ang II/Ang I ratio is similar to our previous finding that ACE inhibition reduced the plasma Ang II/Ang I ratio in humans by 89%.⁷ Also, our study is in agreement with the study by Zisman et al,⁸ who reported that ACE inhibition reduced Ang I conversion to Ang II by 89% in the coronary vascular bed. ACE mRNAs and protein have been identified in human heart,^{15 16} which provides support for a role for ACE in Ang I conversion. Moreover, Zhuo et al¹⁷ reported that the ACE inhibitor perindopril, at 4 mg/d, inhibited ACE in both the endothelium and adventitia of the internal mammary artery of subjects undergoing coronary artery grafts. The role of human heart chymase in cardiac conversion of Ang I to Ang II in vivo remains to be established. Because ACE levels are highest in the atria, whereas chymase levels are highest in ventricles, Urata et al⁶ proposed that the chymase may play a greater role in Ang II formation in ventricles than in atria. Chymase protein and mRNA are reportedly expressed in endothelial cells,⁶ but studies by Zisman et al⁸ indicate that ACE is the main pathway of Ang II formation within the coronary vasculature. Human heart chymase is also located in mast cells⁶ and may contribute to Ang II formation in situations in which mast cell degranulation occurs. Nevertheless, it is not possible to extrapolate from an enzyme's abundance its role in peptide metabolism in vivo. Akasu et al¹⁸ recently reported much higher levels of chymase than ACE in human lung. However, it is generally accepted that ACE plays a dominant role in Ang II formation in lung.

Our data and conclusions are confined to atria and cannot be extrapolated to ventricles. Ethical and practical issues prevent such a study from being performed on ventricular tissue, because of the need to prevent artifactual generation and metabolism of peptides during tissue removal. Although our data indicate a primary role for ACE in Ang II formation in atria, our data do not exclude a role for chymase. Alternative pathways of Ang II formation are likely to predominate during ACE inhibition.

A local kallikrein-kinin system is present in rat hearts,¹⁹ and evidence from animal studies supports a role for kinins in mediating the effects of ACE inhibition on the heart and vasculature.^{20 21} However, only limited information on the role of kinins in the therapeutic effects of ACE inhibition is available in humans. ACE inhibition is reported to increase plasma levels of immunoreactive kinin peptides in humans.^{22 23} The type 2 BK-(1-9) receptor antagonist HOE 140 caused coronary vasoconstriction and reduced flow-mediated dilatation of coronary vessels, which suggested a role for endogenous kinins in the regulation of human coronary vasomotor tone.²⁴ Moreover, HOE 140 prevented the enhancement by ACE inhibition of flow-mediated dilatation in human radial artery, which suggests a role for endogenous kinins in mediating this effect of ACE inhibition.²⁵ In addition, ACE inhibitors potentiate preconditioning through type 2 BK-(1-9) receptor activation in human atrial trabeculae in vitro.²⁶

Our finding that ACE inhibition did not modify bradykinin or kallidin peptide levels is evidence against a role for changes in cardiac kinin peptide levels in mediating the therapeutic effects of ACE inhibition. Several factors may have contributed to the failure of ACE inhibition to modify tissue kinin levels in the present study. Although the doses of ACE inhibitor used in this study were those prescribed by the attending physicians and were sufficient to modify angiotensin peptide levels, it is possible that higher doses are required to inhibit kinin metabolism, because kinins have a much higher affinity for ACE than Ang I.²⁷ Moreover, it is possible that other enzymes, such as neutral endopeptidases 24.11²⁸ and 24.15²⁹ and aminopeptidase P,³⁰ play a more dominant role than ACE in kinin metabolism in the interstitium of atrial tissue, whereas ACE may be a major pathway of kinin metabolism in blood and vasculature.

	Acknowledgments

 
This study was funded by a grant from the National Health and Medical Research Council of Australia. We are grateful to Anthony Wilson for his assistance with the collection of tissues for this study.

Received January 25, 1999; first decision February 26, 1999; accepted March 29, 1999.

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