(Hypertension. 1997;30:1015-1019.)
© 1997 American Heart Association, Inc.
Articles |
High Plasma Level of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline
A New Marker of Chronic Angiotensin-Converting Enzyme Inhibition
From the Broussais Hospital Clinical Investigation Center, INSERM, and Assistance Publique des Hôpitaux de Paris (M.A., L.N., J.M.), and the Service de Pharmacologie et d'Immunologie, CEA, Gif-sur-Yvette (E.E., J.-M.G.), France.
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Abstract |
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Abstract The acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril to healthy subjects transiently increases 5.5-fold the plasma levels of a natural stem-cell regulator, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The aim of this study was to measure plasma Ac-SDKP levels during chronic treatment with all types of ACE inhibitors and to assess its relevance as a marker of ACE inhibition. Plasma levels of Ac-SDKP were blindly determined in age- and sex-matched hypertensive patients either treated (ACEI group, n=27) or not (non-ACEI group, n=23) with an ACE inhibitor for more than 1 month. Geometric mean [range] of plasma Ac-SDKP levels were significantly higher in the ACEI group (3.78 [1.48 to 14.5] pmol/mL) than in the non-ACEI group, with no overlap between the groups (0.75 [0.36 to 1.22] pmol/mL, P<.0001). The measurement of Ac-SDKP in plasma discriminated all the patients of the ACEI group, whereas the simultaneous determination of either in vitro (using hippuryl-histidine-leucine as substrate) or in vivo (angiotensin II/angiotensin I ratio) ACE activity failed to identify nine and five cases, respectively. We conclude that Ac-SDKP accumulates in plasma during chronic ACE inhibitor treatment. The long-term consequences of Ac-SDKP accumulation are unknown. The reliability of plasma Ac-SDKP measurement makes it the best marker of chronic ACE inhibition, which can help to verify patients' compliance to ACE inhibitor treatment.
Key Words: peptides • angiotensin-converting enzyme inhibition • diagnosis • patient compliance
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Introduction |
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Angiotensin I–converting enzyme (kininase II, dipeptidyl carboxypeptidase I, EC 3.4.15.1) is involved in the metabolism of two major vasoactive peptides, Ang I and bradykinin, therefore playing a major role in blood pressure regulation and fluid and electrolyte homeostasis.1 ACE displays activity toward a broad range of substrates, at least in vitro,1 2 and has two homologous N- and C-terminal active domains.3 Ac-SDKP, a regulatory factor of hematopoiesis,4 5 6 is, with LH-RH,7 one of the two natural substrates that are preferentially hydrolyzed by the N-terminal active site of ACE.8 9 Ac-SDKP reversibly prevents the recruitment of pluripotent hematopoietic stem cells and normal early progenitors into S phase of the cellular cycle by maintaining them in G0 phase.4 5 6
Ac-SDKP hydrolysis is blocked by ACE inhibitors such as captopril and lisinopril in vitro.8 9 We therefore investigated effects of the administration of a single 50-mg oral dose of captopril to healthy subjects.10 Captopril immediately induced a 5.5-fold (range: 4 to 8.5) increase in the plasma levels of Ac-SDKP and a 90% to 99% inhibition of in vitro [3H]Ac-SDKP hydrolysis.10 The profile of ACE inhibition as assessed by the hydrolysis of [3H]Ac-SDKP in vitro was very close to that of ACE inhibition assessed by following the time-course evolution of the plasma Ang II/Ang I ratio, which more closely reflects the in vivo plasma and endothelial ACE inhibition than a spectrophotometric method developed by Cushman and Cheung11 (the Cushman assay) using a synthetic substrate such as hippuryl-histidine-leucine (Hip-His-Leu).12
The present study was undertaken to investigate whether (1) plasma Ac-SDKP levels remain permanently elevated during chronic ACE inhibition; (2) all ACE inhibitors, regardless of the presence of a sulfhydryl group or their preferential affinity for the N- or C-terminal active site of ACE, cause an increase in plasma Ac-SDKP levels; and (3) the plasma Ac-SDKP level is a better in vivo marker of ACE inhibition than are standard methods of assessment.
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Methods |
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Subjects
Fifty consecutive white hypertensive patients of both sexes (aged 18 to 75 years) were recruited for the study during either an outpatient visit or a hospitalization at the Broussais Hypertension Clinic. Patients were defined as treated by an ACE inhibitor if this class of drug was prescribed for more than 1 month (ACEI group, n=27). The age- and sex-matched hypertensive control group (non-ACEI group, n=23) consisted of patients either never treated by an ACE inhibitor or for which the ACE inhibitor was withdrawn more than 1 month before inclusion in the study. The second control group consisted of normotensive subjects recruited at the Broussais Hospital Clinical Investigation Center (n=17). The procedures followed were in accordance with institutional guidelines.
Laboratory Methods
In the ACEI group, blood was intentionally sampled at widely
different times from 2 to 48 hours after the last drug intake. In both
the hypertensive and normotensive control groups, blood was sampled
between 8 and 10 AM. For all groups, no special effort was
made to control the subjects' posture and sodium intake, and blood
samples were collected from patients sitting or lying down for at least
5 minutes.
Plasma Ac-SDKP was determined by a competitive enzyme immunoassay,12 which has been previously used for pharmacokinetic studies in humans12 and has a limit of quantification of 0.5 pmol/mL. Captopril (10-4 mol/L) was immediately added to the blood samples for the measurement of plasma Ac-SDKP. These samples were then immediately centrifuged at 2500 rpm at 4°C and stored at -20°C until assay.
Plasma ACE activity was quantified by the Cushman assay (using Hip-His-Leu as substrate).13 When captopril was the ACE inhibitor, blood samples were immediately centrifuged at 4°C and stored at -80°C and plasma ACE activity was determined within 48 hours to minimize dissociation of captopril from plasma ACE.14
The methods of blood sampling and measurement for plasma Ang I and Ang II have been previously described.15 Both peptides were measured after extraction from the same plasma sample by a single Bondelut column.15
Plasma active renin was measured by immunoradiometric assay.16 Plasma aldosterone was measured by radioimmunoassay with a commercially available kit. All hormone assays were performed blind to the treatment. Creatinine clearance was estimated according to the formula of Cockcroft and Gault.17 Significant renal insufficiency was defined as a creatinine clearance of less than 60 mL/min per 1.73 m2.
Statistical Methods
The two hypertensive groups were compared by unpaired Student
t tests. Normality was checked for each variable, and
natural logarithmic transformation was applied when distributions were
skewed. The relationship between two continuous variables was
studied with Spearman's rank correlation test.
Calculations were done with the Statview 4.0 statistical software (Abacus Concepts Inc). Data are expressed as mean±SD and geometric mean (range) for hormonal values in text and tables, or as otherwise specified. Ninety-five percent CI for the ratio of the geometric means between the two hypertensive groups (ACEI/non-ACEI) was calculated for each hormonal parameter because of their skewed distributions.18 A value of P<.05 was considered significant.
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Results |
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Clinical and biological characteristics of the two groups of hypertensive patients are summarized in Table 1
. Mean age and blood pressure, sex
ratio, and smoking status were similar in the two hypertensive groups.
Estimated creatinine clearance was significantly lower in
the ACEI than in the non-ACEI group (P=.005). Eight patients
in the ACEI and 2 patients in the non-ACEI group had a mild renal
insufficiency. Normotensive controls (7 men and 10 women, mean age
52±7 years) were slightly younger than hypertensive patients of both
groups (Table 1). The median duration of the ACE inhibitor
treatment was 4 years (range, 1.5 months to 16 years). The types and
doses of ACE inhibitors administered to the patients at the
time of blood sampling are listed in Table 2. Among the seven different ACE
inhibitors prescribed, one of them, captopril, has a
sulfhydryl group, and two of them (lisinopril and
captopril) are not prodrugs. All types of daily dosages were
represented, ranging from commonly marketed doses to high
doses (enalapril or lisinopril, 20 mg BID, for example). In
the non-ACEI group, 11 of 23 patients had never been treated with any
antihypertensive drug and the remaining were treated either with
calcium channel blockers, ß-blockers, 
-blockers, centrally acting
antihypertensive drugs, or combinations of these drugs.
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Effects of ACE Inhibitor Treatment on Plasma
Ac-SDKP Levels
Irrespective of the time interval between blood sampling and
ACE inhibitor intake, geometric mean plasma Ac-SDKP levels
were five times (95% CI: 3.8 to 6.6) higher in the ACEI group than in
the non-ACEI group (3.78 pmol/mL versus 0.75 pmol/mL,
respectively, P<.0001; Table 3 and the
Figure). The ranges for plasma Ac-SDKP
levels in the ACEI group and the non-ACEI group did not overlap (1.48
to 14.5 pmol/mL versus 0.36 to 1.22 pmol/mL,
respectively; Table 3 and Figure). All patients treated by an ACE
inhibitor, regardless of its chemical characteristics, had
plasma Ac-SDKP levels higher than those measured in both the
hypertensive and the normotensive control groups. Plasma Ac-SDKP levels
were similar in the non-ACEI hypertensive group and the normotensive
subjects, even though age and sex ratio were slightly different between
these two groups (geometric mean [range]: 0.75 [0.6 to 1.22]
pmol/mL versus 0.63 [0.48 to 0.85] pmol/mL,
respectively, NS).
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Plasma Ac-SDKP levels were significantly correlated to
creatinine clearance in the ACEI group (
=.41,
n=27, P=.03) but not in the non-ACEI group
(=.20, n=23, NS). To eliminate a potential confounding
effect of renal insufficiency, plasma Ac-SDKP levels were
analyzed after excluding the patients with mild renal
dysfunction: plasma Ac-SDKP levels in the remaining members of the ACEI
group (n=19) were 4.1 times (95% CI: 3.2 to 5.3) higher than in the
non-ACEI group (n=21; geometric mean [range]: 3.31 [1.48 to 7.13]
pmol/mL versus 0.80 [0.37 to 1.22] pmol/mL,
respectively, P<.0001).
To investigate any time effect on plasma Ac-SDKP after drug absorption during chronic treatment, the tetrapeptide levels were also analyzed, taking into account the time interval between blood sampling and ACE inhibitor intake. Patients with renal dysfunction were excluded to avoid the effect of the accumulation of ACE inhibitors due to their renal route of elimination. Twenty to 24 hours after ACE inhibitor intake, plasma Ac-SDKP levels did not significantly differ from those measured 2 to 15 hours after dose (geometric mean [range]: 2.93 [1.48-7.13] pmol/mL versus 3.70 [2.41-5.44] pmol/mL, respectively, NS ). There was no trend toward a dose-effect relationship on plasma Ac-SDKP levels within the 24 hours after drug intake.
Effects of ACE Inhibitor Treatments on Plasma ACE
Activity (Cushman Assay), Plasma Active Renin,
Angiotensins, and Aldosterone Levels
As expected, mean values for plasma in vitro ACE activity
and the Ang II/Ang I ratio were significantly lower in the ACEI group
than in the non-ACEI group (Table 3
). These differences were larger for
samples collected 2 to 15 hours after drug intake than 20 to 48 hours
after dose in the ACEI group (not shown). Mean plasma active renin and
Ang I levels were significantly higher in the ACEI group than in the
non-ACEI group (Table 3). No significant difference was observed in
terms of plasma aldosterone levels between the groups
(Table 3). Plasma Ang II did not significantly differ between groups.
In the absence of ACE inhibitor treatment, the low plasma
Ang II levels observed in six patients are explained by a low-renin
form of hypertension, including four cases of primary aldosteronism, or
the prescription of ß-blockers (n=2). In nine patients (six in the
non-ACEI group), the low plasma angiotensin concentrations
make the calculation of their ratio inaccurate.
Within the hypertensive ACEI and non-ACEI groups, plasma Ac-SDKP levels were not significantly correlated with either plasma ACE activity or Ang II/Ang I ratio (not shown).
Comparison of the Sensitivity of Plasma Ac-SDKP Measurement Versus
the Measurements of Various Renin-Angiotensin System
Variables for the Detection of ACE Inhibition in Patients
Chronically Treated With ACE Inhibitors
A large overlap of values was observed for plasma ACE
activity, active renin, Ang I, Ang II, and the Ang II/Ang I ratio
between the ACEI group and the non-ACEI group (Table 3 and Figure).
Plasma ACE activity, measured by the Cushman assay, indicated a
significant ACE inhibition (plasma ACE activity <10 mU/mL) only in 11
patients of the ACEI group. Therefore, none of the occasional
measurements of the plasma renin-angiotensin system
parameters was able to discriminate ACEI-treated patients
from untreated patients. In contrast, even at the end of the
theoretical dosing interval for each ACE inhibitor, plasma
Ac-SDKP levels were always higher than in the non-ACEI group (above
1.48 pmol/mL), whereas plasma ACE activity and the Ang II/Ang I
ratio were in the range of values measured in the non-ACEI group in 9
and 5 patients, respectively.
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Discussion |
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This study shows a chronic accumulation of Ac-SDKP in plasma when its degradation is permanently inhibited by long-term ACE inhibitor treatment in hypertensive patients. From 2 to 48 hours after drug intake, plasma levels of Ac-SDKP were fivefold (95% CI: 3.8 to 6.6) higher in all patients of the ACEI group than those of the non-ACEI group, without any overlap of the values between the two groups. These results extend those observed after administration of a single oral dose of captopril, implicating ACE as the major enzyme catabolizing Ac-SDKP in vivo.10 The presence of a sulfhydryl group in the chemical structure of the ACE inhibitor is not essential for inhibition of Ac-SDKP hydrolysis, since with all nonsulfhydryl ACE inhibitors tested, plasma Ac-SDKP was always higher than in the control group. Ac-SDKP is preferentially cleaved by the N-terminal active site of ACE,9 for which captopril has the highest in vitro affinity of all ACE inhibitors;19 nevertheless, all carboxylated ACE inhibitors tested in this study display a detectable inhibitory effect on the N-terminal domain of ACE in vivo.
Plasma Ac-SDKP measurements discriminated all the patients taking an ACE inhibitor from the controls, whereas the Cushman assay and the Ang II/Ang I ratio were unable to classify correctly nine and five cases, respectively. In addition, the plasma Ang II/Ang I ratio could not be determined accurately in nine cases in whom plasma levels of either Ang I or Ang II were below 1 to 2 pg/mL because of the presence of a low renin status. Plasma active renin and aldosterone measurements were even less satisfactory because the overlap between groups was greater due to interindividual variability in response of the renin angiotensin system during chronic ACE inhibition. The first consequence of this result is that Ac-SDKP measurement is more useful to detect an effective in vivo ACE inhibition than the in vivo Ang II/Ang I ratio, which is currently considered to be the most sensitive marker of both endothelial and plasma ACE activity.11 Multiple adjustments of the renin-angiotensin system occur during chronic ACE inhibition, including ACE induction,20 21 a rise in plasma renin,22 a fall in plasma angiotensinogen,23 24 and the return of Ang II toward its initial levels.25 For all these reasons, measurements of the plasma renin-angiotensin system parameters are not appropriate for investigating the presence and magnitude of ACE inhibition. Plasma ACE activity measured by the in vitro assay using the synthetic substrate hippuryl-histidine-leucine has a large range of interindividual variation (between 1 and 6), partly dependent on the insertion/deletion genetic polymorphism of the enzyme,26 27 whereas plasma Ac-SDKP levels are independent of this polymorphism.10 Therefore, isolated values of ACE activity determined by the Cushman assay can be easily interpreted only by comparison with pretreatment levels.
Plasma Ac-SDKP levels during ACE inhibition are independent of the timing of blood samplings, the ACE genotype,26 27 the baseline ACE activity, and the ACE inhibitor used. They are independent of a possible in vitro dissociation of the ACE inhibitor from ACE14 and of an unexpected in vitro generation of angiotensins, always possible despite all the precautions taken to avoid it. Posture of the subjects during blood sampling, sodium intake, and the existence of counterregulatory mechanisms triggered by ACE inhibition do not seem to have a major influence. Plasma Ac-SDKP measurement is therefore the most valuable tool for detecting an effective in vivo ACE inhibition. Like the measurements of resting heart rate and plasma uric acid as markers of compliance to ß-blocker or diuretic treatment, plasma Ac-SDKP measurement, being a simple, accurate endogenous "tracer" of effective intake of an ACE inhibitor by patients, can be recommended as an additional tool to help physicians recognize and detect patients' noncompliance to ACE inhibitor treatment, especially in a chronic asymptomatic disorder such as hypertension,28 but also in patients with chronic heart failure and post–myocardial infarction.
Besides the measurement of the in vivo Ang II/Ang I ratio, other substrates have been claimed to be accurate markers of ACE inhibition. Juillerat et al25 have shown that major differences in the discriminating power of the methods of ACE activity measurements in detecting ACE inhibition can be obtained when using two different synthetic substrates Hip-Gly-Gly and Z-Phe-His-Leu. These major differences were due to (1) the Km and the concentrations of the substrates used in the assays and (2) the nature of the ACE inhibitor used. These authors also showed that it was extremely difficult to correlate the in vitro measurements with the in vivo situation. Therefore, neither of these two substrates could be used as effective tools to measure ACE activity, either for comparing ACE inhibitors or for checking patients' compliance. Nussberger et al29 developed a new assay for ACE activity measurement relying on the timed generation of Ang II in plasma from Ang I added at a 17 pmol/mL concentration, which has the advantage of using the natural substrate Ang I under conditions close to those found in vivo. In studies performed in healthy subjects, these authors have clearly demonstrated that the measurement of ACE activity by the timed generation of Ang II accurately reflects in vivo ACE inhibition and is superimposed on the Ang II/Ang I ratio.29 However, this assay necessitates (1) blood samplings on tubes containing a renin inhibitor, which may not be easily available at the time of an outpatient visit, and (2) a radioimmunoassay, which implies the presence of a laboratory equipped with a gamma counter. For the purpose of checking compliance of numerous patients with ACE inhibitor treatment in a clinical setting, the use of Ac-SDKP measurement in plasma, which accurately reflects the presence or absence of an ACE inhibitor in the body, is easier. It necessitates neither special attention for blood samplings nor a radioimmunoassay and can be performed by nonspecialized laboratories.
One important finding of our study is that plasma Ac-SDKP levels are significantly correlated to creatinine clearance in the ACEI group and not in the non-ACEI group. This fact may suggest that it is the accumulation of the ACE inhibitor in plasma associated with renal failure and not renal failure per se that is responsible for the higher levels of the peptide when the renal clearance of ACE inhibitors is impaired. However, because only very few non-ACEI patients had severe renal insufficiency, the effect of renal failure on plasma Ac-SDKP cannot be precisely assessed and warrants further investigation. The chronic accumulation of Ac-SDKP in plasma during long-term ACE inhibitor treatment could be proposed as an additional explanation of ACE inhibitor–induced hematological toxicity observed in patients with renal failure,30 31 32 in renal transplant recipients,33 34 35 or in patients treated with immunosuppressive drugs affecting bone marrow functions.36
During chronic treatment by ACE inhibitors, the long-term consequences of the accumulation of Ac-SDKP in both plasma and, possibly, tissues are unknown, since the physiological role of this peptide and its precursors, if any, are unknown. It must be emphasized that most of the cardiovascular, renal, and hormonal effects of ACE inhibitors are also observed with the new nonpeptide Ang II receptor antagonists that specifically block the renin-angiotensin system at the level of the type 1 Ang II receptor and do not influence ACE activity. Although the physiological consequences of its accumulation need more investigation, single Ac-SDKP measurements in plasma can be used to obtain an accurate picture of ACE inhibition that will help to verify patient compliance to ACE inhibitor prescription.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from Association Claude Bernard. The help of Than-Tam Guyene, MD, who performed the angiotensin measurements, and of Sandrine Michelet, MSc, who performed the Ac-SDKP measurements, is greatly acknowledged. We thank Dr Gilles Chatellier for his contribution to the presentation of the paper and for his advice on statistics. The authors wish to thank the nursing staff of the Clinical Investigation Center at the Broussais Hospital (Danièle Ménard, Jeanne Meunier, Olivier Picart, and Michèle Godeau), who ran the protocol. The technical contribution of Chistiane Dollin, who performed the assays, is also much appreciated.
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Footnotes |
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Reprint requests to Dr Michel Azizi, Centre d'Investigations Cliniques, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.
Received January 16, 1997; first decision February 28, 1997; accepted May 15, 1997.
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U. Sharma, N.-E. Rhaleb, S. Pokharel, P. Harding, S. Rasoul, H. Peng, and O. A. Carretero Novel anti-inflammatory mechanisms of N-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1226 - H1232. [Abstract] [Full Text] [PDF]
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 M. A. Cavasin, T.-D. Liao, X.-P. Yang, J. J. Yang, and O. A. Carretero Decreased Endogenous Levels of Ac-SDKP Promote Organ Fibrosis Hypertension, July 1, 2007; 50(1): 130 - 136. [Abstract] [Full Text] [PDF]
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H. Peng, O. A. Carretero, T.-D. Liao, E. L. Peterson, and N.-E. Rhaleb Role of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline in the Antifibrotic and Anti-Inflammatory Effects of the Angiotensin-Converting Enzyme Inhibitor Captopril in Hypertension Hypertension, March 1, 2007; 49(3): 695 - 703. [Abstract] [Full Text] [PDF]
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 M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]
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 M. Azizi, J. Menard, S. Peyrard, M. Lievre, M. Marre, and G. Chatellier Assessment of Patients' and Physicians' Compliance to an ACE Inhibitor Treatment Based on Urinary N-Acetyl Ser-Asp-Lys-Pro Determination in the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study. Diabetes Care, June 1, 2006; 29(6): 1331 - 1336. [Abstract] [Full Text] [PDF]
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 L. Waeckel, J. Bignon, J.-M. Liu, D. Markovits, T. G. Ebrahimian, J. Vilar, B. Mees, O. Blanc-Brude, V. Barateau, S. Le ricousse-Roussanne, et al. Tetrapeptide AcSDKP Induces Postischemic Neovascularization Through Monocyte Chemoattractant Protein-1 Signaling Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 773 - 779. [Abstract] [Full Text] [PDF]
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 H. Peng, O. A. Carretero, N. Vuljaj, T.-D. Liao, A. Motivala, E. L. Peterson, and N.-E. Rhaleb Angiotensin-Converting Enzyme Inhibitors: A New Mechanism of Action Circulation, October 18, 2005; 112(16): 2436 - 2445. [Abstract] [Full Text] [PDF]
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D. Wang, O. A. Carretero, X.-Y. Yang, N.-E. Rhaleb, Y.-H. Liu, T.-D. Liao, and X.-P. Yang N-acetyl-seryl-aspartyl-lysyl-proline stimulates angiogenesis in vitro and in vivo Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2099 - H2105. [Abstract] [Full Text] [PDF]
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 S. Charrier, A. Michaud, S. Badaoui, S. Giroux, E. Ezan, F. Sainteny, P. Corvol, and W. Vainchenker Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells Blood, August 15, 2004; 104(4): 978 - 985. [Abstract] [Full Text] [PDF]
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M. A. Cavasin, N.-E. Rhaleb, X.-P. Yang, and O. A. Carretero Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP Hypertension, May 1, 2004; 43(5): 1140 - 1145. [Abstract] [Full Text] [PDF]
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 S. Fuchs, H. D. Xiao, J. M. Cole, J. W. Adams, K. Frenzel, A. Michaud, H. Zhao, G. Keshelava, M. R. Capecchi, P. Corvol, et al. Role of the N-terminal Catalytic Domain of Angiotensin-converting Enzyme Investigated by Targeted Inactivation in Mice J. Biol. Chem., April 16, 2004; 279(16): 15946 - 15953. [Abstract] [Full Text] [PDF]
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H. Peng, O. A. Carretero, D. R. Brigstock, N. Oja-Tebbe, and N.-E. Rhaleb Ac-SDKP Reverses Cardiac Fibrosis in Rats With Renovascular Hypertension Hypertension, December 1, 2003; 42(6): 1164 - 1170. [Abstract] [Full Text] [PDF]
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S. Pokharel, S. Rasoul, A. J.M. Roks, R. E.W. van Leeuwen, M. J.A. van Luyn, L. E. Deelman, J. F. Smits, O. Carretero, W. H. van Gilst, and Y. M. Pinto N-Acetyl-Ser-Asp-Lys-Pro Inhibits Phosphorylation of Smad2 in Cardiac Fibroblasts Hypertension, August 1, 2002; 40(2): 155 - 161. [Abstract] [Full Text] [PDF]
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N.-E. Rhaleb, H. Peng, X.-P. Yang, Y.-H. Liu, D. Mehta, E. Ezan, and O. A. Carretero Long-Term Effect of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline on Left Ventricular Collagen Deposition in Rats With 2-Kidney, 1-Clip Hypertension Circulation, June 26, 2001; 103(25): 3136 - 3141. [Abstract] [Full Text] [PDF]
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N.-E. Rhaleb, H. Peng, P. Harding, M. Tayeh, M. C. LaPointe, and O. A. Carretero Effect of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline on DNA and Collagen Synthesis in Rat Cardiac Fibroblasts Hypertension, March 1, 2001; 37(3): 827 - 832. [Abstract] [Full Text] [PDF]
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H. Peng, O. A. Carretero, M. E. Alfie, J. A. Masura, and N.-E. Rhaleb Effects of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Type 1 Receptor Antagonist in Deoxycorticosterone Acetate-Salt Hypertensive Mice Lacking Ren-2 Gene Hypertension, March 1, 2001; 37(3): 974 - 980. [Abstract] [Full Text] [PDF]
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H. Peng, O. A. Carretero, L. Raij, F. Yang, A. Kapke, and N.-E. Rhaleb Antifibrotic Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline on the Heart and Kidney in Aldosterone-Salt Hypertensive Rats Hypertension, February 1, 2001; 37(2): 794 - 800. [Abstract] [Full Text] [PDF]
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 A. D. Struthers, R. MacFadyen, C. Fraser, J. Robson, J. J. Morton, C. Junot, and E. Ezan Nonadherence with angiotensin-converting enzyme inhibitor therapy: A comparison of different ways of measuring it in patients with chronic heart failure J. Am. Coll. Cardiol., December 1, 1999; 34(7): 2072 - 2077. [Abstract] [Full Text] [PDF]
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 C. Junot, L. Nicolet, E. Ezan, M.-F. Gonzales, J. Menard, and M. Azizi Effect of Angiotensin-Converting Enzyme Inhibition on Plasma, Urine, and Tissue Concentrations of Hemoregulatory Peptide Acetyl-Ser-Asp-Lys-Pro in Rats J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 982 - 987. [Abstract] [Full Text]
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 A D Struthers, G Anderson, R J MacFadyen, C Fraser, and T M MacDonald Non-adherence with ACE inhibitor treatment is common in heart failure and can be detected by routine serum ACE activity assays Heart, November 1, 1999; 82(5): 584 - 588. [Abstract] [Full Text]
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 J. E. Chisi, J. Wdzieczak-Bakala, J. Thierry, C. V. Briscoe, and A. C. Riches Captopril Inhibits the Proliferation of Hematopoietic Stem and Progenitor Cells in Murine Long-Term Bone Marrow Cultures Stem Cells, November 1, 1999; 17(6): 339 - 344. [Abstract] [Full Text]
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C. Junot, J. Menard, M.-F. Gonzales, A. Michaud, P. Corvol, and E. Ezan In Vivo Assessment of Captopril Selectivity of Angiotensin I-Converting Enzyme Inhibition: Differential Inhibition of Acetyl-Ser-Asp-Lys-Pro and Angiotensin I Hydrolysis J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1257 - 1261. [Abstract] [Full Text]
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M. Azizi, E. Ezan, J.-L. Reny, J. Wdzieczak-Bakala, V. Gerineau, and J. Menard Renal and Metabolic Clearance of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) During Angiotensin-Converting Enzyme Inhibition in Humans Hypertension, March 1, 1999; 33(3): 879 - 886. [Abstract] [Full Text] [PDF]
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Y. Le Meur, J.-C. Aldigier, V. Praloran, M. Azizi, and E. Ezan Is Plasma Ac-SDKP Level a Reliable Marker of Chronic Angiotensin-Converting Enzyme Inhibition in Hypertensive Patients? • Response Hypertension, May 1, 1998; 31(5): 1201 - 1202. [Full Text] [PDF]
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