Influence of preventive therapy with quinapril on IL

Transkrypt

Pharmacological Reports
2007, 59, 330338
ISSN 1734-1140
Copyright © 2007
by Institute of Pharmacology
Polish Academy of Sciences
Influence of preventive therapy with quinapril on
IL-6 level in patients with chronic stable angina
Magdalena Gibas1, Jolanta Miszczak-Œmia³ek2, Edyta M¹dry1,
Jerzy G³uszek3, Henryk Witmanowski1, Janusz Piotrowski2
Department of Physiology, University of Medical Sciences, wiêcickiego 6, PL 60-781 Poznañ, Poland
Department of Internal Diseases, Grunwaldzki Hospital, Orzeszkowej 6, PL 60-778 Poznañ, Poland
!
Department of Hypertension and Vascular Diseases, University of Medical Sciences, D³uga 1/2,
PL 61-848 Poznañ, Poland
Correspondence: Magdalena Gibas, e-mail: [email protected]
Abstract:
We hypothesized that beneficial role of angiotensin converting enzyme inhibitors in stable coronary artery disease (CAD) therapy
may involve (among others) their anti-inflammatory effects, which may be reflected by serum interleukin-6 (IL-6) levels. For that
reason, we have investigated the influence of short-term administration of quinapril on serum IL-6 concentration. 124 patients suffering from stable CAD and matched for some of CAD risk factors were enrolled in our study. Patients were randomized to treatment
with quinapril or control (placebo administration). Blood samples were taken twice: before and after four weeks of quinapril administration. The effect of quinapril administration was assessed under double-blind placebo-controlled conditions. We observed that
quinapril reduced serum IL-6 concentration in almost all studied subgroups of patients (p < 0.001). Interestingly, such an effect was
not observed in smokers. Additionally, we found that baseline IL-6 levels were higher in: smokers as compared with nonsmokers
(p < 0.001), patients with total cholesterol (TC) to high density lipoprotein (HDL)-cholesterol ratio (TC/HDL-ch ratio) above 5 as
compared with subjects with TC/HDL-ch £ 5 (p = 0.001), and in patients who did not report any statin therapy in comparison with
patients undergoing statin treatment (p = 0.023). In conclusion, quinapril may interfere with cytokine release by lowering IL-6 levels, which may be of particular importance for secondary prevention of stable CAD.
Key words:
inflammation, coronary artery disease, angiotensin converting enzyme inhibitors, interleukin-6
Abbreviations: AII – angiotensin II, ACE – angiotensin convering enzyme, ACEIs – angiotensin converting enzyme inhibitors, ASA – acetylsalicylic acid (aspirin), BMI – body mass
index, CAD – coronary artery disease, HDL-ch – high density
lipoprotein cholesterol, HMG CoA reductase inhibitors – hydroxymethylglutaryl coenzyme A reductase inhibitors (statins),
IL-6 – interleukin-6, RAS – rennin-angiotensin system, TC –
total cholesterol
330
Pharmacological Reports, 2007, 59, 340348
Introduction
According to the inflammatory concept of atherosclerosis, many investigators concentrate on systemic markers
of inflammation, which may be considered as an independent risk factors for cardiovascular events. Several
studies have demonstrated elevated levels of interleu-
Influence of quinapril on serum IL-6
Magdalena Gibas et al.
kin-6 (IL-6) and other inflammatory markers (mediators)
in acute and chronic coronary syndromes [2, 12, 18].
IL-6, the 22–27 kD glycoprotein secreted by activated monocytes, vascular smooth muscle cells, and
adipose tissue exhibits multiple biological effects. As
a central mediator of injury and inflammation, it stimulates hepatic production of acute-phase proteins,
activates monocytes in the vessel wall, directly increases lipid uptake by macrophages and also exhibits
procoagulant effects on platelets [28]. All these functions suggest a possible role for this cytokine in the
progression of atherosclerosis. Recent studies indicate
a tight link between an increased activity of renninangiotensin system (RAS) and production of inflammatory cytokines in the vascular wall. Locally produced by the inflamed vessels, angiotensin II (AII) is
importantly implicated in atherosclerotic plaque formation in a variety of ways. AII induces vascular
smooth muscle cell proliferation, influences the expression of proinflammatory molecules in the vessel
wall (among them IL-6), enhances reactive oxygen
species production and lipid oxidation, and increases
the uptake of oxidized LDL by macrophages [10, 11,
16]. Thus, AII receptors and angiotensin converting
enzyme (ACE) activity have been reported to be
highly increased in atherosclerotic plaques [20].
Clinical trials are currently ongoing to explore primary and secondary prevention including anti-inflammatory characteristics of the studied pharmacotherapeutics (statins, aspirin) [13, 21]. Recent recommendations of American Heart Association and American
College of Cardiology are highly consistent with results of EUROPA study published in 2003. There are
clinical pieces of evidence for routine prophylactic
usage of angiotensin converting enzyme inhibitors
(ACEIs) in patients with stable coronary heart disease
[8]. Based on the above-presented data, we hypothesized an influence of preventive ACEIs therapy on
vascular inflammation reflected by serum IL-6 level
in patients with chronic stable angina.
Materials and Methods
Patients
We performed our double-blind placebo-controlled
study between June 2004 and March 2005. Study popu-
lation comprised 124 subjects (78 men, 46 women
aged 55 ± 10 years, Caucasians) with clinically stable
angina. The inclusion criteria were: stable angina pectoris of at least 1 year duration confirmed by clinical
symptoms, ECG, positive exercise stress test, and/or
coronary angiography. Patients were randomized to
treatment with quinapril or control (placebo administration).
Exclusion criteria were as follows:
1. Acute coronary event (including myocardial infarction) within the last 3 months,
2. Other than unstable angina acute vascular disorder
(e.g. cerebral stroke) within the last 6 months,
3. Acute infection or allergic response within the last
4 weeks,
4. Surgery (including coronary angiography and coronary artery surgery), or extensive injury within previous 3 months,
5. Chronic inflammatory disease (e.g. asthma, rheumatic diseases, parodontitis etc.); malignancy,
6. Renal and/or hepatic failure, diabetes mellitus,
7. Administration of non-steroidal anti-inflammatory
drugs (excluding aspirin) and/or steroids for a period longer than 4 weeks,
8. De novo administration of HMG-CoA inhibitors, or
aspirin (last 6 weeks).
Patients were matched for some of CAD risk factors (Tab. 1).
Seventy four patients were treated orally with one
of the angiotensin converting enzyme inhibitors – quinapril (the dosage varied between 5 and 10 mg). Fifty
patients received placebo, which was provided by our
laboratory.
Methods
Fasting venous blood samples were taken from each
individual: two samples of blood from each patient
before and 4 weeks after quinapril or placebo administration. To avoid any diurnal variation in IL-6, samples were collected in the mornings of the experimental days between 6.30 and 7.00 a.m. Serum samples
were stored at –80°C. The concentration of IL-6 was
measured by a commercially available high-sensitivity immunoassay (Quatikine human IL-6, R&D Systems). The sensitivity of the assay is 0.01 pg/ml. The
intra-assay coefficient of variation was 8%. IL-6 levels from all patients were above the detection limit.
We also determined blood lipid profile (total choles-
331
terol level, LDL-cholesterol, HDL-cholesterol, and
triglycerides).
The study was approved by the Ethics Committee
of the University of Medical Sciences in Poznañ, and
all patients gave their written, informed consent.
Tab. 1. Characteristics of study population (including CAD risk factors)
Statistics
Age, y
55 ± 8
55 ± 10
Sex, M/F
39/14
12/9
Current smoking, Yes/No
18/35
8/13
29 ± 3.4
27 ± 3.8
54
50
Systolic
129.2 ± 11.7
135.1 ± 10.2
Diastolic
79.4 ± 7.2
79.2 ± 8.0
Cholesterol, mg/dl
243.0 ± 44.3
255.2 ± 53.0
Triglycerides, mg/dl
215.0 ± 152.1
199.0 ± 110.0
BMI, kg/m
Family history of CAD, %
Blood pressure, mmHg:
40.3 ± 16.0
44.2 ± 12.1
185.7 ± 13.7
180.0 ± 17.5
Beta blockers, %
63
86
Ca blockers, %
50
57
Statins, %
57
62
Diuretics, %
21
32
HDL-cholesterol, mg/dl
Results
332
Placebo
(n = 50)
2
Data are expressed as the means ± SEM. Since the
level of IL-6 was not normally distributed, the results
were interpreted according to non-parametric tests.
The Wilcoxon matched pairs test was used for paired
analyses and the Mann-Whitney U test for unpaired
analyses.
Data describing clinical characteristics of the patients
are presented in Table 1. We analyzed baseline IL-6
concentration in all patients. Additionally, we estimated the dependence of IL-6 level and the following
factors: sex, smoking status, level of total cholesterol
(TC), total cholesterol to HDL-cholesterol ratio
(TC/HDL-ch), body mass index (BMI), family history
of CAD, statin therapy, and aspirin (ASA) management. To characterize the effect of quinapril on
plasma cytokine concentration, we compared the level
of IL-6 before and after quinapril or placebo administration. The factors mentioned above were also taken
into consideration.
In patients with stable CAD, serum IL-6 concentrations were significantly decreased after 4 weeks of
quinapril therapy (Tab. 2; p < 0.001). Similar changes
were not observed in placebo group.
We compared baseline IL-6 levels in women and in
men and did not notice any significant differences.
Median serum concentrations of IL-6 in patients were
significantly higher among current smokers than
among non-smokers in both quinapril and placebo
group (p < 0.001). Comparing IL-6 in smokers before
and after quinapril therapy, we did not notice any significant changes, but marked differences were observed in non-smoking patients from our study (p <
0.001). See Table 3.
The differences in baseline IL-6 levels between patients who had BMI £ 30, and those with BMI > 30
did not reach statistical significance. In separate
Patients
(n = 74)
LDL-cholesterol
Medical treatment:
2+
8
5
73
66
100
82/18
0
Nitrates, %
ASA (75 mg/day), %
ACEIs (de novo), %
5 mg/10 mg, %
Tab. 2. Serum IL-6 level in patients before and after quinapril or placebo administration
Quinapril group
(n = 74)
Serum IL-6
[pg/ml]
p
Placebo group
(n = 50)
baseline
after quinapril
baseline
after placebo
3.02 ± 1.76
2.13 ± 1.73
2.98 ± 1.66
2.76 ± 1.85
< 0.001
NS
Data are presented as the mean values ± SD. Data were analyzed
using Wilcoxon test
analyses, 4-week treatment with quinapril resulted in
decreased IL-6 level both in patients with BMI > 30
and BMI £ 30 (p = 0.003 and p < 0.001, respectively).
Interestingly, placebo administration led to an in-
2.49
± 1.30
NS
3.21
± 1.88
M
(n = 51)
= 0.006
1.79
± 1.47
F
(n = 23)
< 0.001
2.01
± 1.08
M
(n = 51)
(after quinapril)
2.34
± 1.12
F
(n = 23)
NS
2.62
± 1.20
M
(n = 27)
(before placebo)
NS
2.08
± 1.44
F
(n = 23)
NS
2.13
± 1.40
M
(n = 27)
(after placebo)
2.55
± 1.71
No
(n = 49)
< 0.001
3.94
± 1.53
Yes
(n = 25)
(before quinapril)
NS
3.68
± 1.48
Yes
(n = 25)
< 0.001
1.34
± 1.25
No
(n = 49)
(after quinapril)
2.21
± 1.38
No
(n = 32)
< 0.001
3.48
± 1.23
Yes
(n = 18)
(before placebo)
Smoking status
NS
3.05
± 1.34
Yes
(n = 18)
NS
2.55
± 1.30
No
(n = 32)
(after placebo)
2.82
± 1.54
NS
3.44
± 2.16
> 30
(n = 27)
< 0.001
2.07
± 1.67
£ 30
(n = 47)
= 0.003
2.28
± 1.88
> 30
(n = 27)
(after quinapril)
2.71
± 1.56
£ 30
(n = 31)
NS
3.30
± 1.98
> 30
(n = 19)
(before placebo)
NS
2.66
± 1.45
£ 30
(n = 31)
= 0.050
3.98
± 0.84
> 30
(n = 19)
(after placebo)
3.33
± 2.05
Yes
(n = 40)
NS
2.51
± 1.00
No
(n = 34)
(before quinapril)
< 0.001
2.43
± 1.99
Yes
(n = 40)
< 0.001
1.65
± 1.04
No
(n = 34)
(after quinapril)
2.44
± 1.87
Yes
(n = 25)
NS
2.48
± 1.95
No
(n = 25)
(before placebo)
Family history
NS
2.31
± 1.90
Yes
(n = 25)
NS
1.50
± 1.80
No
(n = 25)
(after placebo)
Data are presented as the mean values ± SD. Significance of differences in baseline values was calculated according to Mann-Whitney test. Values before quinapril vs. after quinapril and data
before placebo vs. after placebo were analyzed using Wilcoxon test. BMI body mass index; Family history Yes or No positive or negative family history of coronary artery disease
p
p
Serum IL-6
[pg/ml]
£ 30
(n = 47)
(before quinapril)
BMI
Tab. 4. The dependence of IL-6 level (before and after quinapril or placebo administration) and certain factors in patients with stable CAD (BMI and family history of CAD)
before placebo vs. after placebo were analyzed using Wilcoxon test. F female; M male
p
p
Serum IL-6
[pg/ml]
F
(n = 23)
(before quinapril)
Sex
Tab. 3. The dependence of IL-6 level (before and after quinapril or placebo administration) and certain factors in patients with stable CAD (sex and smoking status)
333
334
2.75
± 1.90
NS
3.32
± 1.58
> 250
(n = 29)
< 0.001
1.90
± 1.67
£ 250
(n = 45)
< 0.001
2.39
± 1.78
> 250
(n = 29)
(after quinapril)
3.41
± 2.08
> 250
(n = 21)
= 0.23
2.23
± 1.05
£ 250
(n = 29)
(before placebo)
NS
2.19
± 1.08
£ 250
(n = 29)
= 0.003
2.25
± 1.80
> 250
(n = 21)
(after placebo)
3.53
± 1.45
>5
(n = 30)
= 0.001
2.53
± 1.92
£5
(n = 44)
(before quinapril)
< 0.001
1.60
± 1.57
£5
(n = 44)
< 0.001
2.69
±1.73
>5
(n = 30)
(after quinapril)
3.60
± 1.58
>5
(n = 20)
= 0.001
2.41
± 1.87
£5
(n = 30)
(before placebo)
TC/HDL-ch
NS
2.32
± 1.79
£5
(n = 30)
NS
2.05
± 1.53
>5
(n = 20)
(after placebo)
3.62
± 2.12
= 0.023
2.44
± 1.09
No
(n = 32)
< 0.001
1.70
± 1.27
Yes
(n = 42)
< 0.001
2.51
± 2.03
No
(n = 32)
(after quinapril)
3.71
± 1.97
No
(n = 19)
= 0.001
2.19
± 1.40
Yes
(n = 31)
(before placebo)
= 0.050
1.54
± 0.82
Yes
(n = 31)
NS
3.53
± 1.70
No
(n = 19)
(after placebo)
3.17
± 1.85
Yes
(n = 54)
NS
2.16
± 0.83
No
(n = 20)
(before quinapril)
< 0.001
2.24
± 1.81
Yes
(n = 54)
= 0.050
1.51
± 0.98
No
(n = 20)
(after quinapril)
3.14
± 1.78
NS
2.62
± 0.85
No
(n = 17)
(before placebo)
Yes
(n = 33)
ASA
NS
3.02
± 1.65
Yes
(n = 33)
NS
2.53
± 0.91
No
(n = 17)
(after placebo)
before placebo vs. after placebo were analyzed using Wilcoxon test. ASA aspirin
p
p
Serum IL-6
[pg/ml]
Yes
(n = 42)
(before quinapril)
Statins
Tab. 6. The dependence of IL-6 level (before and after quinapril or placebo administration) and certain factors in patients with stable CAD (prolonged statin therapy and ASA management)
before placebo vs. after placebo were analyzed using Wilcoxon test. TC total cholesterol; TC/HDL-ch total cholesterol to HDL-cholesterol ratio
p
p
Serum IL-6
[pg/ml]
£ 250
(n = 45)
(before quinapril)
TC [mg/dl]
Tab. 5. The dependence of IL-6 level (before and after quinapril or placebo administration) and certain factors in patients with stable CAD (TC and TC/HDL-ch ratio)
crease of IL-6 in patients with BMI above 30 (p =
0.05). The relationship between baseline IL-6 and
positive or negative family history of CAD remained
statistically non-significant. Among subjects with or
without family history of CAD, median plasma concentrations of IL-6 decreased after quinapril administration (p < 0.001 in both cases) and remained unchanged when placebo was administrated (Tab. 4).
We observed higher concentrations of baseline
IL-6 in patients with TC/HDL-ch > 5 as compared
with patients with TC/HDL-ch £ 5 (p = 0.001 in both
quinapril and placebo group). There were no statistically significant differences in baseline IL-6 in subjects from quinapril group with total cholesterol level
above 250 mg/dl and those, who reported TC £ 250
mg/dl. In placebo group, higher levels of IL-6 were
observed in subjects with TC above 250 mg/dl (p =
0.003). In patients with high cholesterol level and
those who had TC £ 250 mg/dl, and also in patients
with TC/HDL-ch index > 5 and patients with TC/
HDL-ch £ 5, higher IL-6 concentrations were observed before administration of quinapril (p < 0.001
in all cases) but there was no significant difference
when placebo group was investigated (Tab. 5).
Patients undergoing statin therapy exhibited lower
baseline IL-6 concentrations than those who did not
take any of HMG-CoA reductase inhibitors (p = 0.023
in quinapril group, p = 0.001 in placebo grup). Longlasting aspirin management (ASA) did not statistically significantly influence baseline levels of IL-6 in
our study participants. In both patients undergoing
statin therapy and those who did not report any lipid
lowering management, quinapril lowered IL-6 level
(p < 0.001 in both cases). Placebo administration resulted in a decrease in serum IL-6 in subjects treated
with statins (p = 0.050). Patients on long-lasting aspirin therapy as well as those who did not use ASA, exhibited significant lowering of IL-6 level after 4 weeks
of treatment with quinapril (p < 0.001 and p = 0.05,
respectively). Significant changes were not noted in
placebo group (Tab. 6).
Discussion
It has been proven in several large clinical trials that
elevated plasma levels of cytokines are related to
atherogenesis and that increased intravascular IL-6
production has direct effect on atherosclerotic plaque
formation and stability [17, 24]. Discovery that cytokine production is elevated not only in acute cardiovascular syndromes but also in stable angina, may indicate prolonged duration of inflammatory processes
in vascular wall [12]. It is generally accepted that AII
plays an important role in atherogenesis. Because AII
stimulates the production of IL-6, some investigators
suggest its role in vascular inflammation and atherogenicity in processes mediated by IL-6 [9, 14]. Previous studies suggested that some ACE inhibitors (captopril, enalapril, cilazapril) might reduce cytokine
synthesis, but the precise mechanism of action is still
unknown [26]. Protective role of ACEIs against development of CAD is now well documented, and reported benefits of ACEIs treatment usually concern
clinical aspects [25, 29]. For example, the results of
EUROPA trial demonstrated evident clinical benefits
from ACEIs therapy as a routine secondary prophylaxis in patients with documented stable angina [8].
We found that 4 weeks of treatment with quinapril reduced serum IL-6 concentration in almost all studied
subgroups of our patients. This suggests that beneficial role of ACEIs in stable CAD therapy may involve
(among others) its anti-inflammatory effects, which
may be reflected in serum cytokine levels. The observation that IL-6 levels are reduced after only four
weeks of ACEIs treatment raises a questions whether
the effect is transient or permanent and what is the
mechanism of their action. So far, however, there are
no studies on the very short anti-inflammatory effects
of ACEIs in patients with stable CAD and we are also
unable to answer this question precisely.
Unexpectedly, we found that the influence of quinapril on IL-6 level was not observed in smokers,
which may be of particular importance in view of prophylaxis and health promotion. Cigarette smoke is
a potent determinant of acute phase response activation and production of many inflammatory cytokines
as shown by Tappia et al. [27]. Many reports indicate
that smoking may promote atherothrombosis partially
through vascular inflammation, which is reflected by
serum levels of inflammatory markers [1, 6]. From
a clinical perspective, it is commonly known that appropriate patient’s lifestyle such as dietary regimen,
regular physical exercise or smoking cessation influence prognosis and may increase the efficacy of CAD
treatment. The present data suggest that smoking may
induce a strong vascular inflammatory response which
is hardly susceptible to early effects of ACEI on se-
335
rum IL-6 concentration. However, the relation between smoking and the efficacy of anti-inflammatory
ACEI therapy, as reflected by serum IL-6 level, are
probably complex and need to be elucidated in detail.
Although our study was designed to assess the effects of quinapril, we also studied the baseline levels
of IL-6 in selected subgroups of our patients. We
demonstrated that among patients with stable CAD,
greatly increased baseline IL-6 levels were associated
with smoking, absence of statin therapy, and the value
of ratio TC/HDL-ch above 5 (as compared with appropriate subgroups of patients). It should be highlighted that the increase in baseline IL-6 was particularly evident in smokers, which may be of great importance for further CAD development and efficacy
of treatment. We did not notice, for example, differences between baseline IL-6 levels comparing patients with and without other risk factors (family history of CAD, BMI above 30, male sex). Our report relates high TC level to elevated serum IL-6 only in
placebo group. It is widely recognized that increased
level of cholesterol is a potent risk factor of CAD development and exacerbation. However, to complete
the view of dyslipidemia as a risk factor of CAD, one
must remember about atheroprotective effect of HDLcholesterol fraction. HDL-ch plays a role in reverse
cholesterol transport, and provides antioxidant enzymes, which neutralize proinflammatory effects of
oxidized lipids on vascular endothelial cells [5, 17].
For that reason many investigators regard the TC to
HDL-ch ratio as an independent and sensitive predictive index [4, 22]. Data from our study demonstrated
markedly increased baseline levels of proinflammatory IL-6 in subjects with high value of TC/HDL-ch
ratio in both groups (quinapril and placebo). These
observations might suggest that patients with impaired lipid metabolism represent highly susceptible
group to chronic vascular inflammation. IL-6, produced by cytokine-activated monocyte/macrophages,
is the major initiator of the acute phase response [3].
Cytokines released at the site of endothelial injury and
acute phase reactants may serve as potent markers of
intravascular inflammation and are involved in pathogenesis of CAD [7]. Thus, increased concentrations of
IL-6 with high levels of TC-HDL-ch in patients with
diagnosed stable angina, might be perceived as significant and additive predictive markers for CAD progression. However, additional prospective studies are
needed to elucidate these issues.
336
It has been established that ASA markedly reduces
serum cytokine levels. However, it exhibits its greatest anti-inflammatory action at doses as high as 1–2 g
[12]. In our study, the prolonged ASA administration
(75 mg daily) in patients with chronic stable angina
was not associated with decreased levels of baseline
IL-6. This may be partially due to the low daily cardioprotective dose of ASA, which has only a little
anti-inflammatory characteristics. Furthermore, Kharbanda et al. observed that ASA protected endothelial
function without modulating systemic IL-6 [15].
Similar effect was described by Musial et al., who
showed that two-week treatment with 300 mg of aspirin per day did not influence the concentrations of serum inflammation markers, among them IL-6 [19].
Numerous crucial trials with statins demonstrated
their pleiotropic action and potential to lower the level
of inflammatory markers in CAD. Recent research on
humans and animals indicate significant reduction in
serum IL-6 concentrations after statin therapy [19, 23,
30]. These reports are likely supported by our findings. In our study, patients regularly treated with
statins had lower baseline level of IL-6.
Limitations of the current study should be considered. Two doses of quinapril were used (5 and 10 mg)
and our study lacks dose-dependent analysis. However, the aim of the study was to investigate whether
quinapril influences IL-6 level or not. Even if dosedependent effect was present, it should not affect the
validity of our results, because most of the patients
were treated with 5 mg of quinapril (more than 80%)
and the net effect was evident. Furthermore, no repeated measurements of IL-6 were carried out and
thus we cannot take into account any variation of IL-6
levels. However, the blood samples were collected at
a uniform time of the day, which means that our data
are not limited by diurnal variation in IL-6. Finally,
we need to continue observations of our patients to estimate if the observed effects are permanent.
Conclusions
We believe that the current data have several important clinical implications. Undoubtedly, the most significant finding of the presented study concerns the
early effect of quinapril treatment on serum IL-6 level.
Considering the inflammatory concept of atherogene-
sis, we support expanding the indications for ACEI
use. ACEIs could, therefore, be appropriate therapeutic agents not only for patients with left ventricular
dysfunction, diabetic patients with hypertension or renal disease, and patients after myocardial infarction
but also may serve as a secondary prevention of stable
CAD.
In conclusion, our study raises the possibility that
quinapril influences the immune regulation by lowering serum IL-6.
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Received:
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