(Circulation. 1999;99:434-440.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Amelioration by Quinapril of Myocardial Infarction Induced by Coronary Occlusion/Reperfusion in a Rabbit Model of Atherosclerosis
Possible Mechanisms
From the Division of Cardiology (S.H., N.Y., T.K., M.H.), First Department of Medicine, Osaka University Medical School; Discovery Research (K.K.), Yoshitomi Pharmaceutical Industries Ltd, Fukuoka; and Cardiovascular Division (S.H.), Osaka Rosai Hospital, Sakai, Japan.
Correspondence to Shiro Hoshida, MD, PhD, Cardiovascular Division, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai 591-8025, Japan. E-mail hoshidas{at}orh.go.jp
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Abstract |
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Background—The increased severity of the myocardial injury produced by coronary occlusion-reperfusion in models of atherosclerosis is associated with an increase in leukocyte accumulation in the ischemic myocardium. Expression of P-selectin, an adhesion molecule involved in the interaction between leukocytes and endothelium, is increased in atherosclerotic vessels. Long-term angiotensin-converting enzyme (ACE) inhibition has been shown to reduce atherosclerotic vascular change in experimental models.
Methods and Results—We examined changes in the size of the infarct resulting from coronary occlusion/reperfusion in normally fed and cholesterol-fed rabbits that were chronically treated with quinapril. Infarct size was significantly larger in the cholesterol-fed versus normally fed rabbits. ACE activity in the ischemic and nonischemic myocardium was significantly reduced by quinapril. Chronic quinapril administration significantly ameliorated the increased myocardial injury in cholesterol-fed rabbits. Quinapril administration markedly increased the myocardial cGMP content and reduced the myeloperoxidase activity in the border region of the ischemic myocardium in cholesterol-fed rabbits. The enhanced expression of P-selectin in myocardial tissue of cholesterol-fed rabbits was also effectively reduced by quinapril treatment. The above effects of quinapril were eliminated by blockade of bradykinin B2 receptors or inhibition of nitric oxide synthesis.
Conclusions—Chronic quinapril treatment ameliorated the severity of myocardial injury produced by coronary occlusion/reperfusion in cholesterol-fed rabbits, possibly because of reversal of the enhanced interaction between leukocytes and endothelium in the ischemic myocardium via a bradykinin-related pathway.
Key Words: hypercholesterolemia • atherosclerosis • myocardial infarction • P-selectin
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Introduction |
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An impairment of coronary endothelium-dependent relaxation (EDR) increases the interaction between leukocytes and endothelium, leading to a progression of the myocardial infarct produced by coronary occlusion/reperfusion.1 2 In atherosclerotic coronary circulation, coronary EDR is known to be impaired but is effectively restored by chronic administration of the angiotensin-converting enzyme (ACE) inhibitor quinapril.3 ACE inhibitors block the degradation of bradykinin, thus increasing the production of nitric oxide (NO). These inhibitors significantly reduce the atherosclerotic area4 5 6 7 and restore EDR7 8 of the aorta in several atherosclerotic models.
The severity of myocardial injury has been shown to be exacerbated by acute hypercholesterolemia.9 10 11 We previously reported that the size of the infarct produced by coronary occlusion/reperfusion is increased in cholesterol-fed rabbits or rabbits with hereditary hyperlipidemia versus normal rabbits.12 13 14 The reduction of infarct size by administration of an NO donor or an antioxidant in these rabbits is associated with a reduction in leukocyte accumulation of the ischemic myocardium. In rabbits with hereditary hyperlipidemia, the expression of P-selectin, an adhesion molecule involved in the interactions between the leukocytes and the endothelium, is increased in the coronary endothelium.14 P-selectin has been shown to be suppressed by NO15 16 but induced by oxidized low-density lipoprotein17 and oxygen radicals.18 Reduction of P-selectin expression may be important in the decrease in the infarct size through the reversal of the enhanced interactions between leukocytes and endothelium.
The purpose of the present study was to investigate the effects of chronic ACE inhibition on infarct size and leukocyte accumulation in the ischemic myocardium of atherosclerotic rabbits. The expression of P-selectin in the myocardial tissue, the content of cGMP in the myocardium of atherosclerotic rabbits, and the effects of blockade of the bradykinin B2 receptor or inhibition of NO synthase were also examined.
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Methods |
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Protocol
A total of 60 male Japanese white rabbits (2.4 to 2.8 kg) were fed a diet of standard laboratory chow (normally fed; n=26) or chow that was supplemented with 1% cholesterol (cholesterol-fed; n=34) for 10 weeks. From the beginning of the diet regimen, 24 cholesterol-fed rabbits and 16 normally fed rabbits received 3 mg · kg-1 · d-1 quinapril in single oral doses for 10 weeks (treated groups). In a preliminary study, this dose of quinapril did not reduce mean arterial pressure in cholesterol-fed rabbits 24 hours after the last administration. Arterial blood samples for measurement of plasma total cholesterol were collected into tubes containing heparin immediately before the 10-week feeding period and at the end of the 10 week-period, 24 hours after the last dose of quinapril.
After 10 weeks on their respective diets and 24 hours after the last dose of quinapril, the rabbits were anesthetized with injections of sodium pentobarbital (30 mg/kg), intubated, and ventilated with the use of a small-animal respirator. The right femoral artery was used for the continuous measurement of heart rate and arterial blood pressure. The right femoral vein was used for drug administration. Experimental myocardial infarction was induced as reported previously.12 13 14 Briefly, a silk thread was passed around a branch of the left coronary artery with a tapered needle, and the ends of the thread were passed through a small vinyl tube. The snare was released after 30 minutes of coronary occlusion. The surgical wounds were repaired 60 minutes after reperfusion, and the animals were returned to individual cages for recovery. Aseptic surgical techniques were observed throughout. Benzylpenicillin (30 000 U/kg) was injected intramuscularly as prophylaxis against infection. The snare was left in place for 48 hours. No rabbits received quinapril during the 48-hour reperfusion phase. Some quinapril-treated rabbits were pretreated with an intravenous bolus of HOE 140, a bradykinin B2 receptor antagonist (26 µg/kg), 15 minutes before the coronary occlusion.19 In some quinapril-treated, cholesterol-fed rabbits (n=6), a competitive NO-synthase inhibitor, NG-L-nitro-arginine methyl ester (L-NAME, 100 µg · kg-1 · min-1)20 was continuously infused beginning before coronary occlusion and lasting for 60 minutes. Forty-eight hours after the reperfusion, each rabbit received an intravenous injection of 1000 U of heparin and was then administered an overdose of pentobarbital. The aortic tissue and the heart were then removed for postmortem evaluation. In additional experiments (n=25), myocardial sampling was done after only 30 minutes of reperfusion to examine the accumulation of leukocytes and the content of cGMP. The border region (nonblue side) of the ischemic myocardium was determined by introducing Evans blue dye after reocclusion of the left coronary branch without staining with triphenyltetrazolium chloride.12 All studies were performed in accordance with the guidelines of the Committee on the Care and Use of Animals.
Assessment of Aortic Atherosclerosis
The surface area of the atherosclerotic lesions was determined
in the thoracic aorta as previously described.7 14
Briefly, adventitial tissue was dissected from the aorta and any
remaining blood was rinsed away. The surface area of the lesion and the
total aortic surface area were measured by planimetry of photographic
images.
To assess EDR, arterial rings 5 mm long were cut and suspended from strain gauges. The isometric circumferential force was measured as previously described.14 Relaxation was measured in rings precontracted by incubation with 1 µmol/L norepinephrine. Endothelial control of vascular tone was assayed by the addition of acetylcholine (ACh, 1 nmol/L to 10 µmol/L), and vasodilation of smooth muscle cells was assessed using sodium nitroprusside (SNP, 1 nmol/L to 10 µmol/L).
Measurement of Infarct Size
The size of the infarct was assessed as reported
previously.12 13 Briefly, Evans blue dye (2%) was
introduced after the reocclusion of the left coronary branch to
estimate the ventricular mass perfused by the occluded
artery (ischemic region). The left ventricle was cut
perpendicular to the apex-base axis into 6 pieces. The slices were then
incubated with 1% triphenyltetrazolium
chloride to stain the noninfarcted region. The area at risk was defined
as the ischemic region/left ventricular mass ratio
and the infarct size as the infarct region/ischemic region mass
ratio.
Assay of ACE Activity
ACE activity was determined spectrophotometrically by a method
modified7 from that of Cushman and Cheung.21
After the 48-hour reperfusion phase, aortic tissues and myocardial
samples obtained from nonischemic and ischemic tissues
were homogenized on ice and were centrifuged for 20
minutes at 1500g (4°C). The supernatant was incubated at
37°C for 60 minutes with
hippuryl-L-histidyl-L-leucine
in 10 mmol/L potassium phosphate buffer (pH 8.3) that contained
300 mmol/L sodium chloride. Hippurate was detected by absorbance
at 228 nm. One unit of ACE activity was defined as the amount of enzyme
that generated 1 nmol of hippurate per minute at 37°C.
Measurement of cGMP Content
The myocardial cGMP content was measured by ELISA (Amersham).
After 30 minutes of reperfusion, hearts were excised and tissue samples
were homogenized in 0.1N hydrochloric acid; the
supernatants obtained by centrifugation were
assayed.
Assessment of Leukocyte Accumulation
Myeloperoxidase (MPO) activity was assayed as previously
described.12 Myocardial tissue was obtained from the
ischemic and nonischemic regions of hearts reperfused
for 48 hours and from nonischemic and border regions of hearts
reperfused for 30 minutes. These samples were frozen rapidly in liquid
nitrogen. One unit of MPO activity was defined as the amount of enzyme
required to degrade 1 µmol peroxide per minute at 30°C.
Immunohistochemistry
Immunohistochemical evaluation was performed as reported
previously.14 The specimens of left ventricle were
incubated with monoclonal mouse anti-human P-selectin (WAPS 12.2,
Endogen Inc., Cambridge, Mass) for 60 minutes at room temperature; they
were then exposed to peroxidase-conjugated affinity purified anti-mouse
IgG (Kirkegaard & Perry Laboratories Inc., Gaithersburg, Md) for 30
minutes. Specific antigen-antibody complexes were visualized by
development in 3-amino-9-ethylcarbazole (Aldrich-Chemie) and
hydrogen peroxide in acetate buffer (0.05 mol/L, pH 5.0). The sections
were counterstained with hematoxylin and then dehydrated. Controls were
obtained by replacing the primary antibody with 10% nonimmune serum or
phosphate-buffered saline. Additional controls were obtained by
omitting the secondary antibody. All controls were negative.
Statistical Analysis
Values are expressed as mean±SEM. The significance of
differences in infarct size, ACE activity, and
hemodynamic changes were determined by analysis
of variance (ANOVA) followed by Scheffé's test as appropriate.
ANCOVA was used to compare the regression lines of ischemic
region mass versus infarcted tissue mass. A level of P<0.05
was accepted as statistically significant.
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Results |
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Mortality and Characteristics
Two rabbits died of ventricular fibrillation during reperfusion, and 1 rabbit in each group died during coronary occlusion. The mortality rate did not differ significantly among the groups. There were no significant differences in body weight or plasma total cholesterol concentration among the groups at the beginning of the 10-week feeding period (Table 1
). After the 10-week feeding period,
there was no significant difference in the plasma total
cholesterol concentration among the groups of
cholesterol-fed rabbits or among the groups of normally fed
rabbits.
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Effect of Chronic Quinapril on Aortic Atherosclerosis
The chronic administration of quinapril effectively reduced the
area of atherosclerotic plaque in the thoracic aorta of the
cholesterol-fed rabbits (Figure 1). Aortic ACE activity was significantly
higher in cholesterol-fed rabbits than in normally fed
rabbits (Figure 1). The activity in both groups was markedly
suppressed by the treatment with quinapril.
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P<0.05 versus group without quinapril.
Both results obtained by ANOVA and Scheffé's test.
In aortic rings from normal-fed rabbits, ACh induced relaxation in a
concentration-dependent manner (Figure 2). Maximal relaxation (complete
elimination of norepinephrine-induced contraction) was
observed at 10 µmol/L. In aortic rings obtained from the
untreated cholesterol-fed rabbits, ACh was less
efficacious, but the chronic administration of quinapril partially
restored the response to ACh. In contrast, the vasodilatory response to
the NO donor SNP was similar in the experimental groups.
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Hemodynamic Variables
There was no significant difference in arterial
pressure among the groups during ischemia and reperfusion (data
not shown). The rate-pressure product, an index of myocardial
oxygen consumption, was similar at all time points. The rate-pressure
product in the 2 groups pretreated with HOE 140 or in the
L-NAME-treated group did not differ from that of the other groups.
Infarct Size
The size of the infarct was significantly greater in the untreated
cholesterol-fed rabbits than in the rabbits fed a normal
diet (Figure 3). The size of the infarct
in the quinapril-treated rabbits fed a normal diet did not differ
significantly from that in the untreated group fed a similar diet.
However, the size of the infarct in the quinapril-treated,
cholesterol-fed rabbits was significantly smaller than that
in the untreated, cholesterol-fed rabbits. The
quinapril-induced reduction in the size of the infarct in
cholesterol-fed rabbits was eliminated by administering a
bradykinin B2 receptor blocker. The size of the
infarct in the quinapril-treated, normally fed rabbits was not affected
by pretreatment with HOE 140. Acute treatment with L-NAME during
coronary occlusion and reperfusion also reversed the
quinapril-induced reduction of infarct size in
cholesterol-fed rabbits. There were no significant
differences among the groups in the area at risk.
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P<0.05 versus quinapril without HOE
140 or L-NAME.
The infarct tissue mass was significantly correlated with the mass of
the ischemic region in all groups. The regression line of data
from the untreated, cholesterol-fed rabbits was
significantly different from that for the untreated, normally fed
rabbits or the 2 quinapril-treated groups (Figure 4). Although not shown, the regression
line for the quinapril-treated, cholesterol-fed rabbits
given HOE 140 or L-NAME was similar to the line for the untreated,
cholesterol-fed rabbits.
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ACE Activity in Myocardial Tissue
ACE activity in ischemic myocardium of the
untreated groups was significantly greater than activity in the
nonischemic myocardium (Figure 5). ACE activity in ischemic and
nonischemic myocardium from
cholesterol-fed rabbits was also higher than activity in
the corresponding tissue from normally fed rabbits. Treatment with
quinapril significantly reduced the ACE activity of the
ischemic and nonischemic myocardium in both
the normally fed and cholesterol-fed rabbits.
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cGMP Content in Myocardial Tissue
cGMP content in nonischemic myocardium after
30 minutes of reperfusion did not differ significantly among the groups
(Figure 6). The content in the border
region of the ischemic myocardium was significantly
reduced, compared with the nonischemic myocardium
in both normally fed and cholesterol-fed rabbits. Chronic
quinapril treatment restored the cGMP content in the border region in
cholesterol-fed rabbits, although HOE 140 pretreatment
eliminated the effect of quinapril. Acute treatment with L-NAME also
reversed the effect of quinapril on the cGMP content in
cholesterol-fed rabbits.
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Accumulation of Leukocytes
In all groups, MPO activity was significantly higher in the
ischemic versus the nonischemic myocardium.
The MPO activity in the ischemic myocardium after
48 hours of reperfusion was significantly higher in the untreated
cholesterol-fed rabbits than that in normally fed rabbits.
MPO activity was effectively reduced by chronic quinapril treatment in
the ischemic myocardium of the
cholesterol-fed rabbits (Figure 7 top). Even after 30 minutes of
reperfusion, MPO activity was significantly higher in the border region
of the ischemic myocardium than in the
nonischemic myocardium in both
cholesterol-fed and normally fed rabbits (Figure 7
bottom). The activity of the border region of
cholesterol-fed rabbits was further increased compared with
normally fed rabbits and was significantly suppressed by chronic
quinapril. Pretreatment with HOE 140 eliminated the quinapril-induced
suppression of MPO activity of the border region in
cholesterol-fed rabbits (Figure 7 bottom). Treatment
with L-NAME also reversed the effect of quinapril in
cholesterol-fed rabbits.
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Expression of P-Selectin
After 30 minutes of reperfusion, P-selectin in the border region
of the ischemic tissue was localized on coronary
endothelium with leukocytic emboli in untreated
cholesterol-fed rabbits (Figure 8B), although the expression of
P-selectin on intravascular platelets could not be ruled out. In
contrast, little or no specific staining for P-selectin was observed on
the myocardium in chronically quinapril-treated
cholesterol-fed rabbits (Figure 8C). Pretreatment
with HOE 140 reversed the reduced expression of P-selectin in
quinapril-treated cholesterol-fed rabbits (Figure 8D). Although not shown, acute treatment with L-NAME also
increased the expression of P-selectin in the treated,
cholesterol-fed rabbits. Rabbits fed a normal diet did not
express P-selectin in postischemic myocardial tissue
(Figure 8A), and the chronic quinapril treatment did not affect
the expression of P-selectin (data not shown).
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Discussion |
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Atherosclerosis in ACE Inhibition
We recently reported that ACE activity increases during the process of atherosclerotic lesion formation in the aorta and that chronic ACE inhibition with enalapril effectively reduces aortic atherosclerotic lesion area in association with a significant reduction of aortic ACE activity.7 Results of the present study are consistent with these previous observations. Moreover, chronic administration of quinapril, which is a more potent inhibitor of ACE activity than enalapril in several tissues,22 reduced both the atherosclerotic lesion area and ACE activity in aorta more effectively than enalapril (compared with data from reference 7).
Mechanism for Limitation of Size of Infarct
Chronic quinapril treatment reduced the severity of myocardial
injury in the cholesterol-fed rabbits to the level observed
in the normally fed rabbits, except during bradykinin
B2 receptor blockade or NO synthase inhibition.
Under these conditions, chronic quinapril ameliorated the reduction of
cGMP content and the increased MPO activity and reduced the increased
expression of P-selectin in the border region of the ischemic
myocardium in cholesterol-fed rabbits.
P-selectin has been shown to be induced by oxidized low-density
lipoprotein and/or lysophosphatidylcholine15 17 and to be
suppressed by NO.15 16 The restoration of cGMP content of
the border region by chronic quinapril may reflect the increased
production of NO. Furthermore, a competitive NO-synthase
inhibition effectively increased the size of the infarct associated
with the augmentation of myocardial MPO activity in quinapril-treated,
cholesterol-fed rabbits. These results suggest that the
efficacy of chronic quinapril in limiting the size of the infarct in
cholesterol-fed rabbits may be related to the reduction of
leukocyte-induced myocardial injury by suppressing the expression of
P-selectin. A reduction in P-selectin expression would result from an
increased production of NO because of a reduction in the
degradation of bradykinin. However, one cannot rule out a more direct
effect of bradykinin on adhesion between leukocytes and
endothelium.23 The expression of other
important adhesion molecules involved in the interaction between
leukocytes and endothelium remains to be
investigated.
Inhibition of Myocardial ACE
Although myocardial ACE activity was suppressed by chronic
quinapril more completely in the present study than in previous
studies with enalapril, the infarct-limiting effect of quinapril did
not differ significantly from that of enalapril in
cholesterol-fed rabbits.24 The suppression of
myocardial ACE activity to some threshold level may be sufficient to
reduce the size of the infarct. A threshold level of bradykinin in
myocardial tissue may be all that is needed to reduce leukocyte
accumulation and infarct size. Because myocardial ACE activity was
completely suppressed 3 days after the last dose of quinapril in the
present study, left ventricular remodeling after
myocardial infarction may be inhibited sufficiently even when treatment
with quinapril commences 2 days after the onset of myocardial
infarction in patients that had received chronic quinapril treatment
before onset of infarction.
ACE Inhibition in Normal Rabbits
Adhesion molecules such as P-selectin and intercellular adhesion
molecule-1 are expressed in the coronary bed of the reperfused
myocardium in normal cats;25 antibodies
against these adhesion molecules have reduced myocardial injury in
normal dogs.26 However, there may be species differences
in the expression of P-selectin in the ischemic
myocardium. P-selectin was not expressed in the
coronary vasculature of the ischemic/reperfused
myocardium and chronic quinapril treatment did not modulate
its expression in normally fed rabbits. Therefore, quinapril could not
further reduce leukocyte accumulation in the border region of the
ischemic myocardium, consistent with the
inability to limit infarct size in normally fed rabbits in the
present study. Several investigators have reported infarct-limiting
effects of acute treatment with ACE inhibitors and its
reversal by bradykinin receptor blockade in normal
animals.27 28 The reason for the discrepancy may lie in
differences in experimental design, such as the timing of infarct size
assessment or ACE inhibitor administration. Failure of
limitation of infarct size by ACE inhibitors has also been
reported in normal dogs29 and rabbits.30
Study Limitations
Although coronary EDR was not measured in all groups,
quinapril has been shown to restore coronary EDR in
humans.3 Myocardial cGMP content and P-selectin expression
were determined after 30 minutes of reperfusion, but examination of the
time course of these parameters may be important in
elucidating the precise mechanism for infarct size-limitation in
cholesterol-fed rabbits. Little work has been done on the
effect of ACE inhibition on platelet function. Furthermore, changes
in healing or collagen deposition at longer time points following
myocardial injury in an ACE inhibitor-treated,
cholesterol-fed rabbits remain to be elucidated. It is
interesting to know how long ACE inhibitors should be
administered to obtain favorable effects on infarct size in
cholesterol-fed rabbits, although short-term treatment with
quinapril for 1 week did not reduce infarct size in our preliminary
study (data not shown).
Conclusions
Chronic quinapril treatment ameliorated the severity of myocardial
injury that resulted from coronary occlusion/reperfusion in
cholesterol-fed, but not normally fed, rabbits. The
improvement was associated with a reduction in the myocardial
accumulation of leukocytes possibly because of an inhibition of
myocardial expression of P-selectin. Bradykinin receptor blockade or
NO-synthase inhibition effectively reversed the favorable effects of
chronic quinapril treatment, suggesting that reduction of bradykinin
degradation may enhance NO production, thus leading to the
reduction of P-selectin expression and the reduction of infarct size
only in the cholesterol-fed rabbits. Chronic inhibition of
ACE may exert favorable effects especially in
pathophysiological conditions that result from an
impaired EDR and an increased expression of P-selectin, conditions
commonly observed in patients with atherosclerosis.
Received April 22, 1998; accepted September 8, 1998.
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  H. Yaoita, K. Yoshinari, K. Maehara, M. Sando, K. Watanabe, and Y. Maruyama Different Effects of a High-Cholesterol Diet on Ischemic Cardiac Dysfunction and Remodeling Induced by Coronary Stenosis and Coronary Occlusion J. Am. Coll. Cardiol., June 21, 2005; 45(12): 2078 - 2087. [Abstract] [Full Text] [PDF]
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 H. L. Lazar Role of Angiotensin-Converting Enzyme Inhibitors in the Coronary Artery Bypass Patient Ann. Thorac. Surg., March 1, 2005; 79(3): 1081 - 1089. [Abstract] [Full Text] [PDF]
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 L. Agullo, D. Garcia-Dorado, N. Escalona, M. Ruiz-Meana, J. Inserte, and J. Soler-Soler Effect of ischemia on soluble and particulate guanylyl cyclase-mediated cGMP synthesis in cardiomyocytes Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2170 - H2176. [Abstract] [Full Text] [PDF]
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 L. Murphey, D. Vaughan, and N. Brown Contribution of bradykinin to the cardioprotective effects of ACE inhibitors Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A37 - A41. [Abstract] [PDF]
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L. Agullo, D. Garcia-Dorado, N. Escalona, J. Inserte, M. Ruiz-Meana, J. A. Barrabes, M. Mirabet, P. Pina, and J. Soler-Soler Hypoxia and acidosis impair cGMP synthesis in microvascular coronary endothelial cells Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H917 - H925. [Abstract] [Full Text] [PDF]
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H. L. Lazar, Y. Bao, S. Rivers, T. Colton, and S. A. Bernard High tissue affinity angiotensin-converting enzyme inhibitors improve endothelial function and reduce infarct size Ann. Thorac. Surg., August 1, 2001; 72(2): 548 - 553. [Abstract] [Full Text] [PDF]
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 S. Fischer, A. A. MacLean, M. Liu, B. Kalirai, and S. Keshavjee Inhibition of angiotensin-converting enzyme by captopril: A novel approach to reduce ischemia-reperfusion injury after lung transplantation J. Thorac. Cardiovasc. Surg., September 1, 2000; 120(3): 573 - 580. [Abstract] [Full Text] [PDF]
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S. Hoshida, N. Yamashita, K. Otsu, T. Kuzuya, and M. Hori Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H256 - H262. [Abstract] [Full Text] [PDF]
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 J.-S. Silvestre, S. Bergaya, R. Tamarat, M. Duriez, C. M. Boulanger, and B. I. Levy Proangiogenic Effect of Angiotensin-Converting Enzyme Inhibition Is Mediated by the Bradykinin B2 Receptor Pathway Circ. Res., October 12, 2001; 89(8): 678 - 683. [Abstract] [Full Text] [PDF]
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