Published online before print May 10, 2001, doi: 10.1161/hh1001.090759
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2001 American Heart Association, Inc.
Integrative Physiology |
Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice
From the Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Mich.
Correspondence to Xiao-Ping Yang, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202. E-mail xpyang1{at}hfhs.org
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Abstract—Using B2 kinin receptor gene knockout mice (B2-/-), we tested the hypothesis that (l) lack of B2 receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT1-ant), whereas lack of B2 receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B2-/- and 129/SvEvTac mice (wild-type control, B2+/+). An ACEi (ramipril, 2.5 mg/kg/d) or AT1-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B2+/+ and B2-/- mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B2-/- mice (respective values for B2+/+ versus B2-/- mice: overall increase in ejection fraction, 64±10% versus 21±5% [P<0.01]; increase in CO, 69±17% versus 23±9% [P<0.01]; overall decrease in LVDd, -24±3% versus -7±4% [P<0.01]; and decrease in LV mass, -38±3% versus -6±6% [P<0.01]). AT1-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B2-/- mice (respective values for B2+/+ versus B2-/- mice: overall increase in ejection fraction, 46±10% versus 25±9% [P<0.01]; increase in CO, 44±14% versus 15±5% [P<0.01]; overall decrease in LVDd, -14±4% versus -6±3% [P<0.01]; and decrease in LV mass, -33±4 versus -16±7% [P<0.01]). The effect of ACEi or AT1-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B2-/- mice. We concluded that (1) lack of B2 kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B2 receptor play an important role in the cardioprotective effect of ACEi and AT1-ant.
Key Words: angiotensin-converting enzyme inhibitors • AT1 receptor antagonist • heart failure • B2 kinin receptors • mice
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Chronic heart failure (CHF) is characterized by left ventricular (LV) pump dysfunction, chamber dilatation, neurohormonal system activation, and exercise intolerance. The renin-angiotensin system (RAS) plays a central role in this process.1 2 3 Over the past decade, clinical and laboratory studies have provided evidence that interruption of the RAS achieved by angiotensin-converting enzyme inhibitors (ACEi) improves cardiac function, regresses LV remodeling, and prolongs survival in patients with CHF.4 5 6 However, it remains unclear whether the benefits of ACEi are entirely due to blockade of angiotensin II (Ang II) formation or partially derived from increased kinins, because ACE is also the major kininase that degrades kinins to inactive fragments.7 8 We and others have previously reported that ACEi attenuated the deterioration of LV function and remodeling in animals with CHF due to myocardial infarction (MI) and that this effect was either blocked by a B2 kinin receptor antagonist (B2-ant)9 10 or blunted in rats with kininogen deficiency due to spontaneous mutation of the kininogen gene,11 indicating that kinins play an important role in the cardioprotective mechanism of ACEi. However, it remains controversial whether kinins play an essential role in regulating blood pressure (BP) and cardiac function under physiological conditions or in the pathophysiology of CHF. It has recently been reported that disruption of the bradykinin B2 receptor gene in mice (B2-/- mice) increased BP, heart weight, and LV chamber dimension.12 13 However, we previously found that blockade of the B2 kinin receptor or genetic kinin deficiency neither altered BP nor aggravated cardiac remodeling and LV dysfunction, although it did partially block the cardioprotective effect of ACEi.9 11 14 We also showed that in B2-/- mice, BP and the severity of ischemia/reperfusion injury did not differ from their wild-type controls (B2+/+).15 However, it is not known whether the chronic maladaptive response to MI (such as LV hypertrophy, chamber dilatation, and dysfunction) is enhanced in B2-/- mice.
Despite treatment with ACEi, some patients still experience worsening symptoms and deterioration of LV function, which may be related to incomplete inhibition of Ang II formation or continued activation of the RAS. Thus, it has been proposed that blockade of the RAS at the receptor level may provide an additional advantage over ACEi. However, our previous study in rats showed that an Ang II type 1 (AT1) receptor antagonist (AT1-ant) had a cardioprotective effect similar to that of ACEi, and that this effect was partially blocked by a B2-ant or Ang II type 2 (AT2) receptor antagonist (AT2-ant),9 indicating that (1) at least in this rat model of heart failure (HF), AT1-ant are not superior to ACEi, although it is not certain whether combined treatment with ACEi and AT1-ant would provide a better effect than either drug alone; and (2) activation of the AT2 receptor during AT1 inhibition might be partially responsible for the cardioprotective effect of AT1-ant either directly or via stimulation of kinins and/or NO and cGMP.16 17 18
To further test the hypothesis that kinins mediate the cardioprotective effect of ACEi and AT1-ant, we produced CHF in B2+/+ and B2-/- mice by ligating the left anterior descending coronary artery (LAD) and studied whether (1) lack of kinin B2 receptors aggravates cardiac remodeling and LV dysfunction, and (2) the cardioprotective effect of ACEi or AT1-ant is diminished or absent in B2-/- mice.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals
B2-/- mice were derived from a breeding pair of homozygous mice on a 129/SvEv genetic background19 and are currently being bred in our Mutant Mouse Facilities. Wild-type 129/SvEvTac mice (B2+/+) purchased from Taconic Farms (Germantown, NY) served as controls. Animals were housed in an air-conditioned room with a 12-hour light/dark cycle, received standard mouse chow, and drank tap water. The Henry Ford Hospital Care of Experimental Animals Committee approved the present study.
Surgical Procedures
Male mice aged 10 to 12 weeks were
anesthetized with sodium pentobarbital (50 mg/kg IP),
intubated, and ventilated with room air using a positive-pressure
respirator. A left thoracotomy was performed via the fourth intercostal
space, the heart was exposed, and the pericardium opened as described
previously.20 The LAD was
ligated with a 9-0 silk suture near its origin between the
pulmonary outflow tract and the edge of the left atrium. MI was
deemed successful when the anterior wall of the LV became cyanotic and
the ECG showed obvious ST-segment elevation. The lungs were inflated by
increasing positive end-expiratory pressure, and the thoracotomy site
was closed. Sham-operated mice were subjected to the same procedure,
except that the suture around the LAD was not tied. Animals were kept
on a heating pad until they were awake.
Measurement of BP and Cardiac Function
Systolic BP
Systolic BP (SBP) was measured in conscious
mice by use of a noninvasive computerized tail-cuff system (BP-2000,
Visitech Systems) as described
previously.21 22
Briefly, the mice were trained for 7 days by measuring SBP daily, after
which SBP was recorded weekly. Three sets of 10 measurements were
obtained during each recording; a set was accepted if the
computer identified >6 successful readings out of 10
measurements.
Echocardiography
Cardiac geometry and function were evaluated with a
Doppler echocardiographic system equipped with a
15-MHz linear transducer (Acuson c256) as described
previously.23 All studies
were performed on awake mice before MI and periodically thereafter. The
following parameters were obtained: (1) LV chamber
dimensions and wall thickness; (2) LV mass, which is equivalent to
1.055[(IVSd+LVDd+PWTd)3-(LVDd)3],
where 1.055 is the specific gravity of the myocardium, IVSd
is interventricular septum thickness, LVDd is
diastolic LV dimension, and PWTd is diastolic
posterior wall thickness (LV mass was normalized for body weight and
expressed as mg/10 g); (3) ejection fraction (EF), which is equivalent
to [(LVAd-LVAs)/LVAd]x100, where LVAd is LV diastolic
area and LVAs is LV systolic area; and (4) cardiac output (CO),
which is equivalent to SVxHR, with SV=CSAxVTI and
CSA=[(AoD/2)2]
, where SV is stroke
volume, HR is heart rate, CSA is aortic cross-sectional area, VTI is
the aortic flow velocity-time integral, and AoD is aortic diameter (CO
was normalized for body weight and expressed as mL/min/10
g).
All primary measurements, such as LV wall thickness, dimensions, and CSA, were traced manually and digitized by goal-directed, diagnostically driven software installed within the echocardiograph. Three beats were averaged for each measurement.
Histopathological Study
Heart Weight, Lung Wet Weight, and Infarct
Size
Mice were killed after 12 weeks of MI, and their
hearts and lungs were weighed. The LV was sectioned transversely into 3
slices from apex to base, rapidly frozen in isopentane precooled in
liquid nitrogen, and then stored at -70°C. For infarct size, 6-µm
sections from each slice were stained with Gomori trichrome to identify
fibrous tissue (infarction). Infarct size was calculated as the ratio
of infarct length to the circumference of both endocardium and
epicardium.24
MCSA and ICF
Sections (6-µm) were cut from each slice and
double-stained with (1) fluorescein-labeled peanut
agglutinin to delineate the myocyte cross-sectional area (MCSA) and
interstitial space, and (2) rhodamine-labeled
Griffonia simplicifolia lectin
I to show the capillaries.9
Four radially oriented microscopic fields were selected from each
section and photographed at a magnification of x100. MCSA was measured
by computer-based planimetry (Jandel). For the interstitial
collagen fraction (ICF), the total surface area (microscopic field),
interstitial space (collagen plus capillaries), and area
occupied by the capillaries alone were measured with computer-assisted
videodensitometry and calculated as per cent total surface area
occupied by the interstitial space minus per cent total
surface area occupied by the capillaries. Average MCSA and ICF were
calculated for each mouse.
Experimental Protocols
Protocol 1 involved comparing the cardiac
phenotype between
B2+/+ and
B2-/- mice before
and after MI and determining whether the development of cardiac
dysfunction and LV remodeling was more severe or accelerated in
B2-/- mice. Each
strain was subjected to either coronary ligation (HF-vehicle)
or sham MI and was followed up for 12 weeks.
Protocol 2 involved determining whether the effect of ACEi or AT1-ant was diminished or absent in B2-/- mice. One week after the operation, each strain was divided into (1) HF-vehicle, (2) HF-ACEi (ramipril, 2.5 mg/kg per day in drinking water, provided by Upjohn), and (3) HF-AT1-ant (L-158809, 3 mg/kg/d in drinking water, provided by Merck). Treatment was continued for 11 weeks. We have previously shown that ramipril at 2.5 mg/kg per day significantly inhibited the vasopressor effect of exogenous Ang I at 12.5, 25, 50, and 100 ng per mouse and that L-158809 at 3 mg/kg per day significantly inhibited the vasopressor effect of exogenous Ang II at 12.5, 25, 50, and 100 ng per mouse.25
Data Analysis
Data were expressed as mean±SE. Two-way
repeated-measures ANOVA was used to detect differences within each
strain. For comparison between strains, repeated-measures ANOVA was
used with a test of interaction to determine whether the average change
after treatment (from week 2 to week 12) was different between
B2+/+ and
B2-/- mice,
taking P<0.05 as being
statistically significant. One-way ANOVA was used for heart and lung
weight and histopathological data. The Simes method was used to
adjust for multiple
comparisons.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Mortality
The mortality rate was similar between the 2 strains. Early mortality (within 24 hours after surgery) was 15.8% in B2+/+ mice and 13.5% in B2-/- mice. During the first week of MI, 40% of the B2+/+ mice and 23% of the B2-/- mice died, mostly from cardiac rupture. During weeks 2 to 12, only 1 B2+/+ mouse and 2 B2-/- mice died. None of the B2+/+ or B2-/- mice that underwent the sham procedure died during or after the operation.
Body, Heart, Lung, and Liver Weight
and Infarct Size
There was no significant difference in any of these
parameters between strains in sham-ligated groups
(Table
).
In the HF-vehicle groups, heart and lung weight increased similarly in
both strains. ACEi or AT1-ant reduced heart
weight to a similar extent in both strains but had no effect on lung
weight. Liver weight was increased only in
B2+/+ mice, and drug
treatment had no effect on it.
|
SBP and HR
Basal SBP and HR were similar for both strains in all
groups. After MI, SBP in the
B2+/+ HF-vehicle
group decreased significantly, which was not seen in the
B2-/- group. ACEi
or AT1-ant did not influence SBP in
B2+/+ but did reduce
SBP in B2-/-
(Figure 1, top). There was a slight increase in HR after MI,
but it did not reach statistical significance. Drug treatment had no
effect on HR
(Figure 1, bottom).
|
Cardiac Function and Remodeling
There was no difference between sham-ligated
B2+/+ and
B2-/- mice with
regard to EF, CO, LVDd, and cardiac mass
(Figure 2). MI caused a significant reduction in EF and CO
and elevation in LVDd and LV mass, occurring as early as 1 week after
MI and progressing similarly over time in both strains
(Figure 2). ACEi significantly increased EF and CO
(Figures 3 and 4) and decreased LVDd and LV mass
(Figures 3 and 5) in both strains with HF; however, the effect
of ACEi was significantly attenuated in
B2-/- mice
compared with B2+/+.
The bar graphs in
Figures 4 and 5 show the average per cent increase in EF and
CO and decrease in LVDd and LV mass from 2 to 12 weeks of treatment
between the 2 strains. The overall increase in EF after ACEi was
64±10% in B2+/+ and
21±5% in B2-/-
(P<0.01), and the increase in
CO was 69±17% in
B2+/+ and 23±9% in
B2-/-
(P<0.01). The overall
reduction in LVDd was -24±3% in
B2+/+ versus
-7±4% in
B2-/-
(P<0.01), and the reduction in
LV mass was -38±3 in
B2+/+ and -6±6%
in B2-/-
(P<0.01).
AT1-ant had a beneficial cardiac effect similar
to ACEi; this effect was also diminished in
B2-/- mice. The
overall increase in EF with AT1-ant was 46±10%
in B2+/+ and 25±9%
in B2-/-
(P<0.01), and the increase in
CO was 44±14% in
B2+/+ and 15±5% in
B2-/-
(P<0.01). The overall
reduction in LVDd was -14±4% in
B2+/+ and -6±3%
in B2-/-
(P<0.01), and the reduction in
LV mass was -33±4% in
B2+/+ and -16±7%
in B2-/-
(P<0.01)
(Figures 4 and 5). Although the ACEi appeared to have a better
protective effect, the difference between ACEi and
AT1-ant did not reach statistical
significance.
|
|
|
|
Myocyte Size and ICF
MCSA and ICF were similar in sham-operated
B2+/+ and
B2-/- mice and
increased similarly after MI in both strains
(Figures 6 and 7). ACEi and AT1-ant
significantly decreased MCSA in both the
B2+/+ and
B2-/- groups, and
no statistical difference between strains was detected
(Figure 7, top). However, the effect of ACEi and
AT1-ant on ICF was observed only in
B2+/+ mice and was
absent in B2-/-
(Figure 7, bottom).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We found that basal SBP and cardiac function as well as morphological and histological parameters were no different in B2-/- mice compared with B2+/+. Development and severity of cardiac dysfunction after MI were also similar in B2-/- and B2+/+, suggesting that kinins acting on the B2 receptor may not play an essential role in the regulation of BP and cardiac function, either under normal physiological conditions or during the development of HF. Inhibition of ACE or blockade of the AT1 receptor improved cardiac function and remodeling, as evidenced by increased EF and reduced LV chamber dimension, mass, and interstitial collagen deposition; these effects were attenuated in B2-/- mice, indicating that kinins are at least partially responsible for the therapeutic effect of ACEi and AT1-ant in HF.
Kinins are vasodilator polypeptides released from low- and high-molecular-weight kininogens by plasma and tissue kallikreins and hydrolyzed mainly by ACE (also called kininase II). The biological action of kinins is mediated by activation of at least 2 known subtypes of G-protein–coupled receptors, B1 and B2.8 26 The B1 receptor is only weakly expressed under physiological conditions but is strongly induced under pathological conditions, such as inflammation or tissue injury,27 28 and is sensitive to des-Arg9-bradykinin, a metabolite of bradykinin. B2 receptors, which are constitutively expressed in most tissues, are sensitive to bradykinin and kallidin and are responsible for most known effects of bradykinin.8 Although the role of endogenous kinins in the regulation of BP and cardiac hemodynamic homeostasis as well as in the pathophysiology of HF has been studied extensively, the data remain controversial. Emanueli et al13 reported that disruption of the B2 receptor led to high BP, LV dilatation, and functional impairment, suggesting that kinins are essential for functional and structural preservation of the heart. However, we found that BP, cardiac performance, and histology in kininogen-deficient rats or B2-/- mice are no different from their wild-type controls.11 14 29 In the present study, we further demonstrated that lack of B2 kinin receptors neither alters BP or cardiac phenotype nor aggravates cardiac remodeling after MI, indicating that either (1) kinins may not play an important role in regulation of BP and function, or (2) there is a compensatory mechanism whereby metabolites of bradykinin act on the B1 receptor to assume some of its vasoactive properties. Tschöpe et al30 recently showed that both B1 and B2 receptors are upregulated after MI. It has also been shown that hindlimb ischemia in mice induced B1 gene overexpression accompanied by an increase in muscular capillary density, and that this angiogenesis was blunted by a B1 receptor antagonist but not affected by B2 blockade.31 Furthermore, Duka et al32 recently reported that the B1 receptor is upregulated in B2-/- mice and that these mice had a hypotensive response to a selective B1 agonist and a hypertensive response to a selective B1 receptor antagonist, indicating a compensatory function of the B1 receptor in maintaining hemodynamic homeostasis when the B2 receptor is absent.
Despite the fact that the hemodynamic and cardiac phenotypes are similar in B2-/- and control mice, we found that B2-/- mice had a diminished response to ACEi and AT1-ant. This agrees with our previous findings that ACEi and AT1-ant improved LV function and structural remodeling in Lewis inbred rats and that these effects were partially blocked by a kinin receptor antagonist,9 suggesting that the cardioprotective effects of ACEi are not solely attributable to inhibition of Ang II formation. In fact, ACE not only converts angiotensin I to Ang II but also degrades kinins to inactive fragments. Furthermore, the affinity of ACE for kinins is higher than for angiotensin I. Thus, inhibition of kinin degradation, which in turn results in increased endogenous kinins, is also largely responsible for the cardioprotection seen with ACEi. The precise mechanism by which kinins protect the heart is not yet well defined. It is known that kinins are potent stimuli for the release of endothelial NO and prostaglandins. Recently, Emanueli et al showed that local delivery of the human tissue kallikrein gene accelerated ischemia-induced hindlimb angiogenesis and preserved energy utilization of ischemic muscle31 and that this effect was blocked by the inhibition of cyclooxygenase or NO synthase,33 indicating a prostaglandin- and/or NO-mediated mechanism. It has also been shown that kinins inhibit collagen gene expression and collagen production via stimulation of arachidonic acid metabolites, particularly prostaglandin I2.34 In addition, kinins and NO may be involved in myocardial energy metabolism. Zhang et al35 recently showed that incubation of coronary microvessels or myocardial slices with ACEi or kininogen significantly increased NO production and decreased myocardial oxygen consumption,35 36 both of which were blocked by a B2 kinin receptor antagonist. They also showed that bradykinin stimulated the release of NO from the mouse myocardium and that this effect is absent in B2-/- mice.37 Using NO synthase (NOS) inhibitors or endothelial NOS knockout mice, Tada et al38 recently reported that NO participates in the regulation of myocardial glucose, lactate, and fatty acid metabolism.38 Perfusing the ischemic heart with bradykinin increases the production of myocardial high-energy phosphates as well as glycogen content, along with a reduction in lactate dehydrogenase and creatinine kinase activity.39 40 Taken together, these data suggest that kinins or NO may reduce oxygen consumption and facilitate energy utilization, thereby contributing significantly to the cardioprotective action of ACEi.
Two major Ang II receptor subtypes, AT1 and AT2, have been identified.41 Most known biological actions of Ang II have been attributed to the AT1 receptor, whereas the role of the AT2 receptor remains controversial. Recent evidence suggests that AT2 activation may antagonize the vasopressor, hypertrophic, and fibrogenic effects of AT1.42 43 44 Tsutsumi et al45 showed that in aortas from mice with overexpression of the AT2 receptor, Ang II caused a significant increase in kininogenase activity and cGMP production, which was further enhanced by an AT1-ant but blocked by an AT2-ant, kinin antagonist, or NOS inhibitor, suggesting that AT2 activation stimulates kinin release, which further promotes NO/cGMP production in a paracrine manner and thus potentiates vasodilatation and regional blood flow regulation. We previously reported that in a rat model of CHF induced by MI, AT1-ant had a cardioprotective effect similar to ACEi and that part of the effect of AT1-ant, such as reducing LV systolic and diastolic volume, was blocked by an AT2-ant or a B2 kinin antagonist.9 In the present study, using B2-/- mice as a model, we further confirmed the role of kinins in the cardioprotective effect of AT1-ant. It is possible that blockade of AT1 increases the level of Ang II, which in turn activates AT2. Activation of AT2 may stimulate the release of NO either directly or via kinins, leading to cardioprotection. We have recently demonstrated that the cardioprotective effect of ACEi or AT1-ant was diminished in endothelial NOS knockout mice with CHF induced by MI (Y.-H. Liu, J. Xu, X.-P. Yang, F. Yang, E.G. Shesely, O.A. Carretero, unpublished data, 2001), which may provide further evidence that endothelium-derived NO plays an important role in the beneficial cardiac effect of ACEi and AT1-ant.
In summary, we have demonstrated that (1) kinins acting via the B2 receptor do not seem to play an essential role in cardiac hemodynamics, morphology, and function either under normal physiological conditions or during the development of HF, inasmuch as none of these parameters differed between B2-/- and B2+/+ mice, and (2) inhibition of ACE or blockade of the AT1 receptor improves cardiac function and regresses remodeling in HF, and this therapeutic effect is partially mediated by kinins, since it was attenuated in B2-/- mice.
|
Acknowledgments |
|---|
This work was supported by National Institutes of Health Grant HL-28982 and American Heart Association Grant 0030232.
|
Footnotes |
|---|
Original received January 5, 2001; revision received March 26, 2001; accepted March 28, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Francis GF. Vasoactive hormone systems. In: Poole-Wilson PA, Colucci WS, Massie BM, Chatterjee K, Coats AJS, eds. Heart Failure: Scientific Principles and Clinical Practice. New York, NY: Churchill Livingstone; 1997:215–234.
2. Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang C, Kubo SH, Rudin-Toretsky E, Yusuf S. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990;82:1724–1729.
3. Dzau VJ. Autocrine and paracrine mechanisms in the pathophysiology of heart failure. Am J Cardiol. 1992;70:4C–11C.
4. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450–1456.
5. Ball SG and the Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821–828.
6. Pfeffer JM. Progressive ventricular dilation in experimental myocardial infarction and its attenuation by angiotensin-converting enzyme inhibition. Am J Cardiol. 1991;68:17D–25D.
7. Dell’Italia LJ, Oparil S. Bradykinin in the heart. Friend or foe? Circulation. 1999;100:2305–2307.
8. Carretero OA. Kinins in the heart. In: Share L, ed. Contemporary Endocrinology: Hormones and the Heart in Health and Disease. Totowa, NJ: Humana Press; 1999:137–158.
9. Liu Y-H, Yang X-P, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:1926–1935.
10. Cohn JN. Structural basis for heart failure. Ventricular remodeling and its pharmacological inhibition. Circulation. 1995;91:2504–2507.
11. Liu Y-H, Yang X-P, Mehta D, Bulagannawar M, Scicli GM, Carretero OA. Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats. Am J Physiol Heart Circ Physiol. 2000;278:H507–H514.
12. Madeddu P, Varoni MV, Palomba D, Emanueli C, Demontis MP, Glorioso N, Dessi-Fulgheri P, Sarzani R, Anania V. Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene. Circulation. 1997;96:3570–3578.
13. Emanueli C, Maestri R, Corradi D, Marchione R, Minasi A, Tozzi MG, Salis MB, Straino S, Capogrossi MC, Olivetti G, Madeddu P. Dilated and failing cardiomyopathy in bradykinin B2 receptor knockout mice. Circulation. 1999;100:2359–2365.
14. Rhaleb N-E, Yang X-P, Nanba M, Shesely EG, Carretero OA. Effect of chronic blockade of the kallikrein-kinin system on the development of hypertension in rats. Hypertension. 2001;37:121–128.
15. Yang X-P, Liu Y-H, Scicli GM, Webb CR, Carretero OA. Role of kinins in the cardioprotective effect of preconditioning. Study of myocardial ischemia/reperfusion injury in B2 kinin receptor knockout mice and kininogen-deficient rats. Hypertension. 1997;30:735–740.
16. Wiemer G, Schölkens BA, Wagner A, Heitsch H, Linz W. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J Hypertens. 1993;11(suppl 5):S234–S235.
17. Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1–7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27:523–528.
18. Siragy HM, Carey RM. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3',5'-monophosphate and AT1 receptor-mediated prostaglandin E2 production in conscious rats. J Clin Invest. 1996;97:1978–1982.
19. Borkowski JA, Ransom RW, Seabrook GR, Trumbauer M, Chen H, Hill RG, Strader CD, Hess JF. Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J Biol Chem. 1995;270:13706–13710.
20. Yang X-P, Liu Y-H, Shesely EG, Bulagannawar M, Liu F, Carretero OA. Endothelial nitric oxide gene knockout mice. Cardiac phenotypes and the effect of angiotensin-converting enzyme inhibitor on myocardial ischemia/reperfusion injury. Hypertension. 1999;34:24–30.
21. Krege JH, Hodgin JB, Hagaman JR, Smithies O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension. 1995;25:1111–1115.
22. Alfie ME, Sigmon DH, Pomposiello SI, Carretero OA. Effect of high salt intake in mutant mice lacking bradykinin-B2 receptors. Hypertension. 1997;29:483–487.
23. Yang X-P, Liu Y-H, Rhaleb N-E, Kurihara N, Kim HE, Carretero OA. Echocardiographic assessment of cardiac function in conscious and anesthetized mice. Am J Physiol. 1999;277:H1967–H1974.
24. Liu Y-H, Yang X-P, Nass O, Sabbah HN, Peterson E, Carretero OA. Chronic heart failure induced by coronary artery ligation in Lewis inbred rats. Am J Physiol. 1997;272:H722–H727.
25. Cavasin MA, Yang X-P, Liu Y-H, Mehta D, Karumanchi R, Bulagannawar M, Carretero OA. Effects of ACE inhibitor, AT1 antagonist, and combined treatment in mice with heart failure. J Cardiovasc Pharmacol. 2000;36:472–480.
26. Nsa Allogho S, Gobeil F, Pheng LH, Nguyen-Le XK, Neugebauer W, Regoli D. Kinin B1 and B2 receptors in the mouse. Can J Physiol Pharmacol. 1995;73:1759–1764.
27. Schanstra JP, Marin-Castaño ME, Praddaude F, Tack I, Ader J-L, Girolami J-P, Bascands J-L. Bradykinin B1 receptor-mediated changes in renal hemodynamics during endotoxin-induced inflammation. J Am Soc Nephrol. 2000;11:1208–1215.
28. Su JB, Hoüel R, Héloire F, Barbe F, Beverelli F, Sambin L, Castaigne A, Berdeaux A, Crozatier B, Hittinger L. Stimulation of bradykinin B1 receptors induces vasodilation in conductance and resistance coronary vessels in conscious dogs. Comparison with B2 receptor stimulation. Circulation. 2000;101:1848–1853.
29. Rhaleb N-E, Peng H, Alfie M, Shesely EG, Carretero OA. Effect of ACE inhibitor on DOCA-salt– and aortic coarctation–induced hypertension in mice. Do kinin B2 receptors play a role? Hypertension. 1999;33:329–334.
30. Tschöpe C, Heringer-Walther S, Walther T. Regulation of the kinin receptors after induction of myocardial infarction: a mini-review. Braz J Med Biol Res. 2000;33:701–708.
31. Emanueli C, Minasi A, Zacheo A, Chao J, Chao L, Salis MB, Straino S, Tozzi MG, Smith R, Gaspa L, Bianchini G, Stillo F, Capogrossi MC, Madeddu P. Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation. 2001;103:125–132.
32. Duka I, Kintsurashvili E, Gavras I, Johns C, Bresnahan M, Gavras H. Vasoactive potential of the B1 bradykinin receptor in normotension and hypertension. Circ Res. 2001;88:275–281.
33. Emanueli C, Zacheo A, Minasi A, Chao J, Chao L, Salis MB, Stacca T, Straino S, Capogrossi MC, Madeddu P. Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol. 2000;20:2379–2385.
34. Gallagher AM, Yu H, Printz MP. Bradykinin-induced reductions in collagen gene expression involve prostacyclin. Hypertension. 1998;32:84–88.
35. Zhang X, Xie Y-W, Nasjletti A, Xu X, Wolin MS, Hintze TH. ACE inhibitors promote nitric oxide accumulation to modulate oxygen consumption. Circulation. 1997;95:176–182.
36. Zhang X, Recchia FA, Bernstein R, Xu X, Nasjletti A, Hintze TH. Kinin-mediated coronary nitric oxide production contributes to the therapeutic action of angiotensin-converting enzyme and neutral endopeptidase inhibitors and amlodipine in the treatment in heart failure. J Pharmacol Exp Ther. 1999;288:742–751.
37. Loke KE, Curran CML, Messina EJ, Laycock SK, Shesely EG, Carretero OA, Hintze TH. Role of nitric oxide in the control of cardiac oxygen consumption in B2-kinin receptor knockout mice. Hypertension. 1999;34:563–567.
38. Tada H, Thompson CI, Recchia FA, Loke KE, Ochoa M, Smith CJ, Shesely EG, Kaley G, Hintze TH. Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart. Circ Res. 2000;86:270–274.
39. Schölkens BA, Linz W, König W. Effects of the angiotensin converting enzyme inhibitor, ramipril, in isolated ischaemic rat heart are abolished by a bradykinin antagonist. J Hypertens. 1988;6(suppl 4):S25–S28.
40. Schoelkens BA, Linz W. Bradykinin-mediated metabolic effects in isolated perfused rat hearts. Agents Actions Suppl. 1992;38:36–42.
41. Whitebread S, Mele M, Kamber B, de Gasparo M. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989;163:284–291.
42. Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, Horiuchi M, Pratt RE, Dzau VJ. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci U S A. 1995;92:10663–10667.
43. Tsutsumi Y, Matsubara H, Ohkubo N, Mori Y, Nozawa Y, Murasawa S, Kijima K, Maruyama K, Masaki H, Moriguchi Y, Shibasaki Y, Kamihata H, Inada M, Iwasaka T. Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Circ Res. 1998;83:1035–1046.
44. Masaki H, Kurihara T, Yamaki A, Inomata N, Nozawa Y, Mori Y, Murasawa S, Kizima K, Maruyama K, Horiuchi M, Dzau VJ, Takahashi H, Iwasaka T, Inada M, Matsubara H. Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest. 1998;101:527–535.
45. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999;104:925–935.
This article has been cited by other articles:
 |
|
 |
|
  J. Xu, O. A. Carretero, E. G. Shesely, N.-E. Rhaleb, J. J. Yang, M. Bader, and X.-P. Yang The kinin B1 receptor contributes to the cardioprotective effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in mice Exp Physiol, March 1, 2009; 94(3): 322 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ishii, T. Amano, T. Matsubara, and T. Murohara Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction Circulation, December 16, 2008; 118(25): 2710 - 2718. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Sanchez de Miguel, S. Neysari, S. Jakob, M. Petrimpol, N. Butz, A. Banfi, C. E. Zaugg, R. Humar, and E. J. Battegay B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart Cardiovasc Res, October 1, 2008; 80(1): 106 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chao, H. Yin, L. Gao, M. Hagiwara, B. Shen, Z.-R. Yang, and L. Chao Tissue Kallikrein Elicits Cardioprotection by Direct Kinin B2 Receptor Activation Independent of Kinin Formation Hypertension, October 1, 2008; 52(4): 715 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Duka, E. Kintsurashvili, I. Duka, D. Ona, T. A. Hopkins, M. Bader, I. Gavras, and H. Gavras Angiotensin-Converting Enzyme Inhibition After Experimental Myocardial Infarct: Role of the Kinin B1 and B2 Receptors Hypertension, May 1, 2008; 51(5): 1352 - 1357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pons, V. Griol-Charhbili, C. Heymes, P. Fornes, D. Heudes, A. Hagege, X. Loyer, P. Meneton, J.-F. Giudicelli, J.-L. Samuel, et al. Tissue kallikrein deficiency aggravates cardiac remodelling and decreases survival after myocardial infarction in mice Eur J Heart Fail, April 1, 2008; 10(4): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Isbell, S. Voros, Z. Yang, J. M. DiMaria, S. S. Berr, B. A. French, F. H. Epstein, S. P. Bishop, H. Wang, R. J. Roy, et al. Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3372 - H3378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cayla, M. Todiras, R. Iliescu, V. V. Saul, V. Gross, B. Pilz, G. Chai, V. F. Merino, J. B. Pesquero, O. C. Baltatu, et al. Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension FASEB J, June 1, 2007; 21(8): 1689 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nahrendorf, C. Badea, L. W. Hedlund, J.-L. Figueiredo, D. E. Sosnovik, G. A. Johnson, and R. Weissleder High-resolution imaging of murine myocardial infarction with delayed-enhancement cine micro-CT Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3172 - H3178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chandrashekhar Embracing Diversity in Remodeling: A Step in Therapeutic Decision Making in Heart Failure? J. Am. Coll. Cardiol., February 20, 2007; 49(7): 822 - 825. [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Shariat-Madar, F. Mahdi, M. Warnock, J. W. Homeister, S. Srikanth, Y. Krijanovski, L. J. Murphey, A. A. Jaffa, and A. H. Schmaier Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin Blood, July 1, 2006; 108(1): 192 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Cavasin, Z.-Y. Tao, A.-L. Yu, and X.-P. Yang Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2043 - H2050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fleming Signaling by the Angiotensin-Converting Enzyme Circ. Res., April 14, 2006; 98(7): 887 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Voros, Z. Yang, C. M. Bove, W. D. Gilson, F. H. Epstein, B. A. French, S. S. Berr, S. P. Bishop, M. R. Conaway, H. Matsubara, et al. Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1004 - H1010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, O. A. Carretero, O. H. Cingolani, T.-D. Liao, Y. Sun, J. Xu, L. Y. Li, P. J. Pagano, J. J. Yang, and X.-P. Yang Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2616 - H2623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Yoshiyama, Y Nakamura, T Omura, Y Izumi, R Matsumoto, S Oda, K Takeuchi, S Kim, H Iwao, and J Yoshikawa Angiotensin converting enzyme inhibitor prevents left ventricular remodelling after myocardial infarction in angiotensin II type 1 receptor knockout mice Heart, August 1, 2005; 91(8): 1080 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, O. A. Carretero, Y. Sun, E. G. Shesely, N.-E. Rhaleb, Y.-H. Liu, T.-D. Liao, J. J. Yang, M. Bader, and X.-P. Yang Role of the B1 Kinin Receptor in the Regulation of Cardiac Function and Remodeling After Myocardial Infarction Hypertension, April 1, 2005; 45(4): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. TSCHOPE, T. WALTHER, J. KONIGER, F. SPILLMANN, D. WESTERMANN, F. ESCHER, M. PAUSCHINGER, J. B. PESQUERO, M. BADER, H.-P. SCHULTHEISS, et al. Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene FASEB J, May 1, 2004; 18(7): 828 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, X.-P. Yang, E. G. Shesely, S. S. Sankey, and O. A. Carretero Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1473 - 1480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. LaPointe, M. Mendez, A. Leung, Z. Tao, and X.-P. Yang Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1416 - H1424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Imig ACE Inhibition and Bradykinin-Mediated Renal Vascular Responses: EDHF Involvement Hypertension, March 1, 2004; 43(3): 533 - 535. [Full Text] [PDF]
|
|
|
|
|
|
C. Tschope, F. Spillmann, C. Altmann, M. Koch, D. Westermann, N. Dhayat, S. Dhayat, J.-L. Bascands, L. Gera, S. Hoffmann, et al. The bradykinin B1 receptor contributes to the cardioprotective effects of AT1 blockade after experimental myocardial infarction Cardiovasc Res, February 15, 2004; 61(3): 559 - 569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Yang, X.-P. Yang, Y.-H. Liu, J. Xu, O. Cingolani, N.-E. Rhaleb, and O. A. Carretero Ac-SDKP Reverses Inflammation and Fibrosis in Rats With Heart Failure After Myocardial Infarction Hypertension, February 1, 2004; 43(2): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kohlstedt, R. P. Brandes, W. Muller-Esterl, R. Busse, and I. Fleming Angiotensin-Converting Enzyme Is Involved in Outside-In Signaling in Endothelial Cells Circ. Res., January 9, 2004; 94(1): 60 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Abadir, R. M. Carey, and H. M. Siragy Angiotensin AT2 Receptors Directly Stimulate Renal Nitric Oxide in Bradykinin B2-Receptor-Null Mice Hypertension, October 1, 2003; 42(4): 600 - 604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Lapointe, Q. T. Nguyen, J.-F. Desjardins, F. Marcotte, A. Pourdjabbar, G. Moe, A. Calderone, and J.-L. Rouleau Effects of pre-, peri-, and postmyocardial infarction treatment with omapatrilat in rats: survival, arrhythmias, ventricular function, and remodeling Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H398 - H405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Schanstra, J. Duchene, F. Praddaude, P. Bruneval, I. Tack, J. Chevalier, J.-P. Girolami, and J.-L. Bascands Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Decreased renal NO excretion and reduced glomerular tuft area in mice lacking the bradykinin B2 receptor Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1904 - H1908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Cavasin, S. S. Sankey, A.-L. Yu, S. Menon, and X.-P. Yang Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1560 - H1569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, O. A. Carretero, Y.-H. Liu, E. G. Shesely, F. Yang, A. Kapke, and X.-P. Yang Role of AT2 Receptors in the Cardioprotective Effect of AT1 Antagonists in Mice Hypertension, September 1, 2002; 40(3): 244 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Nikolaidis, A. Doverspike, R. Huerbin, T. Hentosz, and R. P. Shannon Angiotensin-Converting Enzyme Inhibitors Improve Coronary Flow Reserve in Dilated Cardiomyopathy by a Bradykinin-Mediated, Nitric Oxide-Dependent Mechanism Circulation, June 11, 2002; 105(23): 2785 - 2790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Lapointe, C. Blais Jr, A. Adam, T. Parker, M. G. Sirois, H. Gosselin, R. Clement, and J. L. Rouleau Comparison of the effects of an angiotensin-converting enzyme inhibitor and a vasopeptidase inhibitor after myocardial infarction in the rat J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1692 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujii, A. Wada, T. Tsutamoto, M. Ohnishi, T. Isono, and M. Kinoshita Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure Hypertension, May 1, 2002; 39(5): 952 - 957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Jackman, M. G. Massad, M. Sekosan, F. Tan, V. Brovkovych, B. M. Marcic, and E. G. Erdos Angiotensin 1-9 and 1-7 Release in Human Heart: Role of Cathepsin A Hypertension, May 1, 2002; 39(5): 976 - 981. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||