AJP - Heart Journal of Applied Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H3372-H3378, 2007. First published October 12, 2007; doi:10.1152/ajpheart.00997.2007
0363-6135/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/6/H3372    most recent
00997.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Isbell, D. C.
Right arrow Articles by Kramer, C. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Isbell, D. C.
Right arrow Articles by Kramer, C. M.

Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling

David C. Isbell,1 Szilard Voros,1 Zequan Yang,3 Joseph M. DiMaria,2 Stuart S. Berr,2,3 Brent A. French,2,3 Frederick H. Epstein,2,3 Sanford P. Bishop,5 Hongkun Wang,4 Rene J. Roy,2 Brandon A. Kemp,1 Hiroaki Matsubara,6 Robert M. Carey,1 and Christopher M. Kramer1,2

1Cardiovascular Division, Department of Medicine, 2Department of Radiology, 3Department of Biomedical Engineering, and 4Department of Public Health Sciences, University of Virginia Health System, Charlottesville, Virginia; 5Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and 6Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan

Submitted 29 August 2007 ; accepted in final form 5 October 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Angiotensin II type 2 receptor (AT2R) overexpression (AT2TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac AT2TG are mediated via the bradykinin subtype 2 receptor (B2R). Fourteen transgenic mice overexpressing the AT2R (AT2TG mice), 10 mice with a B2R deletion (B2KO mice), 13 AT2TG mice with B2R deletion (AT2TG/B2KO mice), and 11 wild-type (WT) mice were studied. All mice were on a C57BL/6 background. Mice were studied by cardiac magnetic resonance imaging at baseline and days 1, 7, and 28 after MI induced by 1 h of occlusion of the left anterior descending artery followed by reperfusion. Short-axis images from apex to base were used to compare ventricular volumes and ejection fraction (EF). At baseline, end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were lower and EF higher in AT2TG mice compared with the other three strains. Infarct size was similar between groups. No differences were observed in global remodeling parameters at day 28 between AT2TG and AT2TG/B2KO mice; however, EDVI and ESVI were lower and EF higher in both transgenic groups than in WT or B2KO mice. Both strains lacking B2R demonstrated increased collagen content and less hypertrophy in adjacent noninfarcted regions at day 28. Attenuation of postinfarct remodeling by overexpression of AT2R is not directly mediated via a B2R pathway. However, B2R does appear to have a role in the smaller cavity size and hyperdynamic function observed at baseline in AT2TG mice and in limiting collagen deposition during postinfarct remodeling.

magnetic resonance imaging; remodeling

THE RENIN-ANGIOTENSIN SYSTEM (RAS) plays an important role in postinfarction left ventricular (LV) remodeling. Pharmacological strategies devised to manipulate the RAS can improve both LV function and clinical outcomes following infarction (30–32). Angiotensin II (ANG II) is now recognized as a potent mediator of LV remodeling after myocardial infarction (MI), largely through promotion of vasoconstriction, cellular hypertrophy, and interstitial fibrosis (26). Two major ANG II receptor subtypes have now been characterized, the ANG II type 1 (AT1R) and ANG II type 2 (AT2R) receptors.

While the importance of AT1R-mediated effects on the cardiovascular system are well known (5), only recently has the role of AT2R been recognized. AT2R, which is expressed at low levels in normal myocytes, is upregulated after MI and in other pathological states (6). AT2R promotes vasodilation and inhibits growth and remodeling (34). The importance of this receptor is evident in models of AT2R deletion, in which there is an increased incidence of heart failure, myocardial rupture, and death after infarction (18). Furthermore, experimental evidence suggests that the clinical benefits of post-MI AT1 inhibition, which have now been validated in a large, randomized clinical trial (31), are mediated in part through the AT2R (20, 41). However, the mechanisms through which an increase in cardiac AT2R expression might attenuate post-MI remodeling are incompletely understood.

We previously demonstrated in a murine model (46) that cardiac overexpression of AT2R preserves LV size and function during postinfarct myocardial remodeling. While the nitric oxide (NO)/cGMP cascade mediates many of the antiremodeling benefits of AT2R overexpression (4, 43), the relative importance of bradykinin and its subtype 2 receptor (B2R) has not been assessed. Previous studies in mice with AT2R overexpression in vascular smooth muscle (VSM) demonstrate that AT2R blocks the Na+/H+ exchanger, causing intracellular acidosis, which increases kininogenase activity and bradykinin production (40). cGMP production was also increased. The ANG II-mediated pressor effect was abolished in these animals but reinstated by icatibant (HOE-140), a B2R blocker. This suggests that AT2R increases bradykinin, which in turn stimulates the NO/cGMP system and promotes vasodilatation in VSM (40). AT2R-mediated increases in cGMP and hypotensive effects due to bradykinin and NO have been shown in the aorta of the spontaneously hypertensive rat (15). AT2R effects in the kidney are also mediated by bradykinin (7). The effects of AT1R blockade on blood pressure are affected by AT2R through release of renal bradykinin, which then mediates NO production (37).

The same pathways may apply to myocardial AT2R signaling. We hypothesized that in a murine B2R knockout (B2KO) model simultaneous cardiac overexpression of AT2R would fail to attenuate remodeling in the intact post-MI heart. To test this hypothesis, we used cardiac magnetic resonance imaging (CMR) to image LV dimensions and global function serially after reperfused MI in four strains of mice: 1) wild type (WT) 2) B2R knockout (B2KO) 3) AT2R overexpressing (AT2TG), and 4) AT2TG/B2R knockout (AT2TG/B2KO) mice.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Mouse model. Animal protocols were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, revised 1996) and were approved by the University of Virginia Animal Care and Use Committee. C57BL/6 mice were used as WT mice and served as the background for all other strains. The transgenic (TG) mouse strain with cardiac overexpression of AT2R was developed in the laboratory of Dr. H. Matsubara (Kansai Medical University, Osaka, Japan) (25). The presence of the transgene was confirmed with methods as previously described (46). B2R-deficient TG mice were generously provided by Dr. Samir El-Dahr (Tulane University, New Orleans, LA) (9). After AT2R TG mice were crossbred with homozygous B2KO mice, subsequent generations yielded mice with both cardiac overexpression of AT2R and systemic knockout of B2R. Transgene and knockout mutations were confirmed by Southern blot analysis of genomic DNA from mouse tails. All mice were male and 8–14 wk of age at the start of the study period.

AT2R protein levels. Plasma membranes from the mouse hearts were isolated with a Triton-solubilized 100,000 g membrane preparation based on the method of Nagamatsu et al. (29). Protein concentrations were quantified with a bicinchoninic acid protein assay and subjected to Western blot analysis. The membrane blots were incubated with AT2R antibody, and the 44-kDa band densities were measured by scanning densitometry and normalized with Ponceau staining (35).

Surgery and magnetic resonance imaging. Surgical procedures for the induction of reperfused MI were as reported previously (47). Murine CMR was performed as previously described (4, 41, 46). A 4.7-T MRI system (Varian 200/400 Inova) with Magnex gradients (80 G/cm maximum strength) with a custom-built Litz radio frequency coil (Doty Scientific, Columbia, SC) was used. Contiguous short-axis bright-blood cine images of the LV were obtained with a 2D-FLASH gradient echo sequence (Fig. 1) as previously published (4, 41, 46). Infarct imaging was done on post-MI day 1 as carefully validated against pathological measures of infarct size by our group (45).


Figure 1
View larger version (96K):
[in this window]
[in a new window]

  		Fig. 1. Representative end-diastolic (top) and end-systolic (bottom) short-axis midventricular cine MRI images at post-myocardial infarction (MI) day 28 from each of the 4 groups. Note that the end-diastolic and end-systolic cavity areas are larger in the wild-type (WT) and bradykinin subtype 2 receptor deletion (B2KO) groups than in the transgenic ANG II type 2 receptor-overexpressing (AT2TG) or AT2TG/B2KO group.

 
Image analysis. Short-axis cine images were analyzed with ARGUS image analysis software (Siemens Medical Solutions, Princeton, NJ). Epicardial and endocardial borders were planimetered to determine end-diastolic volume (EDV), end-systolic volume (ESV), LV mass (LVM), and ejection fraction (EF). Volumes and mass were indexed to body weight in grams (EDVI, ESVI, LVMI). Infarct size was measured as previously described (41, 46) and expressed as a percentage of LVM.

Hemodynamic measurements. Invasive hemodynamic measurements were performed after the day 28 CMR examination. The LV pressure was obtained by direct puncturing of the LV via the left fifth interspace with a 27-gauge needle connected to PE-50 tubing. Blood pressure and LV pressure as well as heart rate (HR) and developed pressure (dP/dt) were recorded by a MacLab recording system.

Collagen analysis. We performed collagen analysis using paraffin-embedded sections. Quantitative morphometry was performed on 6-µm slices from the infarct border (adjacent) and remote myocardium that were stained with picric acid Sirius red. Volume percent collagen was determined by measuring a minimum of 30 fields in 3 or 4 sections from each region. Mean area was calculated for each region in each animal.

Myocyte analysis. Three to five tissue samples from each heart were sectioned at 5-µm thickness, stained with picric acid Sirius red, and examined with an Olympus AH2 research microscope and rhodamine epifluorescence. With a x40 objective (x660 on monitor), cross-sectional area was determined on a minimum of 60 myocytes from each animal in adjacent and remote noninfarcted regions, selected from areas judged to be within 20° of true cross section, with a Universal Imaging AT1 image analysis system (Universal Imaging, West Chester, PA). Mean area was calculated for each animal.

Statistical methods. Infarct sizes between groups and noninvasive and invasive hemodynamic parameters were compared by one-way analysis of variance (ANOVA). Regional percent collagen and regional myocyte size between groups were compared by two-way ANOVA with Tukey subtesting. Volumetric parameters were compared between all four groups with F-tests in repeated-measures models, using day 0 data as a covariate. Analyses were carried out with PROC MIXED in SAS 9.1 (SAS Institute, Cary, NC). All values are presented as means ± SE; P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Fourteen transgenic mice overexpressing AT2R (AT2TG), 10 mice with B2R deletion (B2KO), 13 AT2TG with B2R deletion (AT2TG/B2KO), and 11 wild-type (WT) mice were studied. All mice were on a C57BL/6 background.

Baseline parameters. Mean systolic blood pressure in conscious animals at baseline measured with noninvasive tail cuff apparatus was similar between groups (Table 1). Resting HR at baseline was 598 ± 55 beats per minute (bpm) in WT, 522 ± 53 bpm in B2KO, 691 ± 27 bpm in AT2TG (P < 0.001 vs. B2KO and AT2TG/B2KO), and 518 ± 70 bpm in AT2TG/B2KO mice. These differences were no longer apparent while the animals were under anesthesia during baseline imaging (Table 1). Body weight was higher in AT2TG mice compared with other groups at baseline (Table 1). Baseline volumetric parameters were also different among the four strains of mice (Fig. 2). LV EDVI and ESVI were smaller and EF higher in AT2TG mice.


View this table:
[in this window]
[in a new window]

  		Table 1. Heart rate, systolic blood pressure, and LV mass in all four strains of mice at baseline and post-MI days 1, 7, and 28

 

Figure 2
View larger version (16K):
[in this window]
[in a new window]

  		Fig. 2. End-systolic volume index (ESVI), end-diastolic volume index (EDVI), and ejection fraction (EF; %) at baseline in the 4 groups. Center lines represent the median, outer borders of the boxes the 25th and 75th percentiles, and vertical lines the 0th and 100th percentiles. Any outliers are represented by dots. {dagger}P < 0.03 vs. WT, B2KO, and AT2TG/B2KO mice.

 
AT2R protein levels. By densitometry, AT2R protein levels were 145 ± 27 densitometric units (DU) in WT, 328 ± 23 DU in AT2TG (P < 0.001 vs. WT), and 419 ± 41 DU in AT2TG/B2KO (P < 0.001 vs. WT) mice. No difference was noted in AT2R protein levels between AT2TG and AT2TG/B2KO groups.

MRI parameters of postinfarct remodeling. Infarct size on postinfarct day 1 imaging was similar among the four groups (41 ± 5%, 43 ± 7%, 41 ± 10%, and 36 ± 6% in WT, B2KO, AT2TG, and AT2TG/B2KO mice; P = not significant). Systolic blood pressure was not different between groups during the course of the study (Table 1). By post-MI days 7 and 28, body weights were similar between groups (Table 1). By day 28, all groups experienced a decline in LV systolic function and an increase in LV size compared with baseline values (Table 1). However, both LV size and function were better preserved in both TG strains compared with WT and B2KO animals as evidenced by the lower ESVI, EDVI, and higher EF (Table 1 and Figs. 1, 3, 4, and 5). Values shown in Figs. 2–4 for post-MI days 1, 7, and 28 have been adjusted for baseline differences in AT2TG.


Figure 3
View larger version (14K):
[in this window]
[in a new window]

  		Fig. 3. ESVI at baseline and postinfarction days 1, 7, and 28 in all 4 groups. Values have been corrected for baseline differences among groups. *P < 0.05 vs. WT; #P < 0.05 vs. B2KO.

 

Figure 4
View larger version (15K):
[in this window]
[in a new window]

  		Fig. 4. EF (%) at baseline and postinfarction days 1, 7, and 28 in all 4 groups. Values have been corrected for baseline differences among groups. *P < 0.05 vs. WT; #P < 0.05 vs. B2KO.

 

Figure 5
View larger version (14K):
[in this window]
[in a new window]

  		Fig. 5. EDVI at baseline and postinfarction days 1, 7, and 28 in all 4 groups. Values have been corrected for baseline differences among groups. *P < 0.05 vs. WT; #P < 0.05 vs. B2KO.

 
Collagen analysis. Morphometric analysis was performed in all mice in regions both adjacent and remote to the infarct zone, and in all groups collagen content was increased in adjacent noninfarcted regions compared with remote regions (P < 0.01) (Table 2). Both B2KO and AT2TG/B2KO mice had greater collagen content in adjacent regions compared with WT mice. In remote regions, no differences were found among the four strains of mice (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Mean regional collagen content at post-MI day 28

 
Myocyte hypertrophy. Myocyte hypertrophy occurred in all groups on post-MI day 28and was greater in adjacent, noninfarcted regions than in remote regions (Table 3). For comparison purposes, myocyte size in noninfarcted C57BL/6 WT controls is 164 ± 31 µm2. In mice with B2KO, less hypertrophy was noted in adjacent noninfarcted regions.


View this table:
[in this window]
[in a new window]

  		Table 3. Mean myocyte cross-sectional area at post-MI day 28

 
Invasive hemodynamics. Invasive hemodynamic measurements were performed after completion of day 28 postinfarct imaging in six mice per group. LV end-systolic pressure (LVESP) and LV end-diastolic pressure (LVEDP) were similar among the four strains of mice (Table 4). +dP/dt was higher and –dP/dt lower in B2KO and AT2TG/B2KO mice compared with WT mice, while a strong trend was noted between AT2TG and WT mice (P = 0.06) (Table 4).


View this table:
[in this window]
[in a new window]

  		Table 4. Invasive hemodynamic parameters on day 28

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
There were several findings of interest in this study: 1) enhanced baseline function in AT2TG mice is mediated, at least in part, by B2R; 2) based on global volumetric and functional parameters, AT2R-mediated attenuation of postinfarct LV remodeling is largely independent of B2R; 3) in regions adjacent to infarction zones B2R plays an important role in limiting collagen expression but allowing cellular hypertrophy during LV remodeling; and 4) AT2R overexpression offers protection against postinfarct LV remodeling, and this protection is not dependent on the smaller cavity size and higher EF at baseline in AT2TG mice.

This study sought to define the role of B2R in a model of post-MI LV remodeling. In contrast to the low-level, continuous activation of the RAS in chronic congestive heart failure (CHF), there is intense activation of RAS in the acute setting, which initially serves to maintain cardiac output. RAS activation occurs rapidly in MI, with ANG II levels peaking at ~3 days (27). Furthermore, RAS escape, through production of ANG II via pathways independent of angiotensin-converting enzyme (ACE), is less likely to occur in the acute rather than chronic setting. Recently, the importance of bradykinin in mediating the benefits of AT1 blockade in a chronic CHF model was demonstrated in rats (20, 21). The use of either a bradykinin antagonist or kininogen-deficient animals limited the benefits of AT1R antagonism. However, the study drugs were administered 2 mo after surgically induced MI, well after early LV remodeling had taken place (19).

In addition to its direct vasodilatory effects (17), bradykinin can influence cell growth and division, inhibit collagen production, and influence myocardial energy metabolism (2, 12). Two receptor subtypes for bradykinin have been identified, bradykinin subtype 1 receptor (B1R) and B2R. While B2R mediates the majority of known biological effects of bradykinin B1R is upregulated in pathological states, and investigators have become increasingly interested in its role in ischemic injury (3, 10).

Our group previously demonstrated (4) the importance of NO in AT2R mediated attenuation of LV remodeling after infarction. In AT2TG mice treated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester, the beneficial effects of AT2R overexpression after infarct were largely abrogated. While bradykinin is important in the AT2R-mediated production of NO/cGMP in the aorta of spontaneously hypertensive rats (15) and in the kidney (37), the receptor's role in cardiac NO production is less clear. AT2R activation does lead to the formation of bradykinin within the myocardium through induction of an intracellular acidosis via blockade of the Na+/H+ exchanger. It is postulated that this acidic environment stimulates pH-sensitive kininogenases to cleave stored kininogens into kinins (40). Indeed, in a rat model of hypertension (36), infusion of ANG II directly elicited bradykinin release, a response that was AT2R mediated. In one model of AT2R overexpression in VSM cells, ANG II-mediated increases in aortic cGMP could be reversed by treatment with either AT2R or B2R antagonists (40). However, the relative importance of B2R in the AT2R cascade remains incompletely understood. Recent evidence has shown that AT2R may stimulate the release of cGMP and NO independent of B2R (1, 48). It is certainly possible that AT2R signaling occurs downstream of B2R.

Consistent with prior studies using this TG mouse model, cardiac AT2R overexpression resulted in smaller cavity size and an increased EF compared with WT (46). Our findings suggest that B2R may mediate much of these effects of AT2TG on baseline parameters. Although no difference in mean systolic blood pressure was noted between the groups, noninvasive baseline HR in conscious animals was higher in AT2TG mice than in the other three strains. Frequency-dependent potentiation of cardiac contractility could account for some of the enhanced baseline function observed in the AT2TG animals, although some investigators have described a negative force-frequency relationship in small rodent models (28). While the animals were under sedation for cardiac imaging no difference in HR existed between the four groups, consistent with prior studies (46). Heightened response to catecholamines during stress in AT2R-overexpressing animals mediated through B2R could account for these findings and is consistent with known interactions between B2R and the sympathoadrenal system (13, 14).

At study completion, remodeling was attenuated in both TG strains to a similar extent, and both TG strains remodeled to a lesser extent than either WT or B2KO mice. Even with adjustment for baseline differences, AT2TG and AT2TG/B2KO mice remodeled to a similar degree, suggesting that B2R did not play an important role in global measures of postinfarction LV remodeling. Furthermore, the fact that these TG strains experienced similar remodeling despite differences in baseline cavity size and function suggests that decreased wall tension (as a consequence of the smaller cavity at baseline) is not the sole mechanism through which remodeling is attenuated in AT2TG animals.

Morphometric analysis demonstrates that B2R limited collagen deposition in regions adjacent to the infarct zone but had no effect on collagen expression in remote regions. Our findings are consistent with other studies demonstrating the role of B2R in limiting fibrosis in noninfarcted segments after MI (10, 21–23, 44). There may be uncoupling of these two receptor systems for this particular end point. Despite regional differences in collagen expression between strains, global parameters of postinfarct remodeling did not differ between AT2TG/B2KO and AT2TG mice. Similarly, B2KO and WT animals remodeled in a parallel fashion, despite increased collagen deposition in B2KO mice. Interestingly, B2KO and AT2TG/B2KO strains demonstrated less myocyte hypertrophy in infarct adjacent regions at day 28. The kinins are generally believed to exert antihypertrophic effects in the myocardium, but the relationship is a complex one. In one study performed on isolated ventricular myocytes, bradykinin had direct hypertrophic effects on the cells (33). However, in the presence of endothelial cells, bradykinin exerted antihypertrophic effects.

One rationale for administration of both ACE inhibitor and ANG II receptor blocker simultaneously in CHF is to augment levels of bradykinin. While AT2R stimulation enhances production, ACE inhibition prolongs the kinins' half-life. In addition, ACE inhibition appears to potentiate ANG II-mediated increases in bradykinin (38). Our findings, together with those of Liu et al. (21), suggest that the role of bradykinin in AT1R/AT2R manipulation may be less important in the acute than the chronic heart failure setting.

Although B2R is known to be a potent stimulus for endothelial NO release, it may only serve to potentiate AT2R-mediated NO production and not be an essential regulator in the cascade. B1R, which is upregulated in the setting of inflammation or injury, may have signal transduction pathways similar to B2R and promote the production of NO in certain tissues, which we know to be critical to AT2R-mediated attenuation of remodeling (24). Furthermore, the effects of B1R may be exaggerated in this mouse model, because it is known to be upregulated in B2R-deficient mice (8) and may be responsible for cardioprotective effects (16). Further studies investigating the importance of B1R-mediated effects on remodeling and the interaction between the two receptors are warranted.

Limitations. One limitation of the present study is that no sham-operated controls were studied for each group. RAS activation was not directly measured. A subgroup of mice from each group was studied for hemodynamics, and no hemodynamic data were obtained in noninfarcted mice. Additionally, in mice genetically deficient in B2R, some investigators have described progressive LV remodeling and functional impairment, while others have not (11, 44). The B2KO was not a cardiac-specific knockout, and systemic effects of the deletion may have affected the results. The background genetics of the mouse model appears to modulate the impact of B2KO, with C57BL/6 mice being less susceptible to alterations in phenotype, perhaps because of a 10-fold lower plasma renin activity at baseline compared with 129/J mice (23, 42). In most studies of C57BL/6 mice, the B2KO mutation ultimately results in significant cardiac effects, but this process is delayed. In our study on a C57BL/6 background, the B2KO and WT mice were phenotypically similar at baseline, suggesting that age-related dysfunction had yet to occur. Also, the mice studied in this protocol were between 8 and 14 wk in age, younger than the age at which cardiomyopathies have been demonstrated to develop in noninfarcted B2KO mice (11, 23, 39).

Conclusion. B2R plays a role in the small cavity size and enhanced systolic function at baseline in AT2R-overexpressing mice. However, B2R does not mediate the attenuation of remodeling afforded by AT2R overexpression. This may have implications for differential response to medical therapies for postinfarct LV remodeling in the acute and chronic settings that involve B2R.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by American Heart Association Mid-Atlantic Affiliate Grant-in-Aid 0455687U (C. M. Kramer) and National Heart, Lung, and Blood Institute Grant T32-HL-07355 (S. Voros).


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. M. Kramer, Univ. of Virginia Health System, Depts. of Medicine and Radiology, 1215 Lee St., Box 800170, Charlottesville, VA 22908 (e-mail: ckramer{at}virginia.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Abadir PM, Carey RM, Siragy HM. Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice. Hypertension 42: 600–604, 2003.[Abstract/Free Full Text]
  2. Baxter GF, Ebrahim Z. Role of bradykinin in preconditioning and protection of the ischaemic myocardium. Br J Pharmacol 135: 843–854, 2002.[CrossRef][Web of Science][Medline]
  3. Bouchard JF, Chouinard J, Lamontagne D. Role of kinins in the endothelial protective effect of ischaemic preconditioning. Br J Pharmacol 123: 413–420, 1998.[CrossRef][Web of Science][Medline]
  4. Bove CM, Yang Z, Gilson WD, Epstein FH, French BA, Berr SS, Bishop SP, Matsubara H, Carey RM, Kramer CM. Nitric oxide mediates benefits of angiotensin II type 2 receptor overexpression during post-infarct remodeling. Hypertension 43: 680–685, 2004.[Abstract/Free Full Text]
  5. Burnier M. Angiotensin II type 1 receptor blockers. Circulation 103: 904–912, 2001.[Free Full Text]
  6. Busche S, Gallinat S, Bohle RM, Reinecke A, Seebeck J, Franke F, Fink L, Zhu M, Sumners C, Unger T. Expression of angiotensin AT1 and AT2 receptors in adult rat cardiomyocytes after myocardial infarction. A single-cell reverse transcriptase-polymerase chain reaction study. Am J Pathol 157: 605–611, 2000.[Abstract/Free Full Text]
  7. Carey RM, Jin X, Wang Z, Siragy HM. Nitric oxide: a physiological mediator of the type 2 (AT2) angiotensin receptor. Acta Physiol Scand 168: 65–71, 2000.[CrossRef][Web of Science][Medline]
  8. 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 88: 275–281, 2001.[Abstract/Free Full Text]
  9. El Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, Meleg-Smith S. Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development. Physiol Genomics 3: 121–131, 2000.[Abstract/Free Full Text]
  10. Emanueli C, Bonaria SM, Stacca T, Pintus G, Kirchmair R, Isner JM, Pinna A, Gaspa L, Regoli D, Cayla C, Pesquero JB, Bader M, Madeddu P. Targeting kinin B1 receptor for therapeutic neovascularization. Circulation 105: 360–366, 2002.[Abstract/Free Full Text]
  11. 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 100: 2359–2365, 1999.[Abstract/Free Full Text]
  12. Gallagher AM, Yu H, Printz MP. Bradykinin-induced reductions in collagen gene expression involve prostacyclin. Hypertension 32: 84–88, 1998.[Abstract/Free Full Text]
  13. Gardiner SM, Kemp PA, Bennett T, Bose C, Foulkes R, Hughes B. Involvement of beta 2-adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats. Br J Pharmacol 105: 839–848, 1992.[Web of Science][Medline]
  14. Gavras I, Gavras H. Hypertension, vasoactive peptides and coagulation factors. J Hypertens 22: 1091–1092, 2004.[CrossRef][Web of Science][Medline]
  15. Gohlke P, Pees C, Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 31: 349–355, 1998.[Abstract/Free Full Text]
  16. Griol-Charhbili V, Messadi-Laribi E, Bascands JL, Heudes D, Meneton P, Giudicelli JF, Alhenc-Gelas F, Richer C. Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia. FASEB J 19: 1172–1174, 2005.[Abstract/Free Full Text]
  17. Hatta E, Rubin LE, Seyedi N, Levi R. Bradykinin and cardioprotection: don't set your heart on it. Pharmacol Res 35: 531–536, 1997.[CrossRef][Web of Science][Medline]
  18. Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, Inagami T. Targeted deletion of angiotensin II type 2 receptor caused cardiac rupture after acute myocardial infarction. Circulation 106: 2244–2249, 2002.[Abstract/Free Full Text]
  19. Liu YH, Yang XP, Nass O, Sabbah HN, Peterson E, Carretero OA. Chronic heart failure induced by coronary artery ligation in Lewis inbred rats. Am J Physiol Heart Circ Physiol 272: H722–H727, 1997.[Abstract/Free Full Text]
  20. Liu YH, Yang XP, 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 99: 1926–1935, 1997.[Web of Science][Medline]
  21. Liu YH, Yang XP, Shesely EG, Sankey SS, Carretero OA. 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 43: 1473–1480, 2004.[Abstract/Free Full Text]
  22. Madeddu P, Emanueli C, Maestri R, Salis MB, Minasi A, Capogrossi MC, Olivetti G. Angiotensin II type 1 receptor blockade prevents cardiac remodeling in bradykinin B2 receptor knockout mice. Hypertension 35: 391–396, 2000.[Abstract/Free Full Text]
  23. Maestri R, Milia AF, Salis MB, Graiani G, Lagrasta C, Monica M, Corradi D, Emanueli C, Madeddu P. Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice. Hypertension 41: 1151–1155, 2003.[Abstract/Free Full Text]
  24. Marceau F, Hess JF, Bachvarov DR. The B1 receptors for kinins. Pharmacol Rev 50: 357–386, 1998.[Abstract/Free Full Text]
  25. 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 101: 527–535, 1998.[Web of Science][Medline]
  26. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res 83: 1182–1191, 1998.[Abstract/Free Full Text]
  27. McMurray JJ, Pfeffer MA, Swedberg K, Dzau VJ. Which inhibitor of the renin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation 110: 3281–3288, 2004.[Free Full Text]
  28. Meyer M, Bluhm WF, He H, Post SR, Giordano FJ, Lew WY, Dillmann WH. Phospholamban-to-SERCA2 ratio controls the force-frequency relationship. Am J Physiol Heart Circ Physiol 276: H779–H785, 1999.[Abstract/Free Full Text]
  29. Nagamatsu S, Kornhauser JM, Burant CF, Seino S, Mayo KE, Bell GI. Glucose transporter expression in brain. cDNA sequence of mouse GLUT3, the brain facilitative glucose transporter isoform, and identification of sites of expression by in situ hybridization. J Biol Chem 267: 467–472, 1992.[Abstract/Free Full Text]
  30. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 319: 80–86, 1988.[Abstract]
  31. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM, Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 349: 1893–1906, 2003.[Abstract/Free Full Text]
  32. Pitt B, Williams G, Remme W, Martinez F, Lopez-Sendon J, Zannad F, Neaton J, Roniker B, Hurley S, Burns D, Bittman R, Kleiman J. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 15: 79–87, 2001.[CrossRef][Web of Science][Medline]
  33. Ritchie RH, Marsh JD, Lancaster WD, Diglio CA, Schiebinger RJ. Bradykinin blocks angiotensin II-induced hypertrophy in the presence of endothelial cells. Hypertension 31: 39–44, 1998.[Abstract/Free Full Text]
  34. Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 73: 413–423, 1993.[Abstract/Free Full Text]
  35. Salomone LJ, Howell NL, McGrath HE, Kemp BA, Keller SR, Gildea JJ, Felder RA, Carey RM. Intrarenal dopamine D1-like receptor stimulation induces natriuresis via an angiotensin type-2 receptor mechanism. Hypertension 49: 155–161, 2007.[Abstract/Free Full Text]
  36. Siragy HM, Carey RM. Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model. Hypertension 33: 1237–1242, 1999.[Abstract/Free Full Text]
  37. Siragy HM, de Gasparo M, Carey RM. Angiotensin type 2 receptor mediates valsartan-induced hypotension in conscious rats. Hypertension 35: 1074–1077, 2000.[Abstract/Free Full Text]
  38. Siragy HM, de Gasparo M, El Kersh M, Carey RM. Angiotensin-converting enzyme inhibition potentiates angiotensin II type 1 receptor effects on renal bradykinin and cGMP. Hypertension 38: 183–186, 2001.[Abstract/Free Full Text]
  39. Trabold F, Pons S, Hagege AA, Bloch-Faure M, Alhenc-Gelas F, Giudicelli JF, Richer-Giudicelli C, Meneton P. Cardiovascular phenotypes of kinin B2 receptor- and tissue kallikrein-deficient mice. Hypertension 40: 90–95, 2002.[Abstract/Free Full Text]
  40. 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 104: 925–935, 1999.[Web of Science][Medline]
  41. Voros S, Yang Z, Bove CM, Gilson WD, Epstein FH, French BA, Berr SS, Bishop SP, Conaway MR, Matsubara H, Carey RM, Kramer CM. The interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling. Am J Physiol Heart Circ Physiol 290: H1004–H1010, 2006.[Abstract/Free Full Text]
  42. Wang Q, Hummler E, Nussberger J, Clement S, Gabbiani G, Brunner HR, Burnier M. Blood pressure, cardiac, and renal responses to salt and deoxycorticosterone acetate in mice: role of Renin genes. J Am Soc Nephrol 13: 1509–1516, 2002.[Abstract/Free Full Text]
  43. Widdop RE, Jones ES, Hannan RE, Gaspari TA. Angiotensin AT2 receptors: cardiovascular hope or hype? Br J Pharmacol 140: 809–824, 2003.[CrossRef][Web of Science][Medline]
  44. Yang XP, Liu YH, Mehta D, Cavasin MA, Shesely E, Xu J, Liu F, Carretero OA. Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B2 kinin receptor gene knockout mice. Circ Res 88: 1072–1079, 2001.[Abstract/Free Full Text]
  45. Yang Z, Berr SS, Gilson WD, Toufektsian MC, French BA. Simultaneous evaluation of infarct size and cardiac function in intact mice by contrast-enhanced cardiac magnetic resonance imaging reveals contractile dysfunction in noninfarcted regions early after myocardial infarction. Circulation 109: 1161–1167, 2004.[Abstract/Free Full Text]
  46. Yang Z, Bove CM, French BA, Epstein FH, Berr SS, DiMaria JM, Gibson JJ, Carey RM, Kramer CM. Angiotensin II type 2 receptor overexpression preserves left ventricular function after myocardial infarction. Circulation 106: 106–111, 2002.[Abstract/Free Full Text]
  47. Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation 101: 1019–1026, 2000.[Abstract/Free Full Text]
  48. Zhao Y, Biermann T, Luther C, Unger T, Culman J, Gohlke P. Contribution of bradykinin and nitric oxide to AT2 receptor-mediated differentiation in PC12 W cells. J Neurochem 85: 759–767, 2003.[Web of Science][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/6/H3372    most recent
00997.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Isbell, D. C.
Right arrow Articles by Kramer, C. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Isbell, D. C.
Right arrow Articles by Kramer, C. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.