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Cardiovascular Research 2004 61(3):559-569; doi:10.1016/j.cardiores.2003.10.018
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Copyright © 2003, European Society of Cardiology

The bradykinin B1 receptor contributes to the cardioprotective effects of AT1 blockade after experimental myocardial infarction

Carsten Tschöpe*,a, Frank Spillmanna, Christine Altmanna, Matthias Kocha, Dirk Westermanna, Nasser Dhayata, Sameer Dhayata, Jean-Loup Bascandsb, Lajos Gerac, Sigrid Hoffmannd, Heinz-Peter Schultheissa and Thomas Walthera

aDepartment of Cardiology and Pneumology, Charité—University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, D-12220 Berlin, Germany
bINSERM U388, Institut Louis Bugnard, Toulouse, France
cBiochemistry Department, University of Colorado, Denver, CO, USA
dDepartment of Medicine, University Hospital Mannheim, University Heidelberg, Mannheim, Germany

* Corresponding author. Tel.: +49-30-8445-2343; fax: +49-30-78717823. ctschoepe{at}yahoo.com

Received 16 October 2002; revised 18 September 2003; accepted 10 October 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Immunohistochemistry
 5. Discussion
 6. Limitations of the...
 References
 
Objective: To investigate the role of the bradykinin B1 receptor (B1R) on the angiotensin receptor AT1 blockade-dependent cardioprotective effects, we studied the B1R regulation in wild-type rats treated with the AT1 antagonist, irbesartan (IRB), and also in transgenic rats with cardiac overexpression of the human AT1 (TGR-{alpha}MHCAT1) after induction of myocardial infarction (MI). In addition, we treated wild-type rats with IRB and/or the B1R antagonist, B9958, and determined the left ventricular (LV) function. Methods: Untreated, IRB (50 mg/kg/day/p.o.), B9958 (0.1 mg/kg/48 h/s.c.), and IRB/B9958-treated Sprague–Dawley rats were submitted to a permanent occlusion of the left descending coronary artery. Six days and three weeks after induction of MI, the LV function was characterized by using a Millar-tip catheter. Myocardial AT1- and B1-mRNA expression were analyzed by RNase-protection assays, B1R protein density by immunohistochemistry. Results: At both time points, LV function had improved by almost 50% after treatment with IRB but remained unchanged in TGR-{alpha}MHCAT1 after induction of MI compared to their untreated controls. The beneficial effect of IRB was reversed by co-treatment with B9958. The B1R antagonist treatment alone had no effect. A cross-talk between AT1 and B1R was also indicated by an up-regulation of B1R after treatment with IRB on protein and RNA level, while AT1 overexpression reduced B1R expression after induction of MI. Conclusion: These results indicate that the mechanisms of B1R regulation are influenced by the AT1 receptor. Thus, we are able to demonstrate for the first time that the B1R contributes to the cardio-beneficial effects of AT1 blockade.

KEYWORDS Hemodynamics; Infarction; Renin–angiotensin system; Signal transduction


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Immunohistochemistry
 5. Discussion
 6. Limitations of the...
 References
 
The kallikrein–kinin system (KKS) and the renin–angiotensin system (RAS) constitute two interactive regulatory systems involved in a multitude of physiological and pathophysiological actions. Functionally, the various effects of both systems are often opposed to one another. However, the interactions between both systems are complex. Previous studies have shown that ACE inhibitors (ACEI) exert their numerous actions by reducing both angiotensin II (ANG II) generation and bradykinin (BK) degradation [1–3]. The importance of reduced BK catabolism has already been illustrated by the fact that the cardioprotective effects of ACEI were shown to be reduced by co-treatment with the BK B2-receptor (B2R) antagonist icatibant [4,5].

In contrast to the ACEI, the AT1-receptor antagonists do not directly interfere with BK breakdown, because they selectively block the AT1 receptor [6]. Recent experimental evidence, however, points to an unexpected link between AT1 receptor antagonism and the KKS: the increase in vascular cyclic GMP (cGMP), stimulated by nitric oxide (NO) under AT1-receptor blockade, was even more marked than the one seen under ACEI treatment [7]. It was suggested that the unopposed AT2 receptor, which is exposed to more ANG II molecules during AT1-receptor blockade, stimulates the production of NO and, consequently, cGMP, a vasodilator and antiproliferative agent, through an interaction with the B2 receptor [8]. Furthermore, Yang et al. [9] demonstrated that the cardioprotective effect of an AT1 antagonist was similar to an ACEI in control mice with myocardial infarction (MI), and that this effect was reduced in both interventions in B2R knockout mice. Although the reduction of cardioprotective effects after ACE inhibition by co-treatment with icatibant and the findings by Yang et al. [9] indicate the involvement of the B2R [4,5], the first studies in humans demonstrate that the bradykinin B1 receptor (B1R) also contributes to the beneficial effects of ACEI [10].

Since we have already found an up-regulation of both BK receptor types after induction of MI [11,12] and many previous studies have shown the cardioprotective effects of ACEI under this condition, we investigated in this study the role of the B1R on the AT1 blockade-dependent effects using AT1 receptor-transgenic animals and pharmacological interventions in a rat model of MI.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Immunohistochemistry
 5. Discussion
 6. Limitations of the...
 References
 
2.1 Animals
Experiments were performed in male Sprague–Dawley (SD) rats weighing 300–330 g (an age of approximately 10 weeks) (Charles Rivers, Germany) and in 6-week-old human AT1-overexpressing rats (TGR-{alpha}MHCAT1) [13]. The animals were allowed free access to water and standard food under a 12 h light/dark cycle. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.2 Surgical procedures and hemodynamic measurement
MI was induced by the permanent ligation of the left descending coronary artery as described recently by Tschöpe et al. [11]. LV function was determined 6 days and 3 weeks after coronary occlusion.

Starting 48 h after the induction of MI, additional groups of SD rats were treated by gavage with the AT1 antagonist irbesartan (IRB) (50 mg/kg/day), with the B1R antagonist B9958 (0.1 mg/kg/48 h/s.c.) [14], or with IRB co-treated with B9958. All groups were compared with time-matched sham-operated controls or vehicle-treated infarcted rats. Only animals with an infarct size between 40% and 45% determined by densitometry were included in the hemodynamic and molecular analysis. LV peak systolic pressure (LVP, in mm Hg), LV end-diastolic pressure (LVEDP; in mm Hg), the maximal rate of LV pressure rise (dP/dtmax., in mm Hg/s) as a measure of LV systolic contraction and the minimal rate of LV pressure fall (dP/dtmin., in mm Hg/s) as a measure of LV systolic relaxation were recorded via a Millar-tip catheter (2F) system in anaesthetized (ketamine (50 mg/kg; Parke Davis, Berlin, Germany), 2% xylasine (5 mg/kg; Medistar, Holzwickede, Germany; i.p.)), ventilated, open-chest animals at the end points of the study [12].

Finally, hearts from infarcted and sham-operated rats were weighted and LV were macroscopically separated, photographed for densitometry, and snap-frozen. In addition, lung wet weight was determined to further characterize the degree of cardiac failure as well as heart/bodyweight ratio for the degree of LV hypertrophy and remodeling.

2.3 Ribonuclease-protection assay
To detect cardiac B1R and AT1 expression, RNase-protection assays (RPA) were performed as recently described [15,16] using the Ambion RPA II kit (ITC Biotechnology, USA). Anti-sense RNA probes were generated by T7-polymerase transcription using linearized plasmids containing fragments of the B1R or AT1 cDNA. In addition, a plasmid harbouring rat L32 was used as an internal control. Probes were radiolabeled with [32P]UTP, and approximately 5x104 cpm of each probe was hybridized together with 25 µg of total RNA per sample. After RNase A/T1 digestion, 257 bp (Exon 1+Exon 2) and 192 bp (Exon 2) from the B1R, or 352 and 160 bp from rat and human AT1 cDNA were protected, as well as 127 or 130 bp from control rL32 or GAPDH sequences, respectively. The hybridized fragments were then separated by electrophoresis on a denaturing gel and analyzed using the FUJIX BAS2000 Phosphor-Imager system (Raytest, Straubenhardt, Germany). Quantitative analysis was performed by measuring the intensity of the B1R or AT1 bands normalized by the intensity of rL32 or GAPDH.

2.4 Immunohistochemistry
Serial 5-µm-thick, transverse cryosections of Tissue Tec® embedded LV of sham-operated SD animals, infarcted and Irb-treated infarcted rats were placed on Poly-L-Lysin precoated slides and fixed in cold acetone for 10 min. Immunohistochemistry with rabbit anti-B1R (A15C) specific antibodies [17] and peroxidase-conjugated IgG polyclonal anti-rabbit secondary antibody was quantified by digital image analysis as described before [18].

2.5 Statistical analysis
All data are expressed as means±SEM. Data were analyzed using a two-sided analysis of variance (ANOVA) in conjunction with the Student's t-test. The honestly significant difference for multiple comparisons of the immunohistochemical statistics was calculated by the Tukey–Kramer post hoc analysis. P values <0.05 were accepted as significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Immunohistochemistry
 5. Discussion
 6. Limitations of the...
 References
 
3.1 Left ventricular function
IRB-treated rats showed an improved LV function, reduced lung wet weight and heart/body weight ratio compared to vehicle-treated rats 6 days (Table 1) and 3 weeks (LVP: 60.1±2.5 vs. 69.2±2.1 mm Hg, P<0.05; LVEDP: 24.2±3.1 vs. 17.1±2.2 mm Hg, P<0.05; dP/dtmax.: 2969±180 vs. 3758±306 mm Hg/s, P<0.05; dP/dtmin: –2166±227 vs. –2657±295 mm Hg/s, P<0.05) after induction of MI (n=9, per group). To investigate whether an AT1 receptor over-stimulation would lead to an impaired cardiac performance, LV function was also determined in rats overexpressing AT1 driven by an {alpha}MHC (myosin heavy chain) promoter (n=9, per group), which did not differ for anesthesia tolerance, perioperative mortality, and post-operative growth compared to age-matched wild-types. Since this promoter construct is inactive in animals older than 3 months [13], MI was induced in AT1 receptor-transgenic and SD-control rats aged 6 weeks. However, AT1 overexpression led neither to an impairment of the LV function nor to changes in lung wet weight or heart/body weight ratio after 6 days (Table 1) and 3 weeks (LVP: MI 3 weeks SD 54.9±1.8 vs. MI 3 weeks TGR 58.9±4.0 mm Hg, ns; LVEDP: 25.9±4.1 vs. 22.8±2.3 mm Hg, ns; dP/dtmax.: 3158±225 vs. 3239±346 mm Hg/s, ns; dP/dtmin.: –2112±194 vs. –2534±263 mm Hg/s, ns).


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  		Table 1 Basal cardiac characteristics and tip catheter measurements

 
To investigate the role of B1R for the cardioprotective effect of IRB, animals were co-treated with B9958 (n=6). This intervention blunted the improvement of IRB and led to a significant impairment of LV function compared to untreated infarcted rats 6 days after MI (Table 1). However, the B9958-treatment alone did not influence LV function after sham (data not shown) or MI surgery. Hemodynamic changes correlated with changes in lung wet weights and heart/body weight ratio (Table 1).

3.2 Ribonuclease-protection assays
B1R mRNA concentration was measured in homogenates of isolated LV from sham-operated and infarcted, untreated TGR-{alpha}MHCAT1 and SD rats as well as from infarcted SD rats treated with IRB 6 days and 3 weeks after surgery (n≥6, per group).

In vehicle-treated SD rats, B1R-mRNA expression was increased by 59%, (P<0.05) at 6 days and by 150% (P<0.05) at 3 weeks after induction of MI compared to sham-operated rats (Figs. 1 and 2)Go. AT1 blockade led to a further increase of B1R-mRNA at both time points (6 days: by 174%, P<0.05; 3 weeks: by 220%; P<0.01) (Figs. 1 and 2)Go. In contrast, sham-operated animals overexpressing AT1 had equal concentrations of B1R mRNA compared to their controls, but a significant down-regulation of B1R mRNA 6 days to 22.5% (P<0.05) and 3 weeks to 57% (P<0.05) after induction of MI (Figs. 3 and 4)Go. To determine whether this B1R mRNA reduction was correlated to increased AT1 mRNA expression, RPAs were performed to determine AT1 mRNA levels in these transgenic animals (Fig. 5). Whereas total AT1 mRNA did not differ between sham-operated TGR-{alpha}MHCAT1 and control rats, levels were significantly increased compared to age-matched wild-type rats after induction of MI (6 days: by 47%; P<0.05 (Fig. 5B, summary of human and rat AT1 mRNA); 3 weeks: by 57%; P<0.05 (data not shown)) (n=6, per group).


Figure 1
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  		Fig. 1 B1 receptor mRNA expression in the left ventricle (LV) 6 days after induction of myocardial infarction (MI) with or without irbesartan treatment or after sham operation. (A) Representative RNase-protection assay (n=5, each group) showing B1 receptor (192 and 257 bp) vs. rL32 (127 bp) expression. (B) Quantification of B1 receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to rL32 mRNA levels (n=7), *P<0.05, **P<0.01 vs. sham; §P<0.05 vs. SD 6 days MI.

 

Figure 2
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  		Fig. 2 B1 receptor mRNA expression in the left ventricle (LV) 3 weeks after induction of myocardial infarction (MI) with or without irbesartan treatment or after sham operation. (A) Representative RNase-protection assay (n=4, each group) showing B1 receptor (192 and 257 bp) vs. rL32 (127 bp) expression. (B) Quantification of B1 receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to rL32 mRNA levels (n=6), *P<0.05, **P<0.01 vs. sham; §§P<0.01 vs. SD 3 weeks MI.

 

Figure 3
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  		Fig. 3 B1 receptor mRNA expression in the left ventricle (LV) 6 days after induction of myocardial infarction (MI) or after sham operation in AT1-transgenic animals or time-matched SD rats. (A) Representative RNase-protection assay (n=4, each group) showing B1 receptor (192 and 257 bp) vs. GAPDH (130 bp) expression. (B) Quantification of B1 receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to GAPDH mRNA levels (n=6); #P<0.05 vs. SD 6 days MI.

 

Figure 4
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  		Fig. 4 B1 receptor mRNA expression in the left ventricle (LV) 3 weeks after induction of myocardial infarction (MI) or after sham operation in AT1-transgenic animals or time-matched SD rats. (A) Representative RNase-protection assay (n=4, each group) showing B1 receptor (192 and 257 bp) vs. GAPDH (130 bp) expression. (B) Quantification of B1 receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to GAPDH mRNA levels (n=6); #P<0.05 vs. SD 3 weeks MI.

 

Figure 5
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  		Fig. 5 AT1-mRNA expression in the left ventricle (LV) 6 days after induction of myocardial infarction (MI) or after sham operation in AT1-transgenic animals or time-matched SD rats. (A) Representative RNase-protection assay (n=4, each group) showing human and rat AT1-receptor (160 and 352 bp) vs. L32 (127 bp) expression. Quantification of rat (B) and human (C) AT1-receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to L32 mRNA levels (n=6); **P<0.01 vs. SD sham, $$P<0.01 vs. AT1 sham.

 

   4. Immunohistochemistry
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Immunohistochemistry
5. Discussion
 6. Limitations of the...
 References
 
Analysis of cryosections of LV of sham-operated SD animals, infarcted and Irb-treated infarcted rats stained by a specific B1R antibody illustrated an up-regulation of B1R protein in the infarcted (20-fold) but not in the non-infarcted area of the LV (Fig. 6). While the Irb treatment did not significantly alter elevated B1R concentrations in the infarcted area, the antagonist increased the receptor density by 680% in the non-infarcted area (n=6, per group).


Figure 6
Figure 6
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  		Fig. 6 Immunohistochemical analysis of cardiac B1 receptor density in infarcted and non-infarcted areas of SD rats, placebo- or irbesartan-treated, 6 days after induction of MI and in sham-operated hearts. (A) Representative images illustrating B1 receptor staining (x400). (B) Quantification of B1 receptor staining (n=6, each group). AF refers to the area fraction. **P<0.01 vs. SD sham, ##P<0.01 vs. untreated MI rats.

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Immunohistochemistry
 5. Discussion
6. Limitations of the...
 References
 
This study demonstrates for the first time that the B1R contributes to the cardioprotective effects of an AT1 blocker in a rat model of MI. Although, unlike ACEI, AT1 antagonists do not directly influence kinin degradation, our data provides a molecular pathway which indicates an AT1 receptor interaction with the KKS under this condition.

The cardiac KKS is known to be activated in the ischemic heart indicated by an increase in kallikrein, kininogen and kinin formation (for review, see Ref. [19]). In addition, the B1R, which is usually weakly detectable under basal conditions [20,21], and the B2R, are both rapidly up-regulated after induction of MI, as we were able to show recently [11,12,19]. The causes of this activation are not yet fully understood, and may involve beside the RAS also other humoral factors, including cytokines, and mechanical stress [22,23]. However, these data were generated in 3-month-old rats. The non-significant increase in B1R mRNA in our 6-week-old controls for the AT1 transgenic rats, which we had to investigate at this early time point due to a rapidly declining transgene expression after 2 months [13], implies an age dependency for this B1R stimulation under ischemic conditions.

Furthermore, there is increasing evidence to suggest that there are complex interactions between the RAS and KKS (for review, see Ref. [3]): ACE efficiently catabolizes kinins [1,2], angiotensin-derivates, e.g. ANG-(1–7) and ANG-(1–9) show kinin-like effects [24], and KLK probably serves as a pro-renin-activating enzyme [25]. Studies of AT1 antagonists and AT2-transgenic mice lead to the conclusion that an autocrine cascade including BK, NO, prostaglandins, and cGMP is probably involved in AT2 receptor-dependent effects [7]. Recently, we described an AT1-controled mechanism leading to kinin formation which includes a neutral endopeptidase-dependent pathway [26]. Furthermore, it has been shown experimentally that the protective effects of ACEI are at least partially mediated by a direct potentiation of the B2R [27] and B1R [28] response after kinin stimulation.

Although in the last few years, experimental and clinical studies have shown that the cardioprotective effects of ACE inhibition mediated by the KKS are triggered by the B2R [5,29,30], and recent data indicate the importance of the B1R in the actions of ACEI [10,28,31], our study demonstrates first that B1R-dependent effects contributes to the cardioprotective effects of an AT1 receptor blockade, indicated by the blunted beneficial effect of IRB after co-treatment with the B1R antagonist, B9958. Although Lagneux et al. [32] found a detrimental effect of the B1R in an ex vivo model for preconditioning using B1R-deficient mice, our findings indicate a direct beneficial quality of the B1R, which is known to be up-regulated in the ischemic heart [12]. Consequently, we expected an impaired cardiac function in infarcted rats after treatment with the B1R antagonist B9958. However, we could not find any changes in LV function after B1R-blocker treatment in these animals. Thus, we conclude that the B1R axis of the KKS affects the LV function of ischemic hearts only to a minor degree in the absence of an AT1 antagonism. This implies that the blockade of AT1 is necessary to trigger the cardioprotective effects of B1R. Similar results have been found after selective inhibition of the B2R in the ischemic heart after ACE inhibition [29]. Importantly, the cardioprotective effect of the AT1–B1R axis does not seem to be mediated via alterations in AT1 expression after AT1 antagonism, since previous studies have demonstrated that myocardial infarction evokes a dramatic up-regulation of both angiotensin receptor subtypes, which is not influenced by a co-treatment with the AT1 antagonist losartan [33,34]. Moreover, our immunohistochemical analysis discovered that the increase in B1R mRNA expression detected in the whole LV of infarcted animals treated by IRB is due to a further B1R up-regulation in the non-infarcted area, especially in vascular tissue, while the AT1 antagonist does not alter the B1R density in the scar area.

Our finding that the B1R has a cardioprotective potential is in agreement with other findings concerning ischemia-induced cardiac B1R expression: B1R agonists showed a capacity to modulate noradrenaline release [35], to reduce reperfusion arrhythmia [36], and to preserve endothelium-dependent vasodilation [37] under ischemic conditions. Thus, the activation of the B1R axis of the KKS may also belong to the known kinin-dependent cardioprotective effects, which are mediated by an increase in prostaglandins and NO leading to vasodilation [38] and antiproliferative effects produced by suppressing fibroblast growth and collagen synthesis [39].

The suggestion that an interaction exists between the AT1 and the B1R is further underlined by our finding that treatment with IRB leads to a further B1R mRNA up-regulation in both the inflammatory/early fibrogenic phase (6 days post-MI) and the late fibrinogenic phase (3 weeks post-MI) of cardiac wound-healing after induction of MI. Furthermore, we detected a down-regulation of B1R mRNA expression in TGR-{alpha}MHCAT1 demonstrating that AT1 stimulation has an inhibitory effect on B1R expression in the ischemic heart. This effect was not found under basal conditions and is in agreement with previous findings showing that the B1R is only weakly expressed in healthy tissue [21]. Thus, we suggest that in our model, ischemic or inflammatory stimuli lead to an B1R up-regulation controlled by the AT1 receptor. Importantly, this control seems not to be dominantly influenced by hemodynamic alterations, since these parameters did not differ between the infarcted TGR and their controls.

In conclusion, apart from the previously described indirect interaction between the RAS and KKS after AT1 antagonism, defined by an AT2 receptor-dependent increase in BK levels [8], we found an additional direct interaction, which includes an AT1-dependent regulation of the B1R after induction of MI. Thus, an AT1 blockade stimulates the KKS on the ligand and receptor levels. In the absence of AT1 antagonism, BK and desArg9-BK contribute to a minor degree to the maintenance of basal LV function in the healthy and ischemic heart, but they contribute to the cardioprotective effects of a chronic AT1 blockade in experimental MI via both the B2R [9] and the B1R axis. Further studies will have to be undertaken to identify the intracellular pathway leading to an up-regulation of B1R after AT1 blockade and to demonstrate the clinical importance of this cross-talk.


   6. Limitations of the study
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Immunohistochemistry
 5. Discussion
 6. Limitations of the...
References
 
Although the rat model of coronary artery ligation is a well-established model of heart failure, it must be recognized that no animal model will fully represent the complex clinical situation of cardiac failure. Thus, the results of the present study should be further evaluated in clinical trials.

The insignificant increase in B1R mRNA in our 6-week-old controls for the AT1 transgenic mice, which we had to investigate at this early time point due to a rapidly declining transgene expression after 2 months, limits cross-comparison with older untreated and treated infarcted SD rats. This may explain the unimpaired LV function in AT1 transgenic rats with decreased B1 expression. However, it may also be due to the fact that we cannot automatically infer an impairment in cardiac function after reduction of B1 level in AT1 overexpressing hearts from a cardioprotective elevation in B1 concentration after AT1 blockade. This is also supported by the unchanged hemodynamics in B1-antagonist-treated rats.


   Acknowledgements
 
This project was supported from the Deutsche Forschungsgesellschaft (DFG: TS/64-2).


   Notes
 
Time for primary review 00 days


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Immunohistochemistry
 5. Discussion
 6. Limitations of the...
 References
 

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