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(Circulation Research. 2001;0:hh1001.090759.)
© 2001 American Heart Association, Inc.

Article

Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B₂ Kinin Receptor Gene Knockout Mice

Xiao-Ping Yang, Yun-He Liu, Dharmesh Mehta, Maria A. Cavasin, Edward Shesely, Jiang Xu, Fang Liu Oscar A. Carretero

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

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

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

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

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.

View this table: [in this window] [in a new window]   Table 1. Body, Heart, Lung, and Liver Weight and Infarct Size in B2-/- and B2+/+ Mice

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).

View larger version (25K): [in this window] [in a new window]   Figure 1. SBP and HR in sham-operated mice (sham) and mice with HF treated with vehicle, ACEi, or AT1-ant. Basal indicates before surgery; 1w, 1 week after surgery without treatment; and 2–12w, combined data during treatment period (2 to 12 weeks).

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.

View larger version (33K): [in this window] [in a new window]   Figure 2. Comparison of EF, CO, LVDd, and LV mass between B2-/- mice and B2+/+ mice without HF (sham coronary artery ligation) or with HF induced by coronary artery ligation (CL) before surgery (basal) and after surgery (1 to 12 weeks).

View larger version (92K): [in this window] [in a new window]   Figure 3. Two-dimensional M-mode echocardiographs of B2-/- mice and B2+/+ mice with sham coronary ligation (sham) or HF. IS indicates interventricular septum; DD, LV diastolic dimension; and PW, LV posterior wall.

View larger version (34K): [in this window] [in a new window]   Figure 4. Effect of ACEi and AT1-ant on EF and CO in B2-/- mice and B2+/+ mice with HF induced by CL before ligation (basal) and after ligation (1 to 12 weeks). Veh indicates treatment with vehicle. *P<0.01 vs HF-vehicle for both ACEi and AT1-ant. Bar graphs show average per cent increase from 2 to 12 weeks of treatment.

View larger version (34K): [in this window] [in a new window]   Figure 5. Effect of ACEi and AT1-ant on LVDd and LV mass in B2-/- mice and B2+/+ mice with HF induced by CL before ligation (basal) and after ligation (1 to 12 weeks). *P<0.01 vs HF-vehicle for both ACEi and AT1-ant. Bar graphs show average per cent decrease from 2 to 12 weeks of treatment.

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).

View larger version (102K): [in this window] [in a new window]   Figure 6. Representative slides showing MCSA and interstitial collagen deposition (green staining) in B2-/- and B2+/+ mice with either sham coronary ligation (sham) or HF.

View larger version (24K): [in this window] [in a new window]   Figure 7. Effect of ACEi and AT1-ant on MCSA (top) and ICF (bottom) in B2-/- and B2+/+ mice with sham coronary ligation (sham) or HF.

Discussion

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.

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