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(Circulation. 1997;95:1910-1917.)
© 1997 American Heart Association, Inc.

Articles

Differential Effects of Kinins on Cardiomyocyte Hypertrophy and Interstitial Collagen Matrix in the Surviving Myocardium After Myocardial Infarction in the Rat

Kai C. Wollert, MD; Roland Studer, PhD; Kristin Doerfer, BS; Elisabeth Schieffer, MD; Christian Holubarsch, MD; Hanjörg Just, MD; Helmut Drexler, MD

From the Medizinische Klinik III, Arbeitsgruppe Molekulare Kardiologie, Universität Freiburg, Germany.

Correspondence to Helmut Drexler, MD, Abteilung Kardiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str 1, 30625 Hannover, Germany.

	Abstract

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Background Left ventricular remodeling after myocardial infarction (MI) involves the hypertrophic growth of cardiomyocytes and the accumulation of fibrillar collagen in the interstitial space. We evaluated the role of kinins in postinfarction ventricular remodeling and their potential contribution to the antiremodeling effects of ACE inhibition and angiotensin II type 1 (AT1) receptor blockade.

Methods and Results Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant. Additional groups of infarcted rats were treated with the ACE inhibitor lisinopril or the AT1 receptor antagonist ZD7155, each separately and in combination with icatibant. B2 kinin receptor blockade enhanced the interstitial deposition of collagen after MI, whereas morphological and molecular markers of cardiomyocyte hypertrophy (cardiac weight, myocyte cross-sectional area, prepro–atrial natriuretic factor mRNA expression) were not affected. Chronic ACE inhibition and AT1 receptor blockade reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition and AT1 receptor blockade on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy.

Conclusions (1) Kinins inhibit the interstitial accumulation of collagen but do not modulate cardiomyocyte hypertrophy after MI. (2) Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. (3) The effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy are related to a reduced generation/receptor blockade of angiotensin II.

Key Words: myocardial infarction • bradykinin • collagen • hypertrophy

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
In response to an MI, the heart undergoes a remodeling process characterized by an early expansion of the infarcted area, progressive dilatation of the LV, and hypertrophic growth of the surviving myocardium.^{1 2 3} Cardiac hypertrophy is associated with the reexpression of the ANF gene in ventricular myocytes⁴ and an increased deposition of fibrillar collagen in the interstitial space.^{5 6}

ACE inhibitors and AT1 receptor antagonists attenuate the remodeling of the myocyte and nonmyocyte compartments after MI.^{5 6 7 8 9} Angiotensin II may induce cardiomyocyte hypertrophy via the AT1 receptor¹⁰ and stimulate cardiac fibroblast collagen synthesis in vitro.¹¹ Therefore, the beneficial effects of ACE inhibition and AT1 receptor blockade after MI implicate the renin-angiotensin system in the regulation of post-MI ventricular remodeling. ACE (kininase II, EC 3.4.15.1) acts as a potent kinin-degrading enzyme in plasma and tissues,^{12 13 14} and accordingly, plasma and tissue bradykinin levels are increased during ACE inhibition.¹⁵ Cardiomyocytes and cardiac fibroblasts express functional B2 kinin receptors,¹⁶ suggesting that the myocardium not only is a source of kinins^{13 17 18} but also may be a target for kinin-mediated effects. In this regard, the antihypertrophic effects of ACE inhibition in rats with aortic banding and dogs with myocardial necrosis after DC shock can be abolished by the coadministration of a B2 kinin receptor antagonist,^{19 20} indicating that in some pathophysiological situations, kinins mediate the antiremodeling effects of ACE inhibitors.

These previous studies prompted us to investigate the role of the kallikrein-kinin system in postinfarction ventricular remodeling in the rat. We determined (1) whether endogenous kinins not augmented by ACE inhibition are implicated in the regulation of ventricular remodeling, (2) whether kinins contribute to the antihypertrophic effects of ACE inhibition and AT1 receptor blockade in this setting, (3) whether the renin-angiotensin and the kallikrein-kinin systems affect cardiac myocyte and nonmyocyte compartments differently, and (4) whether increased kinin levels during ACE inhibition (and potentially during AT1 receptor blockade) result in an altered myocardial expression of cNOS.

	Methods

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Experimental Infarction
Male Sprague-Dawley rats weighing 250 to 300 g were obtained from the Zentralinstitut für Versuchstierkunde (Hannover, Germany). All animal studies were approved by the ethical committee for animal research at the University of Freiburg. Coronary artery ligation and sham operations were performed as previously described.^{21 22} Animals were allowed free access to a 0.5% sodium standard rat chow.

Drug Administration
The ACE inhibitor lisinopril and the nonpeptide AT1 receptor antagonist ZD7155²³ were dissolved in the drinking water at a concentration of 38.5 mg/L. Chronic treatment of rats with this dosage of lisinopril and ZD7155 results in a comparable (25-fold) rightward shift of the angiotensin I pressure-response curve (Reference 22²² and ZENECA, data on file). The specific B2 kinin receptor antagonist icatibant (Hoe140)²⁴ was dissolved in 0.9% NaCl and administered by Alzet 2ML2 miniosmotic pumps (Alza Corp) at a dosage of 400 µg·kg^-1·d^-1 IP.

Bradykinin Challenges
In a pilot study, we documented a sustained and effective blockade of B2 kinin receptors during treatment with icatibant. Seven days after coronary ligation, treatment with icatibant was initiated (n=4 rats). Untreated MI rats served as controls (n=4). After treatment for 25 days, the animals were anesthetized with halothane (1% in oxygen), and saline-filled catheters (PE 50) were inserted into the right carotid and the tail arteries. Increasing doses of bradykinin (Sigma) were injected into the carotid artery, and the blood pressure responses were recorded via the tail arterial line connected to a Statham P23ID pressure transducer. Compared with control animals, rats treated with icatibant displayed a 35-fold rightward shift of the bradykinin pressure-response curve (data not shown).

Experimental Protocol
Seven days after coronary artery ligation, rats were randomized into six groups and treated with vehicle (tap water) (MI-V group), lisinopril (MI-L), lisinopril and icatibant (MI-L/I), ZD7155 (MI-Z), ZD7155 and icatibant (MI-Z/I), or icatibant alone (MI-I) (n=7 or 8 per group). Sham-operated animals treated with vehicle served as a control group (sham-V, n=6). The following procedures were performed in the early morning hours after treatment for 25 days. After body weights had been determined, the animals were anesthetized with halothane, and a PE 50 catheter was inserted into the right carotid artery. The arterial line was connected to a Statham P23ID pressure transducer, and arterial blood pressure and heart rate were recorded. Subsequently, a blood sample was collected into a chilled tube containing heparin (200 IU/mL) and immediately centrifuged at 4°C. Plasma was snap-frozen and stored in liquid nitrogen until assay of ACE activity. The chest was then opened, and the heart was removed, rinsed in ice-cold saline, blotted dry, and weighed. The atria were dissected from the ventricles, and the LV (including the septum) and the RV free wall were separated and weighed. A transverse slice was cut from the equatorial plane of the LV and immersion-fixed in 10% buffered formalin for later determination of infarct size, mean myocyte CSA, and interstitial CVF. The infarct scar, including the border zone, was then removed from the remaining LV myocardium. In sham-operated animals, corresponding parts of the LV were discarded. LV tissue was divided into halves and stored at -80°C or in liquid nitrogen for later isolation of total RNA and assay of ACE activity, respectively. The RV free wall was snap-frozen and stored in liquid nitrogen until assay of ACE activity. Finally, the kidneys and lungs were removed and stored in liquid nitrogen for subsequent determination of ACE activities.

RNA Isolation and Northern Blot Analysis
Total RNA was isolated according to the acid guanidinium thiocyanate–phenol-chloroform extraction method.²⁵ RNA was subjected to formaldehyde agarose gel electrophoresis and transferred to nylon filters by overnight capillary blotting. The filters were hybridized with prepro-ANF²⁶ and 18S²⁷ cDNA probes labeled with [-³²P]dCTP by random priming (Multiprime DNA Labeling Kit, Amersham) as previously described.²²

Quantification of cNOS mRNA Expression by Competitive RT-PCR
The expression levels of cNOS mRNA in noninfarcted LV tissue were determined by competitive RT-PCR.^{28 29} A cNOS cDNA fragment was amplified from rat LV total RNA by RT-PCR using primers selected on the basis of the human and bovine cNOS cDNA sequences.^{30 31} Subsequently, a competitor cNOS RNA was generated by in vitro transcription from a mutated rat cNOS cDNA containing a 125-bp PflMI-BglII internal deletion compared with wild-type rat cNOS cDNA. Total LV RNA (50 ng) along with increasing quantities of cNOS competitor RNA (0.25x10⁶ to 20x10⁶ molecules) were reverse-transcribed into first-strand cDNA and subsequently amplified by PCR (sense primer, 5'-CTGCGCTGGTATGCCCTCC-3'; antisense primer, 5'-AAGAGCCTCCCCAGCTGCTG-3'; 30 cycles; cycle profile: 1 minute at 94°C; 2 minutes at 65°C; and 3 minutes at 72°C). The RT-PCR products were separated by ethidium bromide agarose gel electrophoresis, visualized by UV irradiation, and analyzed by laser densitometry (Personal Densitometer, Molecular Dynamics). A representative gel is depicted in Fig 1.

View larger version (23K): [in this window] [in a new window]   Figure 1. Competitive cNOS RT-PCR. Band intensities of cNOS target (643 bp) and cNOS competitor (518 bp) products were analyzed by laser densitometry. On right, a 603-bp DNA standard (M) was loaded. To correct for difference in molecular weight, cNOS competitor band intensities were multiplied by 1.24 (643 bp/518 bp). Mean values of duplicate samples were plotted as ratio of competitor to target RT-PCR products against known number of competitor RNA molecules on a log/log scale. At competition equivalence point (log ratio=0), number of target mRNA molecules corresponds to number of competitor RNA molecules.

Histological Analysis
Tissue morphometry was performed in a blinded fashion with a personal computer–assisted digital image analyzer (Quantimet 500CR, Leitz). After formalin fixation, LV tissue slices were embedded in paraffin and cut into 5-µm sections (Zeiss Microtome). The sections were mounted onto slides and stained with Sirius red F3BA (0.1% solution in saturated aqueous picric acid) to allow a clear discrimination between cardiomyocytes and collagen matrix.³² To confirm an equal distribution of MI sizes among the infarcted groups, the ratio of scar length to circumference was determined by planimetric measurement in six sections from the equatorial plane of each ventricle and expressed as percentage.²² Mean myocyte CSA (µm²) was determined from the interventricular septum and the adjacent noninfarcted LV free wall as described previously.³³ Only myofibers with intact cellular membranes from fields with circular capillary profiles and myofiber shapes (indicative of a true transverse section) were analyzed. The circumferences of 40 to 50 cells per LV were traced and digitized to calculate mean CSA. Morphometic analysis of LV sections stained with Sirius red has been used as a sensitive and quantitative method to assess myocardial collagen matrix in hypertensive³⁴ and post-MI rats.^{5 6} We have previously used this method to assess the influence of pharmacological interventions on interstitial collagen in the rat infarct model.^{7 35} Accordingly, interstitial CVF (percent) was measured in the interventricular septum and the adjacent noninfarcted LV free wall. Ten sections per animal and 10 fields per section were scanned and computerized on the basis of their red levels resulting from collagen staining. Interstitial CVF was calculated as the sum of all connective tissue areas divided by the sum of all connective tissue and muscle areas in the respective field. Perivascular and scarred areas were not included in this analysis.^{7 35}

Papillary Muscle Stiffness
To assess the influence of chronic B2 kinin receptor blockade on the passive elastic properties of the myocardium, intact posterior papillary muscles were recovered from separate groups of sham-operated animals treated with vehicle or icatibant for 25 days (n=6 per group). Stress ()–strain () relationships were recorded in vitro as described previously by our group.³⁶ The tangent elastic modulus (d/d) was plotted against instantaneous stress (). The muscle stiffness constant—the slope of the resulting line—was used to compare passive elastic properties of different papillary muscle preparations. After completion of the functional studies, interstitial CVF and mean myocyte CSA were determined morphometrically from the same papillary muscles.

Plasma and Tissue ACE Activities
ACE activities were determined as described previously²² by measurement of the rate of [¹⁴C]hippuric acid generation from [¹⁴C]Hip-His-Leu using the optimal incubation conditions for Hip-His-Leu cleavage.³⁷

Statistical Analysis
Data are presented as mean±SEM. Differences between groups were first evaluated by one-way ANOVA. We then conducted eight prespecified post hoc intergroup comparisons using Student's t test with Bonferroni correction: sham-V versus MI-V to detect differences as a result of MI, MI-I versus MI-V to evaluate the role of endogenous kinins in postinfarction ventricular remodeling, MI-L versus MI-V and MI-Z versus MI-V to assess the effects of treatment with lisinopril and ZD7155, MI-L/I versus MI-L and MI-L/I versus MI-V to evaluate the contribution of kinins to the effects of lisinopril, and finally MI-Z/I versus MI-Z and MI-Z/I versus MI-V to assess the contribution of kinins to the effects of ZD7155. All probability values have been corrected for the total number of comparisons; values of P<.05 were considered to indicate statistical significance.

	Results

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Infarct Sizes and Cardiac Hypertrophy
Seven days after coronary ligation, 45 rats were randomly assigned to six treatment regimens. Six sham-operated animals were treated with vehicle and served as controls. None of the animals died during the 25-day treatment protocol. Mean infarct sizes and body weights did not differ significantly between the experimental groups (Table 1). Total heart weight–to–body weight ratio and RV weights were markedly increased in vehicle-treated MI rats compared with sham-operated controls. Despite the replacement of the infarcted area with a thin wall of scar tissue, LV weights in vehicle-treated MI rats were not different from sham-operated controls. Chronic B2 kinin receptor blockade with icatibant did not significantly alter cardiac weights post-MI. Lisinopril and ZD7155 prevented the reactive increase in total heart weight and RV weight after MI. Moreover, lisinopril and ZD7155 significantly reduced LV weights. The coadministration of icatibant had no effects on the antihypertrophic actions of lisinopril or ZD7155.

View this table: [in this window] [in a new window]   Table 1. Infarct Size and Cardiac Weights

Prepro-ANF and cNOS mRNA Expression in Noninfarcted LV Myocardium
Steady-state prepro-ANF mRNA expression was increased 19.8-fold in the surviving portion of the LV after MI (Fig 2A). The increased prepro-ANF mRNA expression levels were not significantly affected by chronic B2 kinin receptor blockade. Treatment with lisinopril or ZD7155 resulted in a significant reduction of LV prepro-ANF mRNA levels. The reduction of myocardial prepro-ANF expression by ACE inhibition and AT1 receptor blockade was not affected by concomitant B2 kinin receptor blockade.

View larger version (28K): [in this window] [in a new window]   Figure 2. Prepro-ANF and cNOS mRNA expression in noninfarcted LV myocardium. Prepro-ANF mRNA expression data were normalized to 18S expression to control for loading and transfer efficiencies and are presented as fold induction over sham-operated controls (A). cNOS mRNA expression data are presented as number of cNOS mRNA molecules/50 ng total RNA (B). Sham indicates sham-V animals; groups as in text. A, *P<.05, **P<.01 vs MI-V; MI-L/I vs MI-L and MI-Z/I vs MI-Z, P=NS. B, P=NS for all eight prespecified comparisons.

We next determined whether chronic B2 kinin receptor blockade or chronic ACE inhibition/AT1 receptor blockade (alone and in combination with icatibant) would alter cNOS mRNA expression in the noninfarcted LV myocardium. As depicted in Fig 2B, no significant differences in cNOS mRNA expression levels were observed among the experimental groups.

Structural Changes in Noninfarcted LV Myocardium
Vehicle-treated MI rats displayed a 30% increase in mean myocyte CSA compared with sham-operated controls (Fig 3A). A similar increase in mean CSA was observed in MI rats treated with icatibant. Chronic treatment with lisinopril or ZD7155, alone or in combination with icatibant, significantly reduced mean CSA after MI (Fig 3A).

View larger version (28K): [in this window] [in a new window]   Figure 3. Myocyte CSA and CVF in noninfarcted LV myocardium. Myocyte CSA (A) and CVF (B) were determined by quantitative morphometry. Abbreviations as in Fig 2 and text. A, *P<.05, **P<.01 vs MI-V; MI-L/I vs MI-L and MI-Z/I vs MI-Z, P=NS. B, *P<.05, ***P<.001 vs MI-V; #P<.01 vs MI-L; +P<.01 vs MI-Z.

Compared with control animals, a 3.9-fold increase in LV CVF was observed in vehicle-treated MI rats (Fig 3B). CVF in the noninfarcted LV myocardium was further enhanced by B2 kinin receptor blockade. Collagen accumulation was attenuated by chronic ACE inhibition with lisinopril or AT1 receptor blockade with ZD7155. The effects of lisinopril and ZD7155 on LV CVF were partially reversed by the coadministration of icatibant (Fig 3B).

Papillary Muscle Stiffness
Separate groups of sham-operated rats were treated with vehicle (sham-V) or icatibant (sham-I), and passive stress-strain relationships were recorded from intact posterior papillary muscles. Chronic B2 kinin receptor blockade significantly enhanced interstitial CVF (sham-V, 0.96±0.09%; sham-I, 1.74±0.28%; P<.05). The increase in interstitial collagen did not translate into a significant alteration of the myocardial stiffness constant (sham-V, 22.6±3.6; sham-I, 24.5±2.7; P=NS). B2 kinin receptor blockade did not affect mean myocyte CSA (sham-V, 479±14 µm²; sham-I, 474±20 µm²; P=NS).

Arterial Blood Pressure and Heart Rate
Systolic and diastolic blood pressures were decreased in vehicle-treated MI rats compared with controls and were not significantly altered by chronic B2 kinin receptor blockade (Table 2). Treatment with lisinopril and ZD7155 resulted in a comparable reduction of systolic and diastolic blood pressures that was not affected by a coadministration of icatibant. There were no significant differences in heart rate between the experimental groups.

View this table: [in this window] [in a new window]   Table 2. Arterial Blood Pressure and Heart Rate

Plasma and Tissue ACE Activities
MI rats treated with vehicle displayed a significant increase in RV ACE activity and a significant decrease in pulmonary ACE activity compared with sham-operated controls (Table 3). Chronic B2 kinin receptor blockade resulted in a significant reduction of renal ACE activity. Lisinopril inhibited plasma, pulmonary, and renal ACE activities, whereas LV and RV ACE activities remained unchanged. This pattern of plasma and tissue ACE inhibition by lisinopril was not affected by the coadministration of icatibant. Treatment with ZD7155 alone or ZD7155 and icatibant combined resulted in a significant reduction in renal ACE activity and a significant increase in pulmonary ACE activity.

View this table: [in this window] [in a new window]   Table 3. Plasma and Tissue ACE Activities

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study provides the first evidence that endogenous kinins inhibit the interstitial accumulation of collagen in the myocardium in the setting of post-MI ventricular remodeling. By contrast, endogenous kinins do not modulate cardiomyocyte hypertrophy after MI. Our results further suggest that the beneficial effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy after MI are related to an interference with the renin-angiotensin system rather than a potentiation of endogenous kinins. However, kinins appear to contribute to the effects of ACE inhibition and AT1 receptor blockade on myocardial collagen.

Role of the Endogenous Kallikrein-Kinin System in Postinfarction Ventricular Remodeling
LV weights in vehicle-treated MI rats were unchanged compared with sham-operated controls, despite the replacement of the infarcted area with a thin wall of scar tissue, strongly suggesting reactive hypertrophy of the surviving LV myocardium.³⁸ In agreement with previous studies, LV hypertrophy was characterized by an increase in myocyte CSA³³ and an upregulation of prepro-ANF expression,⁴ ie, morphological and molecular markers of cardiomyocyte hypertrophy. Moreover, MI resulted in a severalfold increase in interstitial collagen deposition in the surviving LV myocardium.^{5 6} B2 kinin receptor blockade significantly increased LV CVF but did not alter cardiac weights, LV myocyte CSA, and LV prepro-ANF expression, suggesting that endogenous kinins exert an inhibitory effect on the interstitial deposition of collagen in the myocardium and that endogenous kinins are not involved in the regulation of cardiomyocyte hypertrophy after MI.

The increase in LV interstitial collagen after B2 kinin receptor blockade was not related to a change in blood pressure, suggesting that blood pressure is not the prime determinant of collagen deposition in the noninfarcted LV myocardium. In this regard, a recent study in rats made hypertensive by aortic banding demonstrated that myocardial fibrosis can be prevented by ACE inhibition even in a nonhypotensive dosage.³⁹ Similarly, chronic ACE inhibition in young rats decreases the myocardial collagen content with little or no effect on arterial blood pressure.⁴⁰ In both studies, the decrease in LV interstitial collagen has been attributed to a reduction of angiotensin II formation and/or an inhibition of kinin breakdown within the myocardium.^{39 40} Adult rat cardiac fibroblasts express B2 kinin receptors,⁴¹ and preliminary data suggest that bradykinin increases the collagenolytic activity and decreases the synthesis of type 1 collagen in cultured adult rat cardiac fibroblasts.⁴² In addition, kinins have been shown to stimulate prostanoid and nitric oxide synthesis and to inhibit endothelin-1 secretion through the B2 kinin receptor subtype,^{43 44 45} effects that may all contribute to a kinin-mediated reduction in fibrous tissue formation and/or increase in collagen degradation.^{46 47 48 49 50} On the basis of these in vitro studies, it has been proposed that locally generated kinins may inhibit fibrous tissue formation in the heart.⁵¹ The present study supports this hypothesis and provides the first in vivo evidence that kinins, independently of changes in arterial blood pressure, inhibit the interstitial deposition of collagen in the myocardium.

B2 kinin receptor blockade enhanced LV interstitial collagen deposition in noninfarcted animals too, implying that kinins participate in the regulation of myocardial collagen in the intact LV as well. However, the 81% increase in interstitial collagen did not translate into a significant alteration of the myocardial stiffness constant, as determined in isolated papillary muscle preparations. It therefore appears that this degree of histological change does not affect the passive elastic properties of the myocardium.

Contribution of Kinins to the Effects of ACE Inhibition and AT1 Receptor Blockade After MI
ACE inhibition and AT1 receptor blockade were equally effective in attenuating ventricular remodeling after MI, as suggested by a comparable reduction of total heart weights, LV and RV weights, LV myocyte CSA, LV prepro-ANF expression, and LV CVF. B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on markers of cardiomyocyte hypertrophy. By contrast, the reduction of LV interstitial collagen by ACE inhibition or AT1 receptor blockade was partially reversed by chronic B2 kinin receptor blockade. The beneficial effects of ACE inhibition and AT1 receptor blockade on postinfarction ventricular remodeling were not related to alterations in LV cNOS mRNA expression levels. However, these data do not exclude the possibility that ACE inhibition and/or AT1 receptor blockade enhance NO generation by cNOS via a potentiation of myocardial kinin levels.^{13 52}

Cardiomyocyte Hypertrophy
The present study documents that kinin potentiation does not contribute to the effects of ACE inhibition and AT1 receptor blockade on arterial blood pressure and cardiomyocyte hypertrophy in post-MI ventricular dysfunction. Instead, the effects of ACE inhibition and AT1 receptor blockade on blood pressure and cardiomyocyte hypertrophy appear to be related to an interference with the renin-angiotensin system. Plasma, pulmonary, and renal ACE activities were inhibited by chronic lisinopril treatment. In agreement with our previous results, lisin-opril did not inhibit cardiac ACE activities as measured ex vivo.²² However, it should be kept in mind that the measurement of tissue ACE activities ex vivo may underestimate the actual degree of ACE inhibition achieved in vivo.⁵³ Indeed, myocardial angiotensin II levels are reduced by >70% during chronic treatment with lisinopril, suggesting inhibition of cardiac ACE in vivo (H.D. et al, unpublished data). Moreover, inhibition of myocardial ACE in post-MI rats during chronic lisinopril treatment has also been demonstrated by autoradiography.⁵⁴

In contrast to the results from the present study, B2 kinin receptor blockade abolishes the effects of ACE inhibition on arterial blood pressure and cardiac weights in rats with aortic coarctation,¹⁹ suggesting that kinins may contribute to the antihypertrophic effects of ACE inhibitors in certain pathophysiological situations. However, the antihypertensive and antihypertrophic effects of ACE inhibition in stroke-prone spontaneously hypertensive rats are kinin independent.⁵⁵ The reasons for this discrepancy are not known at the present time.⁵⁶

The contribution of kinins to the cardiovascular effects of ACE inhibitors may depend on the degree of activation of the endogenous kinin-generating system: acute myocardial ischemia/infarction induces an increased release of kinins from the heart and is associated with elevated circulating kinin levels.^{13 57 58} In this situation, B2 kinin receptor blockade increases arterial blood pressure and reverses the hypotensive effect of ACE inhibition.⁵⁹ By contrast, B2 kinin receptor blockade does not alter arterial blood pressure and does not counteract the hypotensive effects of ACE inhibition in normotensive rats without myocardial ischemia, suggesting that kinins are present in subthreshold concentrations.⁶⁰ Likewise, B2 kinin receptor blockade did not change arterial blood pressure and did not attenuate the hypotensive effects of ACE inhibition in the present study. Differences in the activation status of the kallikrein-kinin system might therefore account for the different role of kinins during the acute versus the chronic phase after myocardial ischemia/infarction.

McDonald et al^{20 61} assessed the role of kinins for the antigrowth effects of ramipril in a canine model of localized myocardial necrosis resulting from transmyocardial DC shock. In contrast to the results from the present study, the antigrowth effects of ramipril in dogs with myocardial necrosis were abolished by B2 kinin receptor blockade.²⁰ Furthermore, AT1 receptor blockade failed to inhibit the remodeling process in the canine model.⁶¹ The timing of ACE inhibition and AT1 receptor blockade differed between the studies of McDonald et al and the present investigation: in the canine model, therapy was initiated 1 day after the DC shock procedure. In the present study, by contrast, treatment was started in the chronic phase, ie, 7 days after coronary ligation. Early-onset ACE inhibition in dogs after coronary ligation has been shown to prevent the expansion of the infarcted area, the marked increase in chamber volume, and the increase in LV mass that develop within 2 to 7 days after MI.⁶² Conceivably, the significance of kinin potentiation for the antigrowth effects of ACE inhibitors may be more pronounced in the early phase after myocardial injury, ie, for the effects of ACE inhibitors on infarct size, infarct expansion, early chamber dilatation, and early increase in ventricular mass.

Interstitial Fibrosis
B2 kinin receptor blockade partially reversed the effects of lisinopril and ZD7155 on LV interstitial collagen after MI, suggesting that kinin- and angiotensin II–dependent mechanisms mediate the reduction of myocardial collagen by ACE inhibition and AT1 receptor blockade. Although a contribution of kinins to the beneficial effects of ACE inhibition may not be surprising, given the ability of ACE inhibitors to reduce kinin degradation¹⁵ and to enhance the effects of bradykinin at the B2 kinin receptor level,⁶³ the contribution of kinins to the effects of AT1 receptor blockade was somewhat unexpected. Treatment with ZD7155 resulted in a reduction of renal ACE activity in post-MI rats, confirming our previous results with the AT1 receptor antagonist losartan.⁷ Inhibition of renal ACE correlates with the degree of blood pressure reduction, inhibition of cardiac hypertrophy, and improvement of long-term survival in post-MI rats treated with ACE inhibitors.^{22 64} Therefore, the reduction of renal ACE activity might contribute to the cardiovascular effects of AT1 receptor antagonists: in the face of an effective AT1 receptor blockade, additional benefit may result from a reduction of kinin breakdown. Angiotensin II has been shown to stimulate nitric oxide release from endothelial cells via enhanced kinin formation, an effect that appears to be mediated by the AT2 receptor.⁶⁵ Since angiotensin II levels are increased during AT1 receptor blockade,⁶⁶ AT2 receptor–dependent stimulation of kinin release might mediate part of the effects of AT1 receptor antagonists. As noted above, infarcted rats treated with icatibant alone displayed an increase in LV collagen. Therefore, it cannot be ruled out that the inhibitory action of icatibant on the antifibrotic effects of lisinopril and ZD7155 reflects an inhibition of unaugmented basal kinin levels rather than an inhibition of kinin levels augmented by lisinopril and/or ZD7155.

LV collagen accumulation in MI rats receiving combined treatment with icatibant and lisinopril or ZD7155 was significantly reduced compared with vehicle-treated MI rats. These data indicate that interference with the renin-angiotensin system, independently of kinins, mediates part of the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. In this regard, increased ACE and AT1 receptor binding has been shown to be anatomically coincident with sites of collagen formation within the noninfarcted myocardium after MI, supporting the notion that angiotensin II may regulate fibrous tissue formation in vivo via the AT1 receptor.^{54 67}

	Selected Abbreviations and Acronyms

 

ANF = atrial natriuretic factor AT1 = angiotensin II type 1 cNOS = constitutive nitric oxide synthase CSA = cross-sectional area CVF = collagen volume fraction LV = left ventricle, left ventricular MI = myocardial infarction RT-PCR = reverse-transcription polymerase chain reaction RV = right ventricle, right ventricular

	Acknowledgments

 
This study was supported in part by the Deutsche Forschungsgemeinschaft (Dr 148/6-3 and 148/7-2). We gratefully acknowledge Prof Bernward A. Schölkens (Hoechst) for providing us with icatibant and Drs Anita Löw and Alex A. Oldham (ZENECA) for providing us with lisinopril and ZD7155.

Received July 29, 1996; revision received October 28, 1996; accepted November 19, 1996.

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