© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Development of heart failure following isoproterenol administration in the rat: role of the renin–angiotensin system
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, D-93042 Regensburg, Germany
* Corresponding author. Tel. +49-941-944-7211; Fax +49-941-944-7213; E-mail: eckhard.kromer@klinik.uni-regensburg.de
Received 11 April 1997; accepted 6 August 1997
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Abstract |
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Objective: High dosages of catecholamines induce cardiomyocyte necrosis and interstitial fibrosis in rats. We investigated whether this initial damage is followed by the development of heart failure and assessed the particular role of the renin–angiotensin system using ramipril. Methods and Results: Following the administration of 0 mg or 150 mg isoproterenol/kg 6 groups of Wistar rats were followed for 2 or 16 weeks: Sham, isoproterenol, isoproterenol+ramipril. Isoproterenol induced significant increases of echocardiographically measured left ventricular end-diastolic posterior wall thickness and dimension, whereas ramipril treatment significantly attenuated these changes. Left ventricular end-diastolic pressure was markedly increased in isoproterenol-treated rats and normalized following ramipril. Isoproterenol rats were further characterized by hormonal activations including transient elevations of plasma renin activity, aldosterone and cardiac angiotensin converting enzyme activity. Histomorphological characterization of isoproterenol-treated hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Ramipril treatment only slightly reduced the amount of necrosis as well as the expression of extracellular matrix proteins. Conclusions: In rats, a toxic dosage of isoproterenol caused characteristic myocardial damage that subsequently resulted in mild heart failure. Ramipril administration following isoproterenol was highly effective to attenuate hemodynamic and hormonal alterations as well as the development of left ventricular hypertrophy, but had only little influence on the expression of extracellular matrix proteins. Since angiotensin converting enzyme inhibition had no impact on the initial myocardial injury, the development of heart failure in this model seems to require functional integrity of the renin–angiotensin system.
KEYWORDS ACE=angiotensin converting enzyme; cANP=c-terminal atrial natriuretic peptide (99-126); CTRL group=animals treated with vehicle; ISO group=animals treated with a single dose of isoproterenol; LV=left ventricle; RAM group=animals treated with isoproterenol and with ramipril
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The ability of catecholamines, when administered in supraphysiologic dosages, to induce morphological alterations of the heart resembling severe myocarditis or left ventricular (LV) hypertrophy was already noted early in this century [1–4]. In 1959, Rona and Chappel showed that subcutaneous injections of the synthetic beta-adrenoceptor agonist isoproterenol produced infarct-like lesions of the myocardium in the rat similar to those described in association with pheochromocytomas [5]. Isoproterenol induced myocardial alterations were classified according to extent of myocardial necrosis [6]. Further studies demonstrated that application of isoproterenol very rapidly impaired LV function in a dose-dependent manner [7, 8]. The exact mechanism of isoproterenol-induced myocardial damage has not been clarified, but a mismatch of oxygen supply versus demand following coronary hypotension and myocardial hyperactivity may offer the best explanation for the complex morphological alterations observed in the presence of a patent coronary vasculature [9]. In agreement with this hypothesis, it has been shown that pretreatment with calcium channel blockers blunted the depression of cardiac function [10, 11]. More recently, the interest in isoproterenol induced cardiac alterations was reinforced by the study of Teerlink [12]and coworkers, who demonstrated that administration of isoproterenol induced diffuse myocardial necrosis and finally resulted in progressive LV-enlargement.
Taken together, morphological alterations following isoproterenol application have been substantially characterized. However, it has not been clarified whether heart failure, a complex syndrome with typical hemodynamic and neurohormonal findings, will develop after that initial insult to the myocardium by isoproterenol. In particular, no study has yet addressed the role of compensatory neurohormonal activation in catecholamine-induced cardiomyopathy. Therefore, we studied hemodynamic, echocardiographic and hormonal parameters in addition to histopathological examinations of the myocardium. To further elucidate the dynamic interplay between cardiomyocytes and their surrounding extracellular matrix in this experimental setting, we quantitatively measured fibronectin and laminin expression. These large glycoproteins have been shown to modulate cell motility, growth and differentiation under physiological and pathophysiological conditions besides their known roles for structural integrity [13]. Finally, we studied the potential contribution of the renin–angiotensin system during progression from left ventricular dysfunction to overt heart failure using an angiotensin converting enzyme inhibitor.
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2 Methods |
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2.1 Animals
Normotensive, female Sprague-Dawley rats (body weight: 180–200 g; age: 6 weeks) were obtained from Charles River Wiga. Rats were maintained on standard rat chow (H1003, Alma KG) with water ad libitum. The animals were individually housed in a 12 hour dark/light cycle controlled room. All protocols had been approved by the local standing committee and authority on animal research. The investigation confirmed with the Guide for the Care and Use of Laboratory Animals by the US National Institute of Health (NIH publication No. 85-23, revised 1985).
2.2 Dosage establishment
In order to determine the most efficacious dosage inducing significant myocardial damage along with an acceptable survival rate, 6 different dosages of isoproterenol were tested: 50, 100, 150, 200, 250 and 300 mg/kg body weight (n = 10 for each group). As will be described in detail, 150 mg/kg was found to be the optimal dosage to achieve these goals. dl-Isoproterenol-hydrochloride solutions (Sigma) were prepared under sterile conditions with distilled water immediately before injection.
2.3 Study groups
Animals were randomly assigned to receive one subcutaneous injection of 0 or 150 mg isoproterenol/kg. Isoproterenol rats (CTRL) were further randomly assigned to receive either ramipril (10 mg/kg/day, RAM) or placebo (ISO). Ramipril was started directly after isoproterenol injection and was applied with the drinking water. Its concentration was adjusted daily according to the actual body weight [14]. We knew from initial studies that water intake was slightly reduced the first 3 to 6 hours following isoproterenol administration but normalized during the first day. To assure intake of the full calculated ramipril dose, drinking bottles were refilled twice a day with a small amount of water containing ramipril as a first portion and water ad libitum as the second one. All rats were housed individually and followed for 2 weeks or 16 weeks. Thereafter, they were anesthetized (thiopental sodium, 100 mg/kg intraperitioneally) to perform echocardiography and hemodynamic measurements and were finally killed for biochemical and morphological assessment.
2.4 Echocardiography
LV-dimensions were assessed in vivo by transthoracic echocardiographic examinations using a 7.5 MHz electronic probe (Hewlett Packard Sonos 2500). Left longitudinal imaging was performed at approximately 45° through the left parasternal rib space with a maximum imaging depth of 40 mm. M-mode echocardiography was recorded at the level of the mitral valve at a paper speed of 100 mm/s. LV end-diastolic dimension and LV end-diastolic posterior wall thickness (PWTd) were measured by the leading-edge method from at least three consecutive cardiac cycles on the M-mode tracing as proposed by the American Society for Echocardiography [15].
2.5 Hemodynamics
Central hemodynamic parameters were measured via the right carotid artery (aortic pressure, LV pressure) and right jugular vein (right atrial pressure) using a 2–French catheter pressure transducer (Millar Instruments). Blood flow velocity was measured using a miniaturized 20 MHz directional pulsed Doppler system. Probes consisted of a silastic cuff encased a piezoelectric crystal with insulated copper wire leads (Bioengineering Department, University of Iowa). Following abdominal exposure, flow probes were placed on the right renal artery (0.8–0.9 mm i.d.) and infrarenally on the abdominal aorta (1.2 mm i.d.). Zero flow was determined electronically, obtained values were expressed as KHz Doppler shifts [16].
2.6 Tissue preparation
Hearts were excised, rinsed with saline, and blotted dry. The right ventricle was isolated by dissection along its septal insertion. Specimens for determination of LV–ACE activity (interventricular septum) were snap frozen in liquid nitrogen within 3 minutes and stored at –80°C until analyzed.
2.7 Biochemical studies
10 rats from each group were randomly selected and killed by decapitation. Trunk blood was collected for determination of plasma renin, aldosterone and atrial natriuretic peptide (cANP, 99–126). Plasma renin activity, aldosterone and cANP concentrations were determined by radioimmunoassays using commercially available kits. ACE activity was measured by a modified fluorimetric method. The methods used have been previously described in detail [14]. In animals treated with ramipril we did not measure ACE activity for 2 reasons. First, ACE may be induced during treatment with an ACE inhibitor [17]. Second, a very rapid dissociation of the ACE–ACE–inhibitor–complex may occur in vitro. Therefore, serum as well as cardiac ACE activities might even be found elevated despite significant ACE inhibition in vivo.
2.8 Morphological examination
The left ventricle was serially cut into 1–1,5 mm thick sections from apex to base. Each 5th section was fixed with methanol and ethanol (1:1), processed through ascending grades of alcohol, embedded in paraffin wax, sectioned at 5 µm and subsequently stained with hematoxylin and eosin. Grading was performed according to Rona [6]: Grade 0: no lesions; grade 1: focal lesions of the subendocardial portion of the apex and/or the papillary muscle, composed of fibroblastic swelling or proliferation and accumulation of histiocytes; grade 2: focal lesions extending over wider areas of the left ventricle, with right ventricular involvement; grade 3: confluent lesions of the apex and papillary muscles, with focal lesions involving other areas of the ventricles; grade 4: confluent lesions throughout the heart, including infarct-like massive necrosis, with occasionally aneurysm or mural thrombi. The score for the whole heart was calculated as average of the obtained section scores. Grading was performed by two independent observers who were blinded with respect to administration of isoproterenol and ramipril.
2.9 Morphometry, immunohistochemical staining, and automatic image analysis
Morphometry including automatic image analysis (AIA) was applied to quantitatively assess structural changes of the LV posterior wall using a computer assisted image analysis system device (Olympus Optical, Hamburg, Germany). Frozen specimen were sectioned at 5 µm and fixed with acetone (–20°C) for 10 min. Sections were selected to visualize antigen–antibody complexes with the indirect peroxidase technique. Incubation with the first antibody (Laminin, Sigma; Fibronectin, Boehringer Mannheim) was followed by incubation with the second antibody. After repeated washing with PBS and for indirect immunoperoxidase staining exposure to diaminobenzidine (Sigma), the specimens were dehydrated, embedded with entellan (Merck) [18]. All sections were visualized by light microscopy using an oil immersion objective with a calibrated magnification of x400. Visual fields had 757x506 square-pixels with a resolution of 0.2053 µm/pixel (area=0.0161 mm2). Fields were accepted for quantitative analysis if a) cross-sections of cardiomyocytes were present, b) if cardiomyocytes had a visible nucleus and c) if their cellular membranes were intact. The thickness of laminin layers, that surrounded cardiomyocytes, was similarly determined by marking its borders. For each parameter, 50 visual fields were analyzed to calculate averages (variance<2%). These measurements were performed by 2 independent investigators who were blinded for modality of treatment. Variability was assessed by performing repeated analyses and was calculated as 1% (intraobserver) and 3% (interobserver). Areas positive for fibronectin were automatically marked by contour-finding using differences in staining (8 bit color depth). Volume fractions were calculated as the sum of all positive areas related to the area of the entire visual field. Twenty randomly selected visual fields were analyzed to calculate the average of respective volume fractions (variance <2%).
2.10 Statistical analysis
Statistical analysis was performed using SPSS 6.1 (SPSS) [19]. Results are expressed as mean±SEM. Comparisons between multiple groups were assessed by one-way analysis of variance including a modified least-significant difference (Bonferroni) multiple range test to detect significant differences between 2 distinct groups, which were further analyzed using the Mann–Whitney–U–test. The strength of relation between two variables was assessed by calculation of the product-moment correlation coefficient (r) using CORRELATIONS. Statistical significance was accepted at the level of P<0.05 [20].
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3 Results |
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3.1 Dosage establishment
Isoproterenol dosages of 50, 100, 150, 200, 250 and 300 mg/kg body weight (n = 10 each group) resulted in death rates of 0%, 10%, 20%, 50%, 80% and 90%, respectively, within the first 24 hours. Histomorphological examination of the hearts of non-surviving animals revealed necrotic areas throughout both left and right ventricles. Surviving rats were killed after 2 weeks. Using ISO dosages of
200 mg/kg BW rats revealed hemorrhagic pulmonary edema and additional liver and kidney necrosis and body weight was decreased. Few rats revealed a small tissue injury at the site of injection — without dose dependency. Rats that received an isoproterenol dosage of 150 mg/kg showed marked cardiac enlargement and histomorphological examination revealed confluent lesions throughout both ventricles along with areas of necrosis and scarring. However, this considerable damage to the myocardium was associated with a survival-rate of 80%. Therefore the dosage of 150 mg/kg was selected for our detailed studies.
3.2 Short-term follow-up
3.2.1 Somatic and organ weights (Table 1A)
146 rats were followed for 2 weeks (42 CTRL-rats, 70 ISO-rats and 34 RAM-rats). After 2 weeks, body weight was reduced by about 10% in ISO- and RAM-rats as compared to CTRL-rats (P<0.05). LV-weight/body weight ratio increased about 50% in the ISO as compared to the CTRL group (P<0.0001). However, ACE inhibition with ramipril attenuated this increase by about 60% (P<0.001). Right ventricular weight/body weight ratios did not significantly differ between the groups. The kidney weight/body weight ratio, an index of growth, was unaltered.
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3.2.2 Echocardiography (Table 1A)
ISO-rats showed significant increases of LV–end–diastolic dimensions and of end-diastolic posterior wall thickness. Both changes were attenuated by treatment with ramipril.
3.2.3 Hemodynamic findings (Table 2A)
LV end-diastolic as well as mean right atrial pressures were significantly increased in the ISO group but remained within normal ranges in the RAM group. Heart rate did not significantly differ between the groups. Aortic blood pressure was significantly reduced in ISO rats and further lowered by ACE inhibition. Mean aortic blood flow velocity was significantly reduced in the ISO group. In contrast, the RAM group revealed normal values. Mean renal blood flow velocity did not significantly differ between the groups.
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3.2.4 Biochemical findings (Table 3A)
Plasma cANP levels were doubled in ISO compared to CTRL rats (P<0.01). but remained within the normal range after administration of ramipril. Plasma renin activity was found nearly doubled in the ISO group versus CTRL rats (P<0.01) and was further threefold increased in the RAM group. Plasma aldosterone levels were significantly elevated in the ISO group. Ramipril significantly blunted this change (P<0.01 vs. ISO), however aldosterone levels remained moderately increased in comparison to CTRL rats (P<0.1). LV–ACE activity was significantly increased in ISO rats. In rats that were not treated with the ACE inhibitor there was a close positive correlation between LV / body weight ratio and LV–ACE activity (r = 0.75; P<0.0001; Fig. 1). No changes in serum ACE activity were found.
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CTRL rats and 
ISO rats.3.2.5 Histomorphological and immunohistochemical findings (Table 4A)
Isoproterenol-induced cardiac alterations included myocyte degeneration and necrosis, subsequent interstitial and perivascular fibrosis and myocardial hypertrophy especially of the left ventricle, as shown in Fig. 2 A-B. CTRL rats had a LV pathological score of 0.0 compared to ISO rats with 2.55±0.1 (11% grade 1, 23% grade 2, 66% grade 3). Myocardial damage was slightly but significantly blunted in ramipril treated rats that displayed an LV pathological score of 2.25±0.4 (75% grade 2, 25% grade 3; P<0.016 vs. isoproterenol). Laminin staining was positive throughout the whole LV but did not occur in scars (Table 4A). Irrespective of ACE inhibition it was significantly increased by about 80% in ISO as compared to CTRL rats. Fibronectin deposition was significantly enhanced in the extracellular matrix throughout the whole LV of ISO-treated rats as compared to CTRL rats. Ramipril administration only slightly but not significantly attenuated these alterations (see Fig. 3).
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3.2.6 Long-term follow-up (Table 1B, Table 2B, Table 3B, and Table 4B)
74 additional rats were followed for 4 months (22 CTRL-rats, 27 ISO-rats and 25 RAM-rats;). No deaths occurred later than 24 h after isoproterenol administration. These data are presented in Table 1B, Table 2B, Table 3B, and Table 4B. Body weight, organ weight/body weight ratios and echocardiographic data displayed in general similar findings as compared to short-term follow-up, with the exception that the increase in relative LV weight in ISO treated animals was less (2 weeks vs. 4 months: P<0.001) and nearly normalized after ramipril application. Hemodynamics showed unaltered differences between the 3 groups as compared to short-term follow-up. Mean right atrial pressure and LVEDP were increased in ISO rats as compared to controls. Biochemical findings showed a further increase of cANP in the ISO group after 4 months, and slightly but significantly elevated levels in RAM treated animals. In contrast, plasma renin activity normalized in ISO rats. As compared to short-term measurements plasma aldosterone levels were found less increased in the ISO group and showed normal values in RAM rats. Cardiac ACE was no longer elevated 4 months after isoproterenol-application. The LV-pathological scores did not significantly change. Fibronectin remained significantly elevated after isoproterenol, irrespective of ACE inhibition. Finally, the overexpression of laminin remained unchanged in ISO rats, but was blunted by ramipril (2 weeks vs. 4 months: P<0.0003).
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4 Discussion |
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The principal finding of the present study is that a single injection of isoproterenol induces a syndrome in the rat that displays numerous typical characteristics of mild heart failure. In particular, 2 weeks and 4 months after the toxic dose of isoproterenol echocardiographic studies revealed the development of LV dilatation and hypertrophy. In addition, LV filling pressures and transiently right atrial pressures were found to be markedly elevated whereas aortic blood pressures and flow velocities were reduced. Renal blood flow was not significantly altered indicating preserved autoregulation as it is usually found in mild heart failure. Furthermore, hormonal systems were found to be activated in animals that had received isoproterenol suggesting systemic alterations in response to the primary cardiac insult. The model is characterized by an extraordinary technical simplicity, an excellent reproducibility as well as an acceptable low mortality. Therefore, isoproterenol induced heart failure compares favorably, at least in these regards, with experimental myocardial infarction, the currently most widely used experimental model for this frequent disease [21–26].
To further assess the mechanisms involved in the development of heart failure following isoproterenol injection, we performed distinct morphological and immunohistological studies. Like previous investigators [5, 6, 27, 28]we found that administration of high dosages of isoproterenol primarily resulted in an extensive amount of cardiomyocyte necrosis. Thus, like after experimental myocardial infarction, significant cardiomyocyte loss predominantly of the left ventricle is the initial insult that triggers the development of heart failure. Weber et al. reported that high dosages of catecholamines are followed by myocardial fibrosis and significant alterations in the meshwork of thick and thin collagen fibers [29–31].
The present study, using automatic image analysis, extends these findings showing that expression of laminin, a major component of the basement membranes of endothelial cells and cardiomyocytes, was markedly induced following isoproterenol application. Likewise, isoproterenol injections resulted in the induction of fibronectin, an extracellular matrix protein that colocalizes with fibrillar collagens I and III. Fibronectin shares with laminin important interactions with the entactin/nidogen system, providing structural support and potentially complex growth regulatory functions [32, 33]. Thus, overexpression of laminin, fibronectin and collagens may have a significant impact on both systolic and diastolic function of the heart. Particularly, in case of adaptive fibrosis in pressure-overload experimental cardiac hypertrophy, diastolic LV-function may be further impaired by overexpression of extracellular matrix proteins. This contrasts reparative fibrosis — as in the present experimental setting — where extracellular matrix proteins might predominantly play an important role in preserving structural organ integrity after the initial insult and thereby LV function.
Following the initial isoproterenol related myocardial damage, the further development of heart failure may be modulated by secondary systemic alterations. In the present study, we were interested in the role of neurohormonal systems. In fact, 2 weeks after isoproterenol administration, significant elevations of plasma cANP, plasma renin activity, plasma aldosterone, and cardiac ACE activity were found. After long-term follow-up, we measured elevated plasma cANP and plasma aldosterone in ISO rats. Cardiac ACE activity and plasma renin activity, however, returned to normal values. In experimental myocardial infarction [34, 35], we and others had previously measured increased plasma levels of ANP and found a close correlation of infarct size and right atrial and LV-end-diastolic pressures, emphasizing the value of this parameter as a reliable index of hemodynamic impairment in experimental heart failure. Plasma renin levels may be normal in the chronic mild to moderate state of heart failure under both experimental and clinical conditions, but usually increase during progression to severe heart failure [35–38]. Our data showed a transient activation of the circulating renin–angiotensin system as assessed by plasma renin activity in rats 2 weeks after administration of isoproterenol and a normalization after 4 months. This may be explained by an adaptation of the circulation to the depressed cardiac function and/or by the further increase of cANP that might have suppressed renin secretion, as has already been shown in mild compensated heart failure in dogs [36]. Additionally, we found a close positive correlation of LV–ACE activity and LV / body weight ratio after short-term follow-up, suggesting an proportional induction also of the intracardiac renin–angiotensin system early in this experimental setting. Taken together, this model involves a considerable activation of both the circulating and cardiac renin–angiotensin system during the initial weeks after the isoproterenol induced myocardial insult.
The impact of the renin–angiotensin system on functional alterations secondary to isoproterenol induced myocardial damage was further emphasized by the effects of ACE inhibition. Ramipril, starting immediately after isoproterenol-application, blunted hemodynamic alterations and attenuated LV-dilatation and hypertrophy as well as neurohormonal activation. The present data are in excellent agreement with previous reports that demonstrated reduction of LV hypertrophy by ACE inhibition in rats with ascending thoracic or abdominal aortic banding [14, 39–43]. Likewise, Pfeffer at al. reported beneficial effects of captopril on LV-remodeling, hemodynamics and even survival in rats with moderate-sized experimental myocardial infarctions [23, 24].
As assessed by LV pathological scores, ACE inhibition following isoproterenol application only slightly reduced myocardial damage. However, because we did not address the potential role of ACE inhibition on catecholamine cardiotoxicity but focussed on changes following thereafter, ACE inhibition was started after isoproterenol application. The overexpression of laminin and fibronectin was unaffected by ramipril during short-term follow-up. However, after 4 months of ACE inhibition, the overexpression of laminin was significantly blunted, whereas that of fibronectin persisted. Interestingly, changes of laminin expression occurred in parallel to changes of plasma aldosterone that was not totally normalized by ramipril after 2 weeks but after 4 months. In this context, it may be of interest that aldosterone has also been proposed to stimulate reparative fibrosis, a hypothesis that may also apply to the present findings. Nevertheless, the effects of long-term ACE inhibition on the extracellular matrix proteins were rather mild. This may be of no surprise, since ACE inhibition had no important impact on the initial isoproterenol-induced myocardial damage. In contrast, ACE inhibition was related to substantial improvements of LV hypertrophy and dilatation. The observed hemodynamic alterations seem to be mediated to a considerable proportion by activation of the renin–angiotensin system [17, 43, 44], because ACE inhibition normalized these pathogenetic factors and thereby ameliorated cardiomyocyte remodeling and to a small extent extracellular matrix remodeling. However, the role of other neurohormonal systems, e.g. the sympathetic nervous system, was not addressed in detail in our study and remains to be clarified.
In conclusion, a single injection of isoproterenol induced with minimal variability short- and long-term pathophysiolgical and morphological findings that resembled the syndrome of mild heart failure in the rat. Activation of the renin–angiotensin system seemed to play a crucial role for the progression of hemodynamic alterations and cardiac remodeling. Furthermore, this simple model seems to be very useful to examine therapeutic interventions in chronic heart failure.
This study was supported by a grant from the Sandoz Stifung für therapeutische Forschung.
Time for primary review 29 days.
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