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European Journal of Heart Failure 2002 4(2):131-137; doi:10.1016/S1388-9842(02)00005-3
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© 2002 European Society of Cardiology

Angiotensin II subtype 1 (AT1) receptors contribute to ischemic contracture and regulate chemomechanical energy transduction in isolated transgenic rat ({alpha}MHC-hAT1)594-17 hearts

Hong Hana, Sigrid Hoffmannb, Kai Hua and Georg Ertla,*

a Department of Medicine, Medizinische Universitätsklinik, Universität Würzburg Josef-Schneider Strasse 2, Würzburg 97080, Germany
b Zentrum für Medizinische Forschung Universitätsklinikum Mannheim der Universität Heidelberg, Mannheim, Germany

* Corresponding author. Tel.: +49-931-201-5301; fax: +49-931-201-3453. E-mail address: g.ertl{at}medizin.uni-wuerzburg.de


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: The role of AT1 receptors in myocardial ischemia/reperfusion injury is unclear. We, therefore, investigated the effects of the AT1 receptor antagonist irbesartan (Irb) in isolated hearts of selective myocardial AT1 overexpressing transgenic [transgenic({alpha}MHC-hAT1)594-17] and Sprague–Dawley rats (SD) subjected to ischemia/reperfusion injury.

Methods and results: Hearts of 4-week-old male SD or transgenic rats were isolated and perfused with Krebs–Henseleit buffer with or without 10 µM Irb in Langendorff mode. After 15 min of stabilization, pressure–volume curves were obtained and the hearts subjected to 20 min ischemia followed by 30 min reperfusion. A second set of pressure–volume curves was obtained thereafter. Left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), total coronary flow (CF) and oxygen consumption (MVO2) were recorded continuously. Myocardial efficiency was derived from the slope of relations of MVO2 to pressure/volume area. After 20 min ischemia, LVEDP was significantly higher in transgenic than in SD (35.7±1.8 vs. 29.2±1.0 mmHg, P<0.05) or Irb treated transgenic hearts (24.3±1.6 mmHg, P<0.05). Myocardial efficiency was increased by Irb before ischemia. Ischemia increased efficiency in SD but not in transgenic rats, Irb increased efficiency in transgenic hearts post-ischemia.

Conclusion: Transgenic hearts developed ischemic contracture more rapidly than SD hearts as indicated by higher LVEDP during ischemia. This response was antagonized by Irb, indicating a role of AT1 receptors in ischemic contracture, AT1-receptors also appear to be involved in the control of myocardial efficiency.

Key Words: Angiotensin • Receptor overexpression • Ischemia • Reperfusion

Received February 6, 2001; Revised June 27, 2001; Accepted December 14, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Angiotensin II (AII) plays a major role in cardiovascular homeostasis, including the regulation of blood pressure, salt balance, and tissue remodeling. All components of the renin–angiotensin system have been detected in the heart [14,34], indicating that the heart is not only a target but also a site of endocrine or paracrine AII formation. AII binds to at least two high-affinity receptors designated AT1 and AT2 and most of the known AII effects are mediated via AT1 receptors [30]. The role of AT1 receptors in cardiac dysfunction is not fully understood. Both upregulation of angiotensinogen gene, angiotensin converting enzyme and AT1 receptors in hypertrophied myocardium induced by infarction [11,19] and downregulation of AT1 receptors in failing human heart [9] have been reported. In addition, the importance of AT1 receptors for cardiac performance are not well understood. Direct myocardial effects are masked by the strong effects of AII on systemic and coronary circulation. A more subtle analysis of the role of AT1 receptors for chemo-mechanical energy transduction has not been performed.

Angiotensin converting enzyme inhibitors and AT1 receptor antagonists may limit infarct size and improve post-ischemic contractile function in certain models [4,13]. However, the reports were controversial [3,5,8,17]. Yang and associates found increased AT1 receptor expression immediately after ischemia/reperfusion and suggested that it would be related to cardiac dysfunction [33]. The AT1 receptor antagonist losartan significantly attenuated ischemia/reperfusion induced cardiac dysfunction [26,33]. In the present study, we, therefore, investigated the role of AT1 receptors in myocardial ischemia/reperfusion injury on systolic and diastolic performance of isolated hearts. Since post-ischemic myocardial performance may depend on efficiency of chemo-mechanical energy transition, left ventricular pressure volume area was obtained and related to myocardial oxygen consumption. The creatine kinase (CK) and lactate dehydrogenase (LDH) system were analyzed to see a potential dependence of susceptibility or resistance to ischemia/reperfusion injury on the AT1-receptor. Transgenic rats in which the cDNA for the human AT1 receptor was placed under the control of the 1032 bp {alpha}MHC-promoter [10] were compared with Sprague–Dawley (SD) rats in presence and absence of the AT1 receptor antagonist irbesartan (Irb). In separate animals, in vivo hemodynamic measurements were performed.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Animals
Male 4-week-old SD and AT1 receptor overexpressing transgenic rats [transgenic({alpha}MHC-hAT1)594-17] (TGR) weighing 110–148 g were used in this study. Previous experiments have shown that myocardial AT1 receptor density (Bmax) in these transgenic rats is enhanced 35-fold [10,22]. The rats were kept on a 12-h light–dark cycle at constant temperature with 55% humidity. They were fed normal rat chow and allowed free access to tap water.

2.2. In vivo hemodynamic measurements
Rats were anesthetized with ether. Polyethylene cannulas were inserted into the trachea for artificial ventilation, and into the right carotid artery for pressure measurements. Pressures were measured through a short segment of a fluid-filled PE50 tubing, connected to a microtip manometer (Millar®) via a three-way stopcock, with zero adjusted to mid-chest level. The carotid cannula was briefly advanced into the left ventricle, then withdrawn to the aortic arch while pressures were recorded. Left ventricular systolic (LVSP) and end-diastolic pressures (LVEDP), the maximum rate of rise of left ventricular systolic pressure (dP/dtmax), mean arterial pressure (MAP) and heart rate (HR) were measured under light ether anesthesia and spontaneous respiration.

2.3. Isolated rat heart preparation
Rats were anesthetized by injecting pentobarbital sodium (35 mg/kg) intraperitoneally. The heart was rapidly excised and immersed in ice-cold buffer. The aorta was dissected free, and was mounted onto a cannula attached to a perfusion apparatus as previously described [7]. Retrograde perfusion of the heart was started in the Langendorff mode at constant coronary perfusion pressure (95 mmHg). Krebs–Henseleit buffer was oxygenated with 95% O2 and 5% CO2 and used for perfusion. Coronary flow was measured with an electromagnetic flow probe (Gould Statham Instruments, Hato Rey, Puerto Rico, USA). Pressure was measured through a water-filled latex balloon inserted into the left ventricle and a cannula connected to a Statham P23Db pressure transducer (Gould Instruments, Oxnard, CA, USA). All data were continuously recorded on an 8 channel recorder (Graphtec Corp., Tokyo, Japan). Oxygen consumption was also continuously monitored by measuring oxygen tension of the perfusate leaving the pulmonary outflow tract using a Mikroprocessor OXI 537 oxygen meter (Wissenschaftliche Technische Werkstätten, Weilheim, Germany). ‘Arterial’ oxygen tension was measured in the perfusate, obtained from the aortic cannula directly above the heart. All procedures complied with the guiding principles of the American Physiological Society and were approved by the institutional animal research committee.

2.4. Experimental protocol and groups
In the pilot study (n=5), AII (0.01, 0.1 and 1 µM, bolus injection) induced dose-dependent reductions of coronary flow by –11.2±2.2%, –15.8±2.0% and –25.3±1.9%, respectively. Buffering with Irb (10 µM) effectively antagonized coronary constriction by AII (0, –0.8±1.3% and –1.2±2.2%, respectively for the respective doses of AII). This concentration of Irb was, therefore, used in the main study. For each group, six to seven rats were used (Table 2). All hearts were given approximately 15 min for stabilization with end-diastolic pressure set to approximately 5 mmHg. After stabilization, the first (before ischemia) pressure-volume curves (PVCs) were obtained. Water was injected stepwise (0.02 ml) into the balloon until maximal LVDP was achieved. All parameters were recorded after each step when a new steady state was reached. The balloon was then adjusted to yield LVEDP of approximately 5 mmHg and the heart was allowed to equilibrate for 5 min followed by 20 min of global ischemia and thereafter 30 min of reperfusion. After reperfusion, a second PVC (after ischemia) was obtained. Hearts of group 1 (SD) and group 2 [transgenic({alpha}MHC-hAT1)594-17] were perfused with normal buffer, and hearts of group 3 (SD+Irb) and group 4 [transgenic({alpha}MHC-hAT1)594-17+Irb] were perfused with buffer containing 10 µM Irb. With a colored latex balloon in the left ventricle, hearts were rapidly freeze-clamped using Wollenberger tongues as previously described [12]. With the help of the colored latex balloon the left ventricle was identified in the freeze-clamped sample.

2.5. Enzyme measurements
In 0.1 M phosphate buffer containing 1 mM EGTA and 1 mM β-mercaptoethanol 5–10 mg of left ventricular tissue were homogenized. Aliquots for measurement of protein by the Lowry method were taken before 0.1% Triton X-100 were added. All samples were kept on ice. Total creatine kinase, lactate dehydrogenase and citrate synthase activities were measured using an Ultraspec III spectrophotometer (Pharmacia Biosystems, Freiburg, Germany). The isoenzymes of LDH were determined with the TITAN GEL LD Isoenzyme System (Helena Diagnostika GmbH, Hartheim, Germany), using agarose gel electrophoresis. The CK isoenzyme distribution was measured with the ‘Rapid Electrophoresis System’ (REP, Helena Diagnostika GmbH) as separation unit and the REP CK Isoforms Kit (Helena Diagnostika GmbH) for agarose gel and incubation solution. The agarose gel contained a Tris/barbital buffer with sodium azide as preservative. Quantification of the separated isoenzyme bands was done automatically by the ‘Electrophoresis Data Center’ (EDC, Helena Diagnostika GmbH) [12,27].

2.6. Calculations and statistical analysis
2.6.1. Left ventricular pressure-volume relation
For PVCs, at each filling level left ventricular systolic (LVSP), developed (LVDP) and end-diastolic pressure (LVEDP) was determined and left ventricular volume was evaluated as the sum of the volume of water in the balloon and the volume of the unstretched balloon itself. Regressions between left ventricular systolic pressure and volume of each heart were fitted by a parabolic equation:


Formula 1

(1)
where LVSP is left ventricular systolic pressure, V is left ventricular volume and a, b and c are constants [6,29].

The unstressed left ventricular volume (V0) was represented by the volume intercept at zero pressure.

2.6.2. Pressure–volume area (PVA)
In our model of isovolumic contraction, PVA was calculated as the sum of three areas according to the following formulae, respectively [6,29]:

Area1=(LVSP–LVEDP)x(V–V0)/2
Area2=–a/6x(V–V0)3
Area3=LVEDPx(V–V0)/4
where LVSP is left ventricular systolic pressure; LVEDP is left ventricular end-diastolic pressure; V is left ventricular volume; ‘a’: as in Eq. (1).

2.6.3. Myocardial oxygen consumption (MVO2)
Oxygen consumption per beat was calculated by the formula: MVO2 (10–4 ml O2/beat)=(perfusate PO2 difference across the heart)x(solubility of O2/mmHg)x(coronary flow)/heart rate.

The right ventricle was kept mechanically unloaded throughout the whole protocol and right ventricular MVO2 was considered to be constant during the experiment.

2.6.4. MVO2–PVA relation
The relation of oxygen consumption and pressure-volume area (PVA) for each heart at each filling level was determined by linear regression analysis and the slope and MVO2 intercept were obtained. The slope of this regression served as an estimation of myocardial contractile efficiency to convert ATP to mechanical energy during contraction [6,29].

All data are presented as mean±S.E.M. Data among the various groups of hearts were compared by two-way ANOVA, and significant differences were obtained by Bonferroni test. Variables before and after ischemia were tested by paired Student's t-test. P<0.05 was considered statistically significant. Curve fitting for the left ventricular pressure and volume relation was made by Sigma Plot® (Jandel GmbH, Erkrach, Germany).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Table 1 shows the results of in vivo hemodynamic measurements. There was no significant difference between SD and transgenic rats except mean arterial pressure was somewhat higher in transgenic rats.


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  		Table 1 In vivo hemodynamics

 
Table 2 shows the results for left ventricular performance, CF and MVO2 before and after ischemia in isolated rat hearts. No differences were found among the groups at baseline and after ischemia for any hemodynamic variable. After 30 min reperfusion, LVDP and dP/dtmax significantly decreased compared to before ischemia while LVEDP increased in all groups. Coronary flow tended to be lower after reperfusion in all groups while MVO2 remained unchanged. All hearts stopped beating due to ventricular fibrillation. Time course of LVEDP during ischemia is shown in Fig. 1. LVEDP increased gradually after approximately 10 min of ischemia and it was significantly higher at 20 min of ischemia in transgenic hearts compared with SD hearts. This increase was significantly prevented by Irb in transgenic rats. LVEDP was even significantly lower at 15 min and 20 min of ischemia in hearts perfused with Irb both in SD and TGR rat hearts compared to those without Irb respectively. After 30 min of reperfusion, LVEDP was similar in all groups (Table 2).


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  		Table 2 In vitro hemodynamics before and after 20 min of ischemia followed by 30 min of reperfusion in SD and TGR with or without Irb

 


Figure 1
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  		Fig. 1 Time course of left ventricular end-diastolic pressure (LVEDP) of SD rats ({circ}), SD rats treated with Irb (•), TGR rats ({triangleup}) and TGR rats treated with Irb ({blacktriangleup}) before and during ischemia. Data are shown as mean±S.E.M. *P<0.05 vs. SD; {dagger}P<0.05 vs. baseline in each group; {ddagger}P<0.05 with Irb. vs. without Irb in the same rat type group.

 
Stiffness, derived from the relations of LVEDP to volume index (LV volume/body weight), was higher in transgenic hearts before and after ischemia and was increased post-ischemia in all groups. Irb had no significant effect on the changes in ‘stiffness’ (Table 3).


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  		Table 3 The relations of LVEDP to left ventricular volume index

 
Regression calculations for MVO2–PVA relations are shown in Table 4. The intercepts of the MVO2–PVA relation were identical in all groups before and after ischemia. The slopes of the MVO2–PVA relations were similar in SD and transgenic hearts before ischemia. Irb lowered the slopes of the MVO2–PVA relation in SD and transgenic hearts before ischemia. The slope was reduced after ischemia in SD hearts but not in transgenic hearts. Irb lowered the slope of the MVO2–PVA relation after ischemia in transgenic but not in SD.


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  		Table 4 PVA-MVO2 relation before and after 20 min of ischemia followed by 30 min of reperfusion in SD and TGR with or without Irb

 
The creatine kinase system, lactate dehydrogenase and citrate synthase have been measured and no differences were found between transgenic and SD rats in these variables with or without Irb (data not shown).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
There are two major new findings of the present study. (1) Ischemic contracture occurred earlier in AT1 receptor overexpressing transgenic than in SD hearts indicated by a faster increase of LVEDP during ischemia. The faster proceeding ischemic contracture in transgenic hearts was prevented by the specific AT1 receptor antagonist Irb. (2) The slope of MVO2/PVA relation was lowered by the AT1 receptor antagonist suggesting increased contractile efficiency. Contractile efficiency improved post-ischemia in SD and in transgenic hearts treated with the AT1 receptor antagonist but not in untreated transgenic hearts.

In hearts impaired by ischemia, the renin–angiotensin and killikrein–kinin systems are activated, resulting in increased release of AII and kinins, mostly bradykinin [15]. AII increases Ca2+ influx through the L-type Ca2+ channel and induces Ca2+ release from intracellular stores through AT1 [30]. AII stimulates the Na+–H+ exchange in rabbit ventricular myocytes by an AT1 receptor coupled mechanism [18]. In addition, AII induces the release of catecholamines, which also may result in an increase of [Ca2+]i [30]. Therefore, accelerated ischemic damage in AT1 receptors overexpressing hearts may be related to higher sensitivity to locally released AII and consequently noradrenaline and Ca2+. Interference with the cardiovascular effects of AII may be of benefit to ischemic myocardium by suppressing the release of catecholamines and attenuation of myocardium Ca2+ overload. ACE inhibitors have beneficial effects on post-ischemic contractile function [3,17]. Similarly, previous studies have shown improved recovery after ischemia by AT1 receptor antagonists in isolated working rat hearts [31] and prevention of reperfusion arrhythmias by AT1a receptor knockout or an AT1-antagonist in mice [8]. Infarct size was reduced by losartan in spontaneously hypertensive rats, which overexpress AT1 receptors [13] but not in wild type mice [8]. In contrast, Ford et al. reported blocked recovery of mechanical function by the AT1 antagonist losartan but improved recovery by an AT2 antagonist [5]. Thus, the literature is inconclusive and further studies are required. The present study shows that the AT1 receptor antagonist Irb lowered LVEDP and prevented the more rapid increase which was found in transgenic hearts overexpressing AT1 receptors suggesting that blockade of AT1 receptors is protective during ischemia. An ACE inhibitor reduced myocardial Ca2+ content in reperfused myocardium to normal [28] and the AT1 antagonist could also prevent the increase in intracellular calcium. Another possible mechanism of beneficial effects of AT1 antagonists could be stimulation of AT2 receptors by locally released AII [32]. Previous studies have indicated a link between the stimulation of AT2 receptors and the synthesis and release of local kinin [20,25]. Studies in the spontaneously hypertensive rat have suggested a contribution of endogenous NO and prostaglandins but not kinins to the antihypertensive effect of losartan [1]. Campbell and associates found that the effects of losartan were bradykinin independent [2]. The exact mechanism of the effect of AT1 receptor antagonist remains unclear but our data suggest that it is indeed AT1-receptor related.

4.1. Pressure–volume relation
At similar pre-load, left ventricular performance was consistently depressed after ischemia as indicated by lower LVSP and dP/dtmax. Ventricles appeared to be stiffer in transgenic hearts compared with SD hearts and post-ischemia evidenced by higher slope values (Table 3) and the steeper diastolic pressure–volume curves. Several factors might be involved in the increase of stiffness in transgenic hearts. Firstly, the left ventricular cavity might be smaller or the wall of the left ventricle might be thicker in transgenic hearts compared with SD hearts as the result of the tropic effects of AII [24]. However, heart weight was similar between transgenic and SD hearts in a previous study. Morphologic studies are needed to support this hypothesis. Secondly, myocardial collagen content and type might change in transgenic hearts and contribute to increased stiffness in transgenic hearts. Thirdly, myocardial lusitropy could be changed in AT1 overexpressing transgenic hearts. However, since Irb did not affect the changes of slope among the groups studied, structural (hypertrophy, collagen) are more likely than functional changes. It was essential for these reasons that performance was assessed at identical preload considering end-diastolic volume and pressure. Neither overexpression of the AT1 receptor nor AT1 receptor inhibition had a significant effect on post-ischemic left ventricular performance or coronary flow.

4.2. MVO2–PVA relation
As previously shown by others [21], the intercept of MVO2–PVA relation remained unchanged in various groups post-ischemia, indicating unchanged non-mechanical energy cost [6,29]. However, the slopes of MVO2–PVA relation were reduced after ischemia in SD hearts suggesting increased economy of the myocardial contractile machinery in post-ischemic SD hearts [6,29]. In a previous study, Ohgoshi and coworkers demonstrated a decreased slope of the MVO2–PVA relation in stunned myocardium of dogs [21]. Thus, the efficiency of chemomechanical energy conversion is increased in hearts with left ventricular dysfunction post-ischemia. Mechanisms of the decreased slope of the MVO2–PVA relation and the increased contractile efficiency in post-ischemic myocardium remain unknown. However, the fact that depressed ventricular function persisted in post-ischemic myocardium in SD hearts and rabbit hearts [23] suggests that efficiency is not a limiting factor for contractility in post-ischemic myocardium. Another interesting finding in our study is that the slopes of the MVO2–PVA relation were reduced in SD hearts but not in transgenic hearts after ischemia suggesting a role of AT1 receptors in these changes. Furthermore, the slopes of the MVO2–PVA relation could be reduced by Irb perfusion (SD>transgenic). Since the AT1 receptor antagonist losartan was shown to improve recovery without affecting cellular ATP and PH [31], attenuating Ca2+ overload might contribute to increased efficiency by Irb. In a previous study, Liu and associates also demonstrated improved cardiac efficiency after ischemia by reducing the production of H+ or inhibiting Na+–H+ exchange [16]. Thus, improvement of left ventricular efficiency may also be related to the ability of the AT1 antagonist to attenuate Na+–H+ exchange [18]. Creatine kinase and lactate dehydrogenase systems remained unchanged in transgenic rats post-ischemia/reperfusion injury indicating that changes of these enzyme systems were not involved in the accelerated ischemic contracture of transgenic hearts.

In conclusion, the present study shows that myocardial AT1 receptors are involved in the development of ischemic contracture indicated by an accelerated increase of LVEDP in the hearts overexpressing myocardial AT1 receptors and by the fact that the AT1 receptor antagonist Irb blocked the acceleration of ischemic contracture. In addition, AT1 receptors appear to control myocardial efficiency since the AT1 receptor antagonist increased it and provided improvement in post-ischemic myocardium. In addition, the observations underline that subtle changes of phenotype not detected by crude measurements may be important in transgenic animals.


   Acknowledgements
 
We thank the Max-Delbrück Center Berlin-Buch for supplying the transgenic rat model. This study was supported by Deutsche Forschungsgemeinschaft Sonderforschungsbereich ‘Pathophysiologie der Herzinsuffizienz’ SFB 355/B8 and ‘Forschungsfond’ from Fakultät für Klinische Medizin Mannheim, Universität Heidelberg. Irbesartan was kindly provided by Drs F. Hundt and D. Nisato (SANOFI, München/Germany and Montpellier/France, respectively).


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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