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Ann Thorac Surg 1998;65:474-479
© 1998 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Effects of an Angiotensin II Antagonist on Ischemic and Nonischemic Isolated Rat Hearts

Yosef Paz, MD, Jacob Gurevitch, MD, Inna Frolkis, MD, PhD, Menachem Matsa, MD, Amir Kramer, MD, Chaim Locker, MD, Rephael Mohr, MD, Gad Keren, MD

Department of Thoracic and Cardiovascular Surgery, Elias Sourasky-Tel-Aviv Medical Center, Tel-Aviv, Israel
Department of Cardiology, Elias Sourasky-Tel-Aviv Medical Center, Tel-Aviv, Israel

Accepted for publication August 19, 1997.

Dr Gurevitch, Department of Thoracic and Cardiovascular Surgery, Ichilov Hospital, Elias Sourasky-Tel-Aviv Medical Center, 6 Weizman St, Tel-Aviv 64239, Israel.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Increasing evidence suggests that a locally integrated or intramyocardial renin-angiotensin system plays a significant role in ischemia-reperfusion injury. We evaluated the effects of losartan, an angiotensin II type 1 receptor blocking agent, on ischemic and nonischemic isolated rat hearts.

Methods. Using the modified Langendorff model, hearts were perfused with either low or high doses of losartan (18.2 mmol/L or 182.2 mmol/L, respectively) or with saline added to Krebs-Henseleit solution during phase I of the study. During phase II, hearts were exposed to a 60-minute period of global ischemia. Ischemic arrest was induced with warm cardioplegic solution (KCl, 16 mEq/L) containing either high-dose losartan (182.2 mmol/L) or Krebs-Henseleit solution only.

Results. During phase I of the study, no statistically significant differences were observed between the low-dose losartan group and the control group. However, hearts treated with high-dose losartan demonstrated an increase in peak systolic pressure, maximum first derivative of pressure, pressure-time integral, coronary flow, and oxygen consumption (p < 0.0001). During phase II, hearts treated with losartan showed a significantly better recovery on reperfusion, as reflected by better contractility (p < 0.001), higher oxygen consumption (p < 0.001), higher coronary flow (p < 0.0001), and lower creatine phosphokinase levels (41.1 ± 1.7 versus 73.3 ± 5.6 U/L; p < 0.001).

Conclusions. High doses of losartan have a positive inotropic effect on normally perfused hearts. Given in cardioplegic solution, the drug has a significant protective effect on ischemic isolated rat hearts.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure. There is increasing recognition of the existence of an endogenous or paracrine RAS in the heart. All components of the RAS—angiotensinogen and renin messenger RNAs, angiotensin-converting enzyme, and angiotensin II (Ang II)—previously have been detected in the heart and appear to be functionally integrated [1] [2]. Cardiac Ang II may be involved in the regulation of coronary blood flow, the modulation of sympathetic neurotransmission and cardiac contractility, the stimulation of hyperplasia and hypertrophy, and the maintenance of cardiovascular structure and repair [1] [2] [3] [4]. Angiotensin II interacts with two pharmacologically distinct subtypes of cell-surface receptors, Ang II type 1 and type 2 receptors [5] [6]. The role of type 2 receptors is still unknown; however, type 1 receptors mediate the major cardiovascular effects of Ang II [7].

A significant role of the RAS in the pathogenesis of myocardial ischemia-reperfusion injury has been postulated because of the cardioprotective effect observed with angiotensin-converting enzyme inhibitors [8]. In several experimental studies [9] [10], the administration of Ang II caused cardiac myocyte necrosis or induced myocardial infarction. We hypothesized that locally integrated, intramyocardial Ang II accelerates myocardial ischemia-reperfusion injury, and that this harmful effect is mediated through the cardiac Ang II type 1 receptor.

The purpose of this study was to investigate whether the Ang II type 1 receptor antagonist losartan [11] affects normal, nonischemic, isolated rat hearts and to determine its effect on the recovery of hearts undergoing global cardioplegic ischemia when given in the cardioplegic solution. A modified Langendorff isolated rat heart model was used.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Male Wistar rats (335 to 412 g) were anesthetized and heparinized by the intraperitoneal injection of pentobarbital sodium (30 mg/kg). Their hearts were excised rapidly, immersed in ice-cold saline with heparin, and mounted on the stainless steel cannula of a modified Langendorff perfusion apparatus.

Retrograde aortic perfusion was initiated at a perfusion pressure of 85 mm Hg with an oxygenated modified Krebs-Henseleit buffer solution of the following composition: NaCl, 118 mmol/L; KCl, 4.7 mmol/L; CaCl, 2.0 mmol/L; MgSO4 7H2O, 1.2 mmol/L; KH2PO4, 1.2 mmol/L; glucose, 11.1 mmol/L; and NaHCO3, 25 mmol/L. The perfusate was bubbled continuously with 95% O2 and 5% CO2, maintaining a pH of 7.4 to 7.5. Values of oxygen tension and carbon dioxide tension in the perfusion solution were 450 to 550 mm Hg and 25 to 30 mm Hg, respectively.

The heart temperature was monitored by a thermistor implanted in the right ventricular wall and was maintained carefully at 37°C or 31°C (at ischemia) by means of water jacketing the perfusate reservoir and the isolated heart. The right atrium was removed and the heart was paced to 300 beats/min at 4 V using an external pacemaker (type E4162; Devices Limited, Implants Division), ensuring identical heart rates for all hearts. A water-filled latex balloon was placed in the left ventricular cavity through a small incision in the left atrium and was connected to a Mennen Medical PI 32284 pressure transducer. The balloon was tied and inflated to a volume that produced 0 mm Hg diastolic pressure. Zero calibration of the pressure transducer was examined throughout the experiment.

Hemodynamic Measurements
Left ventricular pressure; time to peak systolic pressure; relaxation time; first derivative of the rise and fall in the left ventricular pressure (dP/dt max, dP/dt min); area calculated under the left ventricular developed pressure curve (pressure-time integral), which correlates with oxygen consumption [12]; and coronary flow (collected effluent in 1 minute) were measured. The various parameters were recorded continuously and measurements were taken at 10-minute intervals.

Ethics
All animals received humane care as described in the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Protocol
Fifty rats were divided randomly into five subgroups of 10 animals each. Three subgroups were studied under the phase I protocol, which was designed to check the direct effect of losartan on normally perfused hearts.

Control measurements were recorded after a 15-minute period of stabilization. Thereafter, hearts were perfused for a 60-minute period with Krebs-Henseleit solution containing either low-dose losartan (18.2 mmol/L), high-dose losartan (182.2 mmol/L), or saline (control group) added to modified Krebs-Henseleit solution using an infusion pump (0.5 mL/min). Hemodynamic measurements were recorded every 10 minutes.

The other two subgroups were studied under the phase II protocol, which was designed to assess the effect of high-dose losartan given in cardioplegic solution on ischemic hearts. After a 15-minute period of stabilization and a 30-minute period of perfusion, warm cardioplegia was initiated for 2 minutes (37°C; perfusion pressure, 60 mm Hg; KCl, 16 mEq/L in Krebs-Henseleit solution) with or without high-dose losartan (182.2 mmol/L), and then a 60-minute period of global ischemia at 31°C was applied to the arrested heart. Creatine phosphokinase activity was measured spectrophotometrically in the effluent at the first minute of reperfusion after ischemia. Thereafter, measurements of left ventricular function were taken every 10 minutes during the 30 minutes of the reperfusion period. Throughout the study, experiments were alternated between the control and the experimental limbs to avoid bias or differences in results.

Oxygen Consumption
Perfusate afferent and efferent gases were measured after 15 minutes of stabilization, 1 minute before cardioplegia, at 10 minutes of reperfusion, and at the end of reperfusion. Samples were withdrawn from the Langendorff perfusion apparatus and from the right ventricle using a tiny polyethylene catheter inserted through a pulmonary artery incision. Oxygen consumption was calculated using the following formula [13]:

Finally, the hearts were dried at 90°C for 24 hours to achieve a constant weight. The wet-to-dry weight ratio was calculated for each heart.

Statistics
Results are presented as the mean plus or minus the standard error. To avoid differences in baseline values, the value of the first 15 minutes of contraction of each heart was used as its individual control. All control values of left ventricular function, coronary effluent, and oxygen consumption were considered as 100%. Coronary effluent was normalized to grams of dry heart weight. Data were analyzed by Student’s paired or unpaired t-test (between various groups at baseline measurements and for creatine phosphokinase levels). Two-way analysis of variance with repeated measures for time and drug effects was calculated for all parameters, before and after ischemia. Statistical evidence was established at the level of p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Phase I
All measured parameters, obtained after 15 minutes of stabilization, were statistically similar for the three groups of hearts (those treated with high- and low-dose losartan and control hearts), as summarized in Table 1.


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  		Baseline Measurements in Phase I1

 
Although hearts treated with low-dose losartan demonstrated a trend toward improvement in hemodynamic performance (Fig 1C), using analysis of variance, no statistically significant differences in contraction amplitude, dP/dt max, dP/dt min, time-pressure integral, coronary flow, or oxygen consumption were found between this group and the control group, which was not perfused with the drug (Fig 1; Table 2).



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  		Hemodynamic performance of isolated rat hearts during 1 hour of perfusion: control group (white bars), hearts treated with low-dose losartan (dashed bars), and hearts treated with high-dose losartan (black bars). In spite of the gradual deterioration observed in the control group, hearts treated with high doses of losartan, but not with low doses, demonstrated a significantly better peak systolic pressure (A), dP/dt max (B), and pressure-time integral (C) compared with control hearts (p < 0.0001 for all hemodynamic parameters using analysis of variance). Results are presented as each heart’s percentage of baseline measurements.

 

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  		Coronary Flow in Phase I (mL/min)

 
Hearts treated with high-dose losartan, however, demonstrated significantly better myocardial performance during 1 hour of normal perfusion, manifested by improved peak systolic pressure (p < 0.0001) (Fig 1A), dP/dt max (p < 0.0001) (Fig 1B), time-pressure integral (p < 0.0001) (Fig 1C), and coronary flow (p < 0.0001; Table 2), compared with control hearts. The comparison between hearts treated with high- and low-dose losartan using analysis of variance demonstrated similar differences.

Oxygen consumption after 1 hour of perfusion was higher in the high-dose losartan group than in the low-dose losartan group and the control group (3.28 ± 19 mmol · h-1 · g-1 versus 2.04 ± 0.109 mmol · h-1 · g-1 and 2.15 ± 0.134 mmol · h-1 · g-1, respectively; p < 0.05).

Phase II
No statistically significant differences were observed in any of the measured parameters, obtained after 15 minutes of stabilization, between the hearts treated with losartan and the control hearts (Table 3). Moreover, using two-way analysis of variance, there were no statistically significant differences between the two groups after a 30-minute period of normal preischemic perfusion (Fig 2).


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  		Baseline Measurements in Phase II1

 


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  		Before ischemia, the control group (white bars) and the high-dose losartan group (black bars) demonstrated similar hemodynamic performance (peak systolic pressure [A], dP/dt max [B], and pressure-time integral [C]). Results are presented as each heart’s percentage of baseline measurements. After ischemia, the control group demonstrated a significant deterioration in myocardial hemodynamics. Hearts treated with losartan exhibited improved recovery compared with control hearts (p < 0.0001 for all variables using analysis of variance). (Rep = reperfusion.)

 
After 1 hour of global cardioplegic ischemia, the control hearts demonstrated significant deterioration in left ventricular function, whereas the hearts treated with losartan showed significantly better recovery in all the measured hemodynamic parameters (p < 0.0001 for all parameters) (see Fig 2). At the end of the reperfusion period (30 minutes after ischemia), the coronary flow in the control group was 64.6% ± 2.9% of baseline measurements, whereas the coronary flow in the losartan group was 89.9% ± 3.6% of baseline measurements (p < 0.0001).

Although oxygen consumption decreased significantly in the control group (to 58.3% ± 6.4% of baseline measurements; p < 0.001), it remained almost unchanged after 1 hour of global ischemia and 30 minutes of reperfusion in the losartan group (88.6% ± 2.1% of baseline measurements; p = not significant).

After ischemia, at the first minute of reperfusion, effluent creatine phosphokinase levels of the losartan-treated hearts were lower than those of the control hearts (41.1 ± 1.7 U/L versus 73.3 ± 5.6 U/L, respectively; p < 0.001).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This report shows that high doses of the Ang II type 1 receptor blocking agent losartan, given in cardioplegic solution before ischemia, significantly improve the coronary flow, mechanical left ventricular performance, and myocardial recovery of ischemic-reperfused isolated rat hearts compared with untreated control hearts. The improved oxygen consumption and lower enzymatic discharge were evidence of greater viability and lower rates of cellular injury, which correlated well with the improvement in myocardial hemodynamic performance. The correlation between the peak systolic pressure and the pressure-time integral, and between oxygen consumption in the Langendorff apparatus and that in the isolated working heart, has been demonstrated previously [12].

The unequivocal results of this study, which was performed in a blood-free environment and in an isolated heart model, emphasize the role of a local or paracrine RAS in the evolution of ischemia-reperfusion injury. This applies particularly to Ang II, which has a dominant coronary vasoconstrictive effect [14]. The fact that losartan has a protective effect on ischemic-reperfused hearts means that the paracrine or locally activated Ang II exerts its deleterious effect on the myocardium through the type 1 receptors. Yoshiyama and associates [15] recently demonstrated that exogenous Ang II accelerates myocardial ischemia-reperfusion injury primarily through type 1 receptors. Tan and colleagues [9] showed that cardiac myocyte necrosis is induced by Ang II, and Gavras and co-workers [10] induced myocardial infarction in rabbits subjected to intravenous administration of Ang II.

We recently demonstrated that the angiotensin-converting enzyme inhibitor captopril, given in cardioplegic solution, improves the recovery of isolated rat hearts subjected to ischemia-reperfusion [16], and we proposed several mechanisms that might be responsible for the cardioprotective effect of the drug, such as inhibition of the RAS and free radical scavenging. Interestingly, several non–angiotensin-converting enzymes are capable of inducing the production of Ang II. High levels of chymase, for example, were detected in ventricular cardiac myocytes [17]. The activity of chymase is not blocked with angiotensin-converting enzyme inhibitors. This protease is responsible for the production of 80% of the Ang II in the myocardium [17].

Losartan is a highly specific Ang II type 1 receptor antagonist, and the cardioprotective effects of this drug might be explained solely by the fact that it prevents the untoward effects of Ang II on ischemic reperfused hearts. Losartan is a relatively new, orally administered, nonpeptide, long-acting drug that has been found to be effective for hypertension and congestive heart failure [18]. It only recently has been reported that this drug protects against myocardial ischemia-reperfusion injury when administered orally 1 week before the induction of ischemia [15].

It might be interesting for the cardiac surgeon to assess the role of cardioplegic pretreatment with losartan on the recovery of the myocardium undergoing prolonged ischemia. This study demonstrated the cardioprotective effects of high doses of losartan when given in cardioplegic solution. This study also showed that losartan improves the coronary flow and myocardial contractility of isolated nonischemic rat hearts. It was essential that the effects of the drug (in different doses) on normally perfused isolated hearts (phase I) be evaluated in an introductory study before it was tested on ischemic reperfused hearts (phase II). The losartan dose used in phase II was based on the results of phase I.

It appears that, in addition to a significant increase in coronary flow, this drug has a positive inotropic effect when it is given in high doses. This is an interesting observation because Ang II thus far has been characterized as a positive inotropic substance [18] [19], and therefore losartan was predicted to decrease myocardial contractility. In a recently published study, however, Ang II demonstrated a biphasic pressor response in the rabbit coronary vascular bed, and a decline in peak left ventricular pressures was observed during coronary vasoconstriction [20]. In our study, the most dominant effect of the drug was its improvement of coronary flow, and only consequently its improvement of myocardial contractility. An additional explanation might be the possibility that hearts undergoing the phase I protocol also were exposed to a certain degree of ischemia, primarily because they were paced continuously. The RAS was activated, causing minimal deterioration in myocardial function, which was observed during the 1 hour of perfusion in the control group. Hence, losartan attenuated this deterioration and might have been acting as an "antiischemic" agent, namely reversing or antagonizing the deleterious effects of Ang II on ischemic hearts.

Caution definitely is needed in drawing direct clinical conclusions from this experimental study. The study has several limitations. We dealt with the isolated, nonworking rat heart model; the myocardium of "healthy" animals was tested in extreme globally ischemic conditions and in a blood-free environment. Moreover, possible systemic side effects of losartan were not apparent using this model. In an in vivo situation, the drug might leak into the circulation. Its unwanted adverse hemodynamic effects should be monitored carefully. However, the results of this study were significant and important. The cardioprotective effects of the Ang II type 1 receptor antagonist losartan support the hypothesis that a local or paracrine RAS plays an important role in the evolution of ischemia-reperfusion injury. Further experimental studies of this drug, performed in more clinically relevant models, are needed to examine the use of losartan in cardioplegic solution during open heart operations or in other conditions of acute myocardial ischemia.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
All represented data were analyzed statistically by Yael Villa, MSc, School of Mathematics, Tel-Aviv University. We thank Mrs Lynda Hemi for her help in editing the manuscript.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Baker KM, Booz GW, Dostal DE Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol 1992;54:227-241.[Medline]
  2. Dzau VJ Cardiac renin-angiotensin system. Molecular and functional aspects. Am J Med 1988;84:22-27.[Medline]
  3. Johnston CI Renin-angiotensin system: a dual tissue and hormonal system for cardiovascular control. J Hypertens 1992;10:S13-S26.
  4. Dostal DE, Baker KM Evidence for a role of an intracardiac renin-angiotensin system in normal and failing hearts. Trends Cardiovasc Med 1993;3:67-74.
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  8. Mehta PM, Pazyklenk K, Kloner RA Cardioprotective effects of captopril in myocardial ischemia, ischemia/reperfusion and infarction. Eur Heart J 1990;11:B94-B99.
  9. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991;69:1185-1195.[Abstract/Free Full Text]
  10. Gavras H, Brown JJ, Lever AF, Macadam RF, Robertson JIS Acute renal failure, tubular necrosis, and myocardial infarction. Lancet 1971;2:19-22.[Medline]
  11. Chiu AT, McCall DE, Price WA, et al. Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 1990;252:711-718.[Abstract/Free Full Text]
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  15. Yoshiyama M, Kim S, Yamagishi H, et al. Cardioprotective effects of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-reperfusion injury. Am Heart J 1994;128:1-6.[Medline]
  16. Gurevitch J, Pevni D, Frolkis I, et al. Captopril in cardioplegia: protective effects on the ischemic heart. Ann Thorac Surg 1997;63:627-633.[Abstract/Free Full Text]
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