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Ann Thorac Surg 1995;60:1698-1703
© 1995 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Different Effects of an Adenosine A1 Analogue and Ischemic Preconditioning in Isolated Rabbit Hearts

Robert D. Lasley, PhD, Mark A. Noble, Patrick J. Konyn, Robert M. Mentzer, Jr, MD

Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin

Accepted for publication July 18, 1995.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Ischemic preconditioning reduces infarct size, but its effects on postischemic function are variable. Adenosine, which is thought to play a role in ischemic preconditioning, reduces both infarct size and postischemic dysfunction. The purpose of this study was to compare the cardioprotective effects of ischemic preconditioning and an adenosine A1 receptor agonist on recovery of function and infarct size in isolated rabbit hearts.

Methods. Krebs buffer-perfused hearts (at least 7 per group) were subjected to 60 minutes of global ischemia (37°C) and 60 minutes of reperfusion. Ventricular function was assessed by measuring left ventricular developed pressure, and infarct size (percentage of the left ventricle) was determined by tetrazolium staining.

Results. Control hearts exhibited 34% ± 6% infarct size and 56% ± 4% recovery of preischemic left ventricular developed pressure. Ischemic preconditioning reduced infarct size to 13% ± 1% but had no effect on recovery of function (65% ± 5%). Hearts treated with the adenosine A1 agonist R-phenylisopropyladenosine for 5 minutes immediately before ischemia exhibited both reduced infarct size (10% ± 2%) and enhanced postischemic recovery of left ventricular developed pressure (86% ± 3%). Termination of the R-phenylisopropyladenosine treatment before ischemia eliminated its beneficial effects. The adenosine A1 receptor antagonist DPCPX blocked both of the effects of R-phenylisopropyladenosine but did not block ischemic preconditioning.

Conclusions. These results demonstrate fundamental differences between the cardioprotective effects of adenosine A1 receptor activation and ischemic preconditioning.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Ischemic preconditioning is the phenomenon whereby a brief period of ischemia and reperfusion renders the heart more resistant to injury after a prolonged occlusion. Ischemic preconditioning-induced infarct size reduction was first observed in the canine model by Murry and associates [1] and has been observed since in pigs [2], rabbits [3], and rats [4]. Ischemic preconditioning has also been reported to have numerous beneficial metabolic effects [5, 6]. There is much interest in determining the mechanism of preconditioning because it is thought that the endogenous mediator(s) of this potent form of cardioprotection may prove beneficial to patients undergoing cardiac operations.

The exact mechanism of ischemic preconditioning remains unknown, but there is evidence that adenosine, with its well-known cardioprotective properties, may play a role in this phenomenon. It has been shown that myocardial adenosine levels increase during the brief preconditioning occlusion [7], that administration of adenosine and adenosine A1 receptor agonists mimics the infarct size-reducing effects of preconditioning [3, 8–11], and that adenosine antagonists block ischemic preconditioning [3, 9, 10]. However, there are differences in the cardioprotective effects of these two interventions. Ischemic preconditioning has been shown to decrease infarct size, but there are conflicting reports regarding its effects on postischemic ventricular function. Preconditioning improves postischemic function in the isolated rat heart [6, 12–14] but not in canine myocardium in situ [15, 16]. There are conflicting reports on the ability of preconditioning to attenuate ventricular dysfunction in rabbit myocardium [17–21]. Adenosine pretreatment, however, improves postischemic function in all three species [22–24].

The purpose of this study was therefore to compare the effects of ischemic preconditioning and adenosine A1 agonist treatment on postischemic ventricular function and infarct size. We used the globally ischemic isolated perfused rabbit heart preparation to measure infarct size and recovery of function in the same heart.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Isolated Perfused Heart Preparation
All animals in this study received humane care according to the guidelines set forth 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 the Institute of Laboratory Animal Resources, published by the National Institutes of Health (NIH publication 85-23, revised 1985). Experiments were conducted on New Zealand white rabbits of either sex (2 to 3 kg). Rabbits were anesthetized with pentobarbital sodium (65 mg/kg intraperitoneally), a tracheostomy was performed, and the animals were ventilated with room air and administered heparin (500 U/kg intraperitoneally). The heart then was excised rapidly and placed immediately in ice-cold Krebs-Henseleit buffer to produce cardiac arrest. After cannulation of the aorta, the hearts were perfused at a constant perfusion pressure of 70 mm Hg with Krebs-Henseleit buffer consisting of the following (in mmol/L): NaCl, 118; KCl, 4.7; MgSO4, 1.2; KH2PO4, 1.2; CaCl2, 1.5; NaHCO3, 25.0; and glucose, 11.0. The perfusate was maintained at 37°C in a constant-temperature reservoir and was bubbled with 95% O2/5% CO2, resulting in a pH of 7.35 to 7.45, partial pressure of carbon dioxide 35 to 40 mm Hg, and partial pressure of oxygen 560 to 620 mm Hg. Myocardial temperature was maintained at 37°C by submersing the heart in a water-jacketed chamber filled with Krebs-Henseleit buffer. The hearts were paced at 180 beats/min by electrodes placed on the right ventricle. Pacing was maintained for the first 5 minutes of ischemia and was resumed during the reperfusion period.

Ventricular function was assessed by measuring left ventricular developed pressure (LVDP) with a fluid-filled latex balloon connected by a polyethylene catheter to a pressure transducer (Gould Model P23XL, Cleveland, OH). The balloon was inserted into the left ventricle after cutting the mitral valve and was inflated to yield an end-diastolic pressure of 10 mm Hg. Once the left ventricular balloon volume was set during the preischemic perfusion, it was maintained constant during ischemia and reperfusion. Coronary flow rate was determined with an in-line flow probe (Carolina Medical Electronics, Inc, King, NC). The postischemic recoveries of LVDP and coronary flow were expressed as percentages of the preischemia/pretreatment values. All experimental data were recorded on a Gould Model RS 3400 chart recorder.

Experimental Protocols
All hearts (n = 7 to 8 per group) were submitted to 60 minutes of global normothermic (37°C) ischemia and 60 minutes of reperfusion after the control perfusion or treatment regimens. The following groups were studied: (1) control, (2) ischemic preconditioned, (3) pretreatment with the adenosine A1 agonist R-phenylisopropyladenosine (PIA), (4) PIA preconditioning, (5) ischemic preconditioned plus the adenosine A1 receptor antagonist DPCPX, and (6) PIA pretreatment plus DPCPX. Control hearts were perfused for 35 minutes before ischemia/reperfusion. Ischemic and PIA preconditioning were induced by 5 minutes of ischemia/PIA infusion (1 µmol/L) followed by 10 minutes of reperfusion/washout after 20 minutes of equilibration. Pretreatment with PIA consisted of 5 minutes of treatment with PIA (1 µmol/L) immediately before global ischemia. In group 5, hearts were treated with DPCPX (2.5 µmol/L) for 10 minutes before 5 minutes of ischemic preconditioning, and then reperfused for 10 minutes with normal Krebs buffer. In group 6, PIA (1 µmol/L) and DPCPX (2.5 µmol/L) were infused simultaneously for 5 minutes immediately before ischemia.

Measurement of Infarct Size
After 60 minutes of reperfusion, the hearts were perfused for 5 minutes at constant pressure (70 mm Hg) with a 1% (w/v in phosphate-buffered saline solution) triphenyltetrazolium chloride (TTC) solution (37°C). The hearts were placed in 10% formalin overnight. The following day, the atria and great vessels were removed, and the hearts were sliced into four to five pieces (approximately 2 mm thickness) from base to apex. To quantitate the area at risk and infarct size, we placed the heart slices between two Plexiglas plates separated by an exact 2-mm distance and photographed them with a 35-mm camera. An extension tube placed on the camera lens produced a fourfold magnification of the slices. Developed slides were projected, and the left ventricle and TTC-negative stained regions were traced on clear transparency film. Total area of the left ventricle and TTC-negative area were then quantified by planimetry. Infarct size was expressed as the percentage of the left ventricle that stained negative for TTC.

Chemicals
The adenosine receptor agonist PIA and the adenosine A1 receptor antagonist DPCPX were obtained from Research Biochemicals, Inc. (Natick, MA). We dissolved PIA directly in the Krebs-Henseleit buffer. A 10-mmol/L stock solution of DPCPX was made in dimethyl sulfoxide and was then diluted in the buffer. The final dimethyl sulfoxide concentration in the Krebs buffer was 0.4% (vol/vol). Triphenyltetrazolium chloride was obtained from Sigma Chemical Co (St. Louis, MO).

Statistics
Results are expressed as mean ± standard error of the mean. Differences between group means were determined by analysis of variance followed by Duncan's post hoc test. Differences within groups were determined by repeated-measures analysis of variance followed by Dunnett's post hoc test. A p value less than 0.05 was considered statistically significant.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Preischemic LVDP and coronary flow values are shown in Table 1Go. There were no differences in LVDP or coronary flow among the groups before preischemic treatments. Ischemic preconditioning was associated with a 25% ± 3% decrease in LVDP before the prolonged ischemia, but neither PIA pretreatment, PIA preconditioning, nor PIA plus DPCPX altered LVDP. Ischemic preconditioning in the presence of DPCPX reduced LVDP by 25% ± 6%.


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  		Table 1. . Left Ventricular Function and Coronary Flow Before Prolonged Ischemiaa
 
Pretreatment with PIA and PIA preconditioning increased coronary flow 72% ± 9% and 53% ± 8%, respectively. Ten minutes after terminating the PIA infusion in the latter group, coronary flow remained 24% ± 2% greater than at baseline. Treatment with DPCPX reduced PIA-induced vasodilatation, as coronary flow increased only 33% ± 6% above baseline.

There were no differences in the recovery of coronary flow among the groups (Fig 1Go). Although PIA pretreatment and ischemic preconditioning appeared to exhibit higher coronary flows at 5 and 10 minutes of reperfusion, these effects were not statistically significant. After 60 minutes of reperfusion, the recovery of coronary flow ranged from 73% ± 3% in control hearts to 84% ± 6% in ischemic preconditioned hearts.



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  		Fig 1. . Reperfusion coronary flow (CF) rates expressed as a percentage of preischemic values. Recovery of coronary flow in all PIA-treated groups was expressed as a percentage of preischemic coronary flow before PIA infusion. (Groups, in order: ISCH PC = ischemic preconditioning [5 minutes ischemia, 10 minutes reperfusion]; PIA = PIA pretreatment; PIA PC = PIA preconditioning [5 minutes infusion, 10 minutes washout]; PC + DPCPX = ischemic preconditioning + DPCPX; PIA + DPCPX = PIA pretreatment + DPCPX.)

 
End-ischemic and reperfusion left ventricular end-diastolic pressures (LVEDP) are illustrated in Figure 2Go. Pretreatment with PIA resulted in significantly lower LVEDP at the end of 60 minutes' ischemia (18 ± 1 mm Hg) compared with control hearts (45 ± 6 mm Hg). This effect of PIA was blocked by DPCPX (39 ± 5 mm Hg) and was not evident with PIA preconditioning (38 ± 6 mm Hg). Ischemic preconditioning had no effect on end-ischemic LVEDP. Pretreatment with PIA resulted in significantly lower LVEDP throughout reperfusion compared with control, PIA-preconditioned, and PIA plus DPCPX-treated hearts. Ischemic preconditioning was associated with reduced reperfusion contracture at 5, 10, and 60 minutes of reperfusion (p < 0.05 versus control).



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  		Fig 2. . Left ventricular end-diastolic pressure (LVEDP) at end-ischemia and during reperfusion. The LVEDP was set at 10 mm Hg during the preischemic period. (*p < 0.05 versus control; groups and abbreviations as in Figure 1Go.)

 
Figure 3Go shows the effects of the various treatments on postischemic recovery of function. Control hearts recovered 56% ± 4% of preischemic LVDP. Preconditioning with neither ischemia (65% ± 5%) nor PIA (64% ± 5%) was associated with significantly improved recovery of function. Hearts pretreated with PIA immediately before ischemia recovered 86% ± 3% of preischemic LVDP (p < 0.05 versus control). The beneficial effect of PIA was blocked by the adenosine A1 receptor antagonist DPCPX (56% ± 5% recovery), whereas DPCPX had no effect on recovery of function in ischemic-preconditioned hearts (61% ± 6%).



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  		Fig 3. . Postischemic recovery of left ventricular developed pressure (LVDP) expressed as a percentage of preischemic LVDP. Treatments were carried out as described in Material and Methods. (*p < 0.05 versus control; groups and abbreviations as in Figure 1Go.)

 
The effects of ischemic preconditioning and PIA treatments on infarct size are shown in Figure 4Go. Because the hearts were globally ischemic, the area at risk was the entire left ventricle. Control infarct size was 34% ± 6% of the left ventricle, a value significantly greater than that observed in PIA-pretreated (10% ± 2%) and ischemic-preconditioned hearts (13% ± 1%). Preconditioning with PIA reduced infarct size to 23% ± 4% of the left ventricle (32% smaller than in control hearts), but this effect was not statistically significant. The adenosine A1 receptor antagonist DPCPX blocked the protective effect of PIA (28% ± 8% infarct size), but had no effect on ischemic preconditioning-induced infarct size reduction (15% ± 4%).



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  		Fig 4. . Myocardial infarct size determined by TTC staining after 60 minutes of global ischemia and 60 minutes of reperfusion. The area at risk is the entire left ventricle. (*p < 0.05 versus control; LV = left ventricle; groups and abbreviations as in Figure 1Go.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The results of this study in the isolated rabbit heart indicate that ischemic preconditioning and the adenosine A1 agonist PIA both reduce infarct size, but recovery of postischemic ventricular function is enhanced only with adenosine A1 agonist pretreatment. The beneficial effects of PIA dissipated when the treatment was terminated before ischemia (ie, PIA preconditioning). Adenosine A1 receptor antagonism with DPCPX blocked the beneficial effects of PIA on infarct size and postischemic function, but did not block ischemic preconditioning-induced infarct size reduction. These results illustrate the differences between the cardioprotective effects of adenosine A1 receptor activation and ischemic preconditioning and suggest that adenosine A1 receptor activation does not initiate the infarct size-reducing effect of ischemic preconditioning.

The first major finding in this study was that although ischemic preconditioning reduced infarct size, it did not enhance postischemic function in the isolated rabbit heart, results identical to those reported by Sandhu and colleagues [18]. Bolling and associates [20] also reported the lack of effect of ischemic preconditioning on postischemic function. In contrast, Omar and co-workers [17], Hendrikx and colleagues [19], and Illes and associates [21] reported that ischemic preconditioning improved postischemic function in isolated rabbit hearts. It is not clear why the results of these rabbit preconditioning studies are so divergent, because these conflicting results have been obtained in both crystalloid- and blood-perfused preparations, with and without cardioplegia, and independent of perfusate calcium levels.

In contrast, there are numerous reports that ischemic preconditioning enhances postischemic function in isolated rat hearts [6, 12–14]. We used the same ischemic preconditioning protocol in this study that we [12] and others [6, 13, 14] have used to functionally precondition isolated rat hearts. Although both rat and rabbit preconditioned hearts exhibited lower postischemic end-diastolic pressures, only in the rat did we observe improved postischemic developed pressure. Because it has been reported that ischemic preconditioning does not attenuate postischemic dysfunction in the dog [15, 16] or the guinea pig [6], it is possible that the rat exhibits a unique functional response to ischemic preconditioning.

Pretreatment with the adenosine receptor agonist PIA reduced infarct size, and in contrast to ischemic preconditioning, it attenuated postischemic dysfunction. Both of these cardioprotective effects of PIA were blocked by the adenosine A1 antagonist DPCPX, consistent with the hypothesis that adenosine A1 receptor activation reduces infarct size [8] and enhances postischemic function [22]. However, we observed that a transient exposure to the adenosine A1 agonist PIA that was terminated before ischemia (ie, PIA preconditioning) did not exert functional cardioprotection. A similar lack of functional protection by preconditioning with adenosine and adenosine A1 agonists has been observed in isolated rabbit [19] and rat [13, 14] heart preparations. Hendrikx and colleagues [19] reported that a transient infusion of 10 µmol/L PIA, a tenfold greater concentration than used in this study, did not improve postischemic function in the isolated rabbit heart. Adenosine preconditioning also fails to exert functional protection in the in situ canine [24] and porcine [25] regional ischemia preparations.

We also observed similar differences between PIA pretreatment and PIA preconditioning on infarct size. The pretreatment protocol reduced infarct size by 70%, but PIA preconditioning reduced infarct size by only 32%, which did not achieve statistical significance. This inability of PIA preconditioning to reduce infarct size differs from the results of Liu and colleagues [26], who reported that a transient infusion of adenosine in the Krebs-perfused rabbit heart did reduce infarct size. One explanation for the lack of effect of PIA preconditioning in our study could be the longer ischemia time (60 minutes, versus 30 minutes by Liu and colleagues). Yao and Gross [9] reported that in canine myocardium, the infarct-reducing effect of adenosine preconditioning disappeared with a more rapid time course than did that of ischemic preconditioning. In our study, we observed a similar reduction in infarct size (13% of the region at risk) with ischemic preconditioning as did Liu and colleagues (9%) [26]. The infarct reduction with our PIA pretreatment protocol is also similar to that reported in in situ models [3, 8], where the long half-life of intravenously administered adenosine analogues precludes their washout before ischemia.

An interesting finding in this study is that adenosine/A1 agonist preconditioning reduced infarct size by 32% (although not statistically significant) but did not attenuate stunning. This is consistent with observations in numerous other studies on adenosine cardioprotection [9, 11, 13, 14, 19, 24, 25]. At this point there is no explanation for this phenomenon, but it may be related to the different causes of reversible and irreversible ischemic injury or the different mechanisms by which adenosine reduces this injury.

Although the ability of the adenosine receptor antagonist 8-(p-sulfo-phenyl)-theophylline to block ischemic preconditioning has been well described [3, 10], there are conflicting results on the ability of the selective A1 antagonist DPCPX to block ischemic preconditioning-induced infarct size reduction. It has been reported that DPCPX blocks ischemic preconditioning in the dog [27] but not in the rabbit [26]. We observed that DPCPX blocked the infarct size-reducing effect of the adenosine A1 agonist PIA, but it did not block that of ischemic preconditioning. These results suggest that although adenosine A1 receptor activation does reduce infarct size, adenosine A1 receptor activation is not necessary for ischemic preconditioning-induced infarct size reduction in the rabbit heart.

Our observation that DPCPX did not block ischemic preconditioning is consistent with that of Liu and colleagues [26], who reported that a 12.5-fold lower concentration of DPCPX (200 nmol/L) did not block ischemic preconditioning in the isolated rabbit heart. We used a higher dose of DPCPX because the results of preliminary studies indicated that 1 µmol/L DPCPX did not block the protective effect of 1 µmol/L PIA. Based on their results with other adenosine receptor agonists and antagonists and negative results with DPCPX, Liu and colleagues [26] hypothesized that ischemic preconditioning may be mediated by the adenosine A3 receptor. However, the presence of A3 receptors and their physiologic relevance have yet to be confirmed in ventricular myocardium. In addition, PIA at the concentration used in this study (1 µmol/L) binds to the adenosine A3 receptor [28], yet its cardioprotective effects were blocked completely by the adenosine A1 antagonist DPCPX.

The phenomenal infarct size-reducing effect of ischemic preconditioning has raised the possibility that preconditioning itself or a ``preconditioning mimetic'' agent may prove beneficial in the setting of cardiac operations. However, the majority of studies in the whole heart, including this one, have indicated that neither ischemic preconditioning nor adenosine preconditioning attenuates postischemic dysfunction. In contrast, the preconditioning mimetic agent adenosine does enhance postischemic function when administered immediately before ischemia. These results indicate that much work remains to be done to determine the mechanisms by which adenosine and ischemic preconditioning protect the ischemic heart.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by a grant to Dr Lasley from the American Heart Association, Wisconsin Affiliate, and to Dr Mentzer (R01 HL-34579) from the National Institutes of Health.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Lasley, Department of Surgery, University of Wisconsin School of Medicine, H4/383 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-0001.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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  14. Cave AC, Collis CS, Downey JM, Hearse DJ. Improved functional recovery by ischemic preconditioning is not mediated by adenosine in the globally ischemic isolated rat heart. Cardiovasc Res 1993;27:663–8.[Abstract/Free Full Text]
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Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1754 - H1761.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
M. S. Jahania, R. D. Lasley, and R. M. Mentzer Jr
ISCHEMIC PRECONDITIONING DOES NOT ACUTELY IMPROVE LOAD-INSENSITIVE PARAMETERS OF CONTRACTILITY IN IN VIVO STUNNED PORCINE MYOCARDIUM
J. Thorac. Cardiovasc. Surg., April 1, 1999; 117(4): 810 - 817.
[Abstract] [Full Text] [PDF]

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 Ann. Thorac. Surg.Home page
B. Faris, J. Peynet, M. Wassef, A. Bel, C. Mouas, M. Duriez, and P. Menasche
Failure of Preconditioning to Improve Postcardioplegia Stunning of Minimally Infarcted Hearts
Ann. Thorac. Surg., December 1, 1997; 64(6): 1735 - 1741.
[Abstract] [Full Text]

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