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Interact CardioVasc Thorac Surg 2007;6:363-368. doi:10.1510/icvts.2006.136317
© 2007 European Association of Cardio-Thoracic Surgery
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ESCVS article - Cardiac general

The protective effect of prior ischemia reperfusion adenosine A1 or A3 receptor activation in the normal and hypertrophied heart{star}

Edith Hochhausera,*, Dorit Leshemb, Oleg Kaminskia, Yelena Cheporkoa, Bernardo A. Vidnea and Asher Shainbergb

a Department of Cardiothoracic Surgery, The Cardiac Research Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 49100, Tel Aviv University, Israel
b Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel

Received 10 May 2006; received in revised form 14 November 2006; accepted 15 January 2007

{star} Presented at the 55th International Congress of the European Society for Cardiovascular Surgery, St Petersburg, Russian Federation, May 11–14, 2006.

*Corresponding author. Tel.: +972-3-9376284; fax: +972-3-9211478.

E-mail address: hochhaus{at}post.tau.ac.il (E. Hochhauser).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Objectives: The increased susceptibility to ischemic injury of hypertrophied hearts has long been recognized. The purpose of this study was to investigate the effects of pre-ischemic pharmacological preconditioning (PC) with adenosine A1 or A3 receptor activation, on the recovery of the isolated myocardium post cardioplegic ischemia. In addition, we examined the p38 MAPK activation in this process. Materials and methods: WKY and SHR hearts were subjected to two different modes of treatment. (1) In the perfusion mode- (the first window of PC) isolated rat hearts were perfused for 10 min with Krebs Henseleit solution and then A1 receptor agonist (CCPA) or A3 receptor agonist (Cl-IB-MECA), 10  nM for 20 min, followed by 30 min of warm cardioplegic ischemia and 30 min of reperfusion. (2) In the injection mode (the second window of PC) 100 µg/kg CCPA or Cl-IB-MECA, were administered 24 h before the experiment. Isolated hearts were perfused for 30 min with KH and then subjected to the same protocol as described above. Results: Recovery of hemodynamic parameters was always better in the normal vs. hypertrophied hearts. CCPA improved recovery of left ventricular developed pressure, coronary flow and ATP levels of the hearts (normal and hypertrophied) in both modes of treatment. Cl-IB-MECA was partially beneficial especially in the injected mode. Increased phosphorylation of p38 MAPK relative to baseline, in both early (perfused) and late (injected) modes of treatment especially in the WKY hearts, is demonstrated. Conclusion: CCPA in both modes of treatment and Cl-IB-MECA, especially in the injected mode, were beneficial in protecting the normal and hypertrophied perfused isolated rat heart subjected to normothermic cardioplegic ischemia. This protection was partially related to the increased phosphorylation of p38 MAPK.

Key Words: Adenosine receptors; Ischemia; CCPA; Cl-IB-MECA; Hypertrophied heart; p38; Isolated heart


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Strategies for protecting the heart from surgically related ischemic and reperfusion injury have evolved over the past decades. However, older patients with severe injury and complex surgical cases, require prolonged ischemic time and hence, specific therapy to adequately restore contractile function and morphology. Ischemia and reperfusion injury strike not only myocytes but also vascular endothelium [1]. The increased susceptibility of the hypertrophied left ventricle to ischemic injury has long been recognized. These hearts have lower base levels of ATP and have ischemic contracture sooner than normal hearts [2].

Ischemic preconditioning (IPC) is the phenomenon whereby brief ischemic episodes render the heart more resistant to subsequent ischemic insults [3]. This cardioprotective phenomenon has been divided into two distinct phases: an early phase (the first window) which is seen within 2–4 h post-ischemia and a late phase (the second window) which is manifest 24–72 h later. Adenosine (ADO) is one of the agents that has been proposed to trigger both early and delayed preconditioning [4]. The activation of A1 and A3 mimicked CCPA and Cl-IBMECA, respectively, and the blockade of these receptors abolished the effect of preconditioning [5]. We have shown that this protection is mediated by the opening of the mitochondrial KATP channels [6].

The role of mitogen activated protein kinases (MAPKs) in ischemic injury with enhanced activation of p38 MAPK has been documented and may play an important role in metabolic adaptations [7, 8]. Controversy surrounds the role of this kinase in executing pathophysiological responses to ischemia reperfusion. On the one hand, in the isolated perfused rat heart, p38 MAPK has been shown to be activated during global ischemia, and sustained throughout reperfusion [9, 10]. Inhibition of p38 activation during ischemia was beneficial [11]. On the other hand, when protection was blocked from IPC by ADO receptor antagonist, the increased phosphorylation of p38 MAPK during ischemia disappeared [12]. ADO and A1 receptor activation (A1RA) attenuate the I/R-induced cardiac dysfunction through antioxidant and anti-apoptotic actions and modulation of p38 MAPK [13]. Moreover, administration of sb203580 resulted in the significant blockade of A1RA late PC protection with decreased expression of phosphorylated p38 MAPK during ischemia in the mouse heart [14]. There are various isoforms of p38 that promote differing physiological functions such as hypertrophy, apoptosis and cell survival [15].

The combination of different methods of adenosine receptor agonists administration to the hypertrophied hearts before cardioplegic arrest, has not been mentioned in the literature. We hypothesized that the use of these agonists during cardiac surgery would be beneficial to the hypertrophied heart. Therefore, in this study we aim to explore: (1) Whether pharmacological PC of the hypertrophic heart using CCPA or Cl-IB-MECA before cardioplegic arrest (a clinically relevant model) synergistically improves cardiac function after ischemia compared to the normal heart. (2) To investigate the involvement of p38 MAPK in this process. Two different modes of administration were tested: perfusion of the studied drug immediately before ischemia, or IV injection 24 h before the ischemic period.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Animal care complied with the Principles of Laboratory Animal Care and the Guide for the Care and Use of Laboratory Animals of Tel Aviv University, Israel.

Adult male rats (200–250 g) of the Wistar Kyoto (WKY) normotensive strain and Wistar Kyoto spontaneously hypertensive strain (SHR) were used in this study [16]. Blood pressure was monitored by means of the tail-cuff method (Blood Pressure Meter, Letica Scientific Instrumentation, Barcelona, Spain). Heparin (100 units/rat), was administered intraperitoneally. After 30 min, the animals were anesthetized with diethyl ether. Their hearts were rapidly excised and mounted on the stainless steel cannula according to the modified Langendorff system. Retrograde aortic perfusion was initiated at a perfusion pressure of 90 cm H2O with modified Krebs-Henseleit buffer solution (KH), which contained 118 mM NaCl, 25 mM NaHCO3, 1.2 mM KH2PO4, 1.2 mM MgSO4 .7H2O, 2.5 mM CaCl, 4.7 mM KCl, 11.1 mM glucose, bubbled with a mixture of O2 95%/CO2 5%, resulting in a pH of 7.35–7.40. PO2 and PCO2 values in the perfusion medium were 550–650 and 25–30 mmHg, respectively. The pulmonary artery was incised to facilitate drainage. The cardioplegic solution was prepared by the addition of KCl 16 mM to the KH solution. Temperature was maintained at 37±0.5 °C, by placing a thermostatic water jacket around the perfusate reservoir and the isolated heart. The temperature of the heart was monitored with a micro thermocouple in the right ventricle connected to a digital thermometer (Webster Laboratories Altadena, CA, USA) [5].

Epicardial pacing wires were connected to the right ventricle and the aortic cannula. After completion of the preparation at 300 bpm (5 V, 10-ms duration), using an external Harvard stimulator (Edenbridge, Kent, England), pacing commenced. A latex balloon filled with water was inserted into the left ventricular cavity through a small incision in the left atrium and connected to a Statham Medical P132284 pressure transducer (Mennen Medical, Inc., Clarence, NY). The balloon was tied and inflated to a volume producing a diastolic pressure of 0–5 mmHg. Left ventricular developed pressure (LVP) was continuously monitored during the experiment and recorded every 10 min using AT-CODAS Software (Dataq Instr. Inc., Akron, OH). Only hearts with LVP over 70 mmHg were included in the study. Coronary flow was measured by collecting the effluent flow into a calibrated beaker for 1 min at 10 and 30 min of the stabilization period, and at 1, 10, 20, 30 min of reperfusion [5]. Creatine kinase (CK) was measured immediately before ischemia and at 1 and 30 min of reperfusion using commercial kits (Sigma Chem. Co., St. Louis, MO, USA).

We conducted a dose-finding pilot study before the main experiments, in which we tested different concentrations of the studied compounds, and those that gave the best results in terms of LVP and CF, were chosen.

The experimental compounds were 2-chloro-N6-cyclopentyladenosine (CCPA), 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA), 10 nM in KH (perfused) or IV injected mode, 100 µg/kg.

2.1. Experimental protocol

Drug perfusion group: Isolated hearts were perfused with KH solution for 10 min followed by 20 min of drug perfusion. Cardioplegic solution was administered for 2 min, and ischemia was maintained for 30 min, at 37 °C. At the end of the ischemic period the hearts were reperfused with KH for 30 min.

Drug injected group: Rats were injected intravenously with the experimental drug 24 h before the experiment. Isolated hearts were perfused for 30 min with KH and then subjected to the same protocol as described above. At the end of each experiment, myocardial tissue was frozen in liquid nitrogen and kept at –70 °C until analyzed.

2.2. Experimental groups

Drug perfused group: Control I/R; CCPA; Cl-IB-MECA (n=10 in each group). Drug injected group: CCPA (n=10); Cl-IB-MECA (n=10). Vehicle injected group were exactly the same as the control non-injected ones (n=3, data not shown).

2.3. ATP concentration

Myocardial tissue was harvested in 1 ml cold 5% trichloroacetic acid. The cell extract was used to measure ATP content using a luciferin-luciferase bioluminescence kit (ATP Bioluminescence Assay Kit CLSH, Boehringer, Mannheim, Germany).

2.4. Western blotting

Heart tissue samples (20 mg) were homogenized in lysis buffer and quantified for protein levels using a commercial assay (Bio-Rad, Israel). Proteins (100 µg/sample) were separated using SDS polyacrylamide gel (10%) under denaturing conditions and electrotransferred onto nitrocellulose (Bio-Rad, Israel) overnight at 20 V. Membranes were blocked with 5% nonfat milk in Tris-buffered saline containing 0.1% Tween 20 (TBST) 1 h at 37 °C. Primary antibodies (anti-phosphorylated p38, and unphosphorylated p38 from Santa Cruz (CA, USA) were used at a 1:500 dilution in TBS with 5% nonfat milk. After incubation with the primary antibodies (overnight at 4 °C), rabbit peroxidase-conjugated secondary antibodies were added (dilution of 1:10,000) for 1 h at room temperature. Films were developed using an enhanced chemiluminescence method and exposed to X-ray films [11]. The absorbance density of each lane was quantified by densitometry after digital scanning of each lane. Density is normalized as the fraction of the total density at baseline.


   3. Statistical analysis
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistical analysis
4. Results
 5. Discussion
 References
 
All results are expressed as ±S.E. of the mean. Values of the stabilization period were considered as 100%. ANOVA was used to compare groups; the Bonferoni test was used to compare differences between the groups at every point checked.


   4. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistical analysis
 4. Results
5. Discussion
 References
 
4.1. Blood pressure (BP) and ratio of heart-to-body weight

Using the tail cuff technique, BP of the SHR was higher than WKY animals (185±11 and 132±15 mmHg, P<0.0001). The ratio of heart-to-body weight in the WKY heart was smaller than in the hypertrophied (SHR) hearts (3.2*10–3±0.5*10–4 vs. 5.03±10–3±0.31*10–4, P< 0.0001).

Baseline parameters: no differences were found in either LVP or in CF in all the different groups tested (Table 1).


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  		Table 1 Baseline hemodymic parameters

 
4.2. Hemodynamic recovery

Figs. 1 and 2 show the percent recovery after ischemia of the hemodynamic parameters at 10 min and at the conclusion of the experiment of both perfused and injected groups. In the drug perfused protocol of LVP and coronary flow, CCPA was beneficial in both WKY and SHR hearts compared to the CL-IB-MECA or control groups, P<0.005. In the drug injected mode both Cl-IB-MECA and CCPA were beneficial for the recovery of LVP and CF in both WKY and SHR hearts. In the LVP recovery was always better in WKY compared to SHR hearts.


Figure 1
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  		Fig. 1. LVP expressed as % of preischemic value in perfused or injected modes of treatment with adenosine receptor agonists. LVP at various time points following cardioplegic ischemia. Values represent means±S.E. *=P<0.05 vs. ischemia (control).

 

Figure 2
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  		Fig. 2. Coronary flow rate expressed as % of preischemic value in perfused or injected modes of treatment with adenosine receptor agonists. Coronary flow rate at various time points following cardioplegic ischemia. Values represent means±S.E. *=P<0.05 vs. ischemia (control).

 
4.3. Biochemical markers of ischemia and reperfusion damage

CK levels in the CCPA and in the CL-IB-MECA perfused or injected hearts were lower than in the control group, in both the WKY and SHR hearts (P<0.005). However, in the hearts perfused with CL-IB-MECA, CK levels were similar to the control group in both WKY and SHR groups (Fig. 3).


Figure 3
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  		Fig. 3. Release of creatine kinase in perfused or injected modes of treatment with adenosine receptor agonists. Release of CK to the coronary effluent during stabilization period and at various time points following cardioplegic ischemia. Values represent means±S.E. *=P<0.05 vs. ischemia (control).

 
4.4. ATP levels

There were statistically significant differences between the ATP levels in WKY and SHR hearts treated with CCPA and CL-IB-MECA in both perfused and injected modes, compared to controls (P<0.005). However, in the SHR group, ATP levels were higher in the injected than in the perfused hearts (Fig. 4).


Figure 4
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  		Fig. 4. ATP levels in hearts subjected to 30 min of ischemia followed by 30 min of reperfusion after treatment with adenosine receptor agonists. ATP was determined in myocardial extracts after ischemia and reperfusion. Values represent means±S.E. *=P<0.05 vs. ischemia (control)=P<0.05 vs. stabilization of the same group.

 
4.5. Phosphorylation of p38 MAPK

Drug treatment induced phosphorylation of p38 MAPK in both normal and hypertrophied hearts. Phosphorylated p38 in drug treated groups was higher in WKY hearts than in SHR, compared to baseline. Moreover, band density was higher in the hypertrophied, compared to WKY hearts, in all hearts including control and ischemic groups (Fig. 5).


Figure 5
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  		Fig. 5. Western blots of total and phosphorylated p38 MAPK in hearts subjected to 30 min schemia followed by 30 min reperfusion after treatment with adenosine receptor agonists. Panel A represents WKY hearts and panel B, SHR hearts. Band density of hosphorylated p38 MAPK was higher in the SHR compared to WKY hearts including control and ischemic groups Western blot of phosphorylated p38 MAPK and unphosphorylated protein were measured with specific polyclonal antibodies. Proteins (100 µg/sample) were layered on an SDS polyacrylamide gel (10%) under denaturing conditions and electrotransferred onto nitrocellulose overnight at 20 V. C. Ratio of the protein expression of phosphorylated p38 MAP kinase post ischemia reperfusion compared to baseline, *P<0.05 vs. control I/R from the same hearts.

 

   5. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Statistical analysis
 4. Results
 5. Discussion
References
 
The increased susceptibility of the hypertrophied hearts to ischemic injury during cardiac operations is known [2]. SHR hearts were used because we have demonstrated that these hearts are hypertrophied and more susceptible to ischemic injury [16]. In almost all of the variables checked, the high vulnerability of the hypertrophied myocardium compared with the normal myocardium was dominant: hypertrophied hearts had a lower contraction amplitude recovery and coronary perfusate volume, a higher level of CK, and a lower level of ATP. The beneficial effect of selective activation of A1AR with CCPA, in both modes of treatment was more effective in the hypertrophied than in the normal WKY hearts. Injection of adenosine A3RA with Cl-IB-MECA 24 h before ischemia proved advantageous to both normal and hypertrophied hearts. Although activation of p38 MAPK was superior in the hypertrophied hearts due to adenosine receptor activation, the proportion in the normal, compared to control hearts subjected to ischemia and reperfusion, was greater. It seems that p38 phosphorylation in adenosine receptors signaling is crucial.

It was found that the combined effect of PC and cardioplegia at 37 °C did not afford additive protection to the normal heart [17]. In this work we found that both normal and hypertrophied hearts can benefit from ADO receptors activation either given immediately before or 24 h before cardioplegic ischemia. In the search for an efficient, reliable and easy method of cardioprotection, administration of ARA is one of the better-characterized mechanisms for the normal heart. Pretreatment with IPC or Ado was beneficial both to the hypertrophied and normal heart [18]. Unlike the short half life and arrhythmogenic effect of ADO, adenosine receptor agonists have very mild chronotropic effects and longer half life [19]. These agonists may optimize protection offered to patients during heart surgery and maximize the benefit of the operation, leading to a superior outcome.

Both adenosine A1 and A3 receptors trigger preconditioning protection by endogenous adenosine [19]. Adenosine binds A1 receptor with a greater affinity than the adenosine A3 receptor in rabbit hearts (KiA1=28 nM; KiA3=532 nM). We and others have reported the infusion of the rat hearts with either CCPA or Cl-IB-MECA significantly limited infarct size, and attenuated postischemic cardiodynamic dysfunction and CK release [5, 19]. Mechanical recovery of the hearts with CCPA in both modes of treatment, was beneficial in the normal and hypertrophied hearts. No differences were found when the drugs were delivered immediately before ischemia or injected 24 h prior to the ischemic insult. Cl-IB-MECA was beneficial only when it was injected 24 h prior to ischemia. The use of CCPA showed improved results. The different effects of A1 and A3 could be due to the lower amount of membrane receptors and intracellular function. Overexpression of A1R led to cardiac protection, whereas A3 overexpression resulted in a gene dose-dependent AV block and pronounced sinus nodal dysfunction [20, 21].

We have previously shown that ADO agonist pretreatment incremented ATP levels in both isolated hearts and cardiac myocytes [5, 22]. Protection of the mitochondrial respiratory chain and its impact on mitochondrial bioenergetics after AR activation may be an important factor associated with increased resistance to hypoxia. As shown in our previous study, activation of both subtypes of ARs promotes preservation of adequate amounts of ATP and maintenance of mitochondrial metabolism at a level sufficient for cell survival [22]. In this study we further explored the role of these agonists and ATP regeneration and found that ATP levels were augmented both in the normal and the more vulnerable hypertrophied hearts. CCPA and Cl-IB-MECA were efficient in both modes of treatment.

p38 Mitogen-activated protein kinase (MAPK), also known as stress-activated protein kinase, is a family of isoenzymes activated in the myocardium by oxidative stress, including ischemia-reperfusion [7, 8]. The importance of p38 activation in cardioprotection is being debated. Some authors report that pharmacological inhibition of p38 MAPK blocks preconditioning [23, 24] and that anisomycin, a p38 MAPK activator, mimics the anti-infarct effect of ischemic preconditioning in isolated rabbit hearts [25]. Other studies suggest that p38 MAPK activation is deleterious, so that inhibition of p38 MAPK per se, is beneficial during sustained ischemia [11]. Explanations for the controversial findings might relate to the relative balance between different isoforms of p38 in different species and different experimental models and protocols. We are the first to report that activation of p38 due to pharmacological preconditioning with adenosine receptor activation was beneficial in both normal and hypertrophied hearts. Both early and late A1 and A3 activation in the normal hearts triggered p38 phosphorylation. In the hypertrophied hearts, p38 phosphorylation was observed in the non-treated heart, pre and post ischemia. This could be the result of the p38 involvement in the progress of hypertrophy because different p38 MAPK isoforms may promote hypertrophy, cell death or survival [15]. It seems that p38 MAPK phosphorylation was possibly synergistically augmented after AR activation in the hypertrophied hearts.

In conclusion, pharmacological interventions with ADO receptor agonists especially CCPA, administered prior to cardioplegic ischemia, offered significant protection. Hypertrophied hearts could benefit from AR agonist treatment more than the normal heart. By optimizing protection during ischemia and reperfusion, the heart may receive maximum benefit from this procedure, leading to substantially superior outcomes.


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

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