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Eur J Cardiothorac Surg 2006;30:96-102
© 2006 Elsevier Science NL

Effects of inosine on reperfusion injury after heart transplantation

Gábor Szabó a , * , Nicole Stumpf a , Tamás Radovits a , Karin Sonnenberg a , Domokos Gerö a , Siegfried Hagl a , Csaba Szabó b , Susanne Bährle c

a Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
b Department of Physiology and Experimental Clinical Research, Semmelweis University, Budapest, Hungary
c Department of Cardiology, University of Heidelberg, Heidelberg, Germany

Received 4 October 2005; received in revised form 12 March 2006; accepted 4 April 2006.

* Corresponding author. Tel.: +49 6221 566246; fax: +49 6221 565585. (Email: dzsi{at}hotmail.com).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: Inosine, a break-down product of adenosine, has been recently shown to exert inodilatory and anti-inflammatory properties. We investigated the effects of inosine on ischemia/reperfusion injury in a rat heart transplantation model. Methods: Intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of ischemic preservation, reperfusion was started after application of either saline vehicle (control, n = 12) or inosine (100 mg/kg, n = 12). Coronary blood flow, left ventricular function, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside, and high energy phosphate content were measured after 1 and 24 h of reperfusion. In addition, the activation of the poly(ADP-ribose) polymerase was detected by immunhistology. Results: After 1 h, coronary blood flow (4.1 ± 0.3 ml/(min g) vs 2.9 ± 0.3 ml/(min g), p < 0.05), left ventricular systolic pressure (102 ± 9 mmHg vs 83 ± 4 mmHg, p < 0.05) and dP/dt (2765 ± 609 mmHg/s vs 1740 ± 116 mmHg/s, p < 0.05) were significantly higher in the inosine group in comparison to control. Vasodilatatory response to sodium nitroprusside was similar in both groups. Acetylcholine resulted in a significantly higher increase in coronary blood flow in the inosine group (76 ± 5% vs 48 ± 9%, p < 0.05). Energy charge potential was significantly higher in the inosine group (1.69 ± 0.10 µmol/g vs 0.74 ± 0.27 µmol/g, p < 0.05). After 24 h, there was no difference between the groups in basal coronary blood flow, left ventricular systolic pressure, dP/dt, and the response to sodium nitroprusside. However, acetylcholine led to a still significantly higher response in the inosine group (112 ± 13% vs 88 ± 7%, p < 0.05). Immunhistologic stainings revealed activation of poly(ADP-ribose) polymerase in control animals which was abolished by inosine. Conclusions: Thus, inosine improves myocardial and endothelial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothelial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway.

Key Words: Transplantation • Reperfusion injury • Inosine • Endothelial function • Rat


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Ischemia–reperfusion injury is a common condition during cardiac surgery. Myocardial performance within the first hour after the surgical procedure determines the patient's state not only during the postoperative period but also in the long time outcome, especially after heart transplantation when an extended time of ischemia is followed by reperfusion. During ischemia, cellular ATP is degraded into AMP, adenosine inosine, and hypoxanthine. Adenosine and its primary metabolite inosine are ubiquitous nucleosides that can be released from ischemic or reperfused tissue [1]. Adenosine is generally considered to act primarily through cell surface adenosine receptors [2] modulating numerous physiological and pathophysiological events in multiple tissue [3,4]. Inosine was generally considered an inactive metabolite. However, some past and recent works suggested that inosine may exert inotropic, vasodilatoty and anti-inflammatory effects [5–7]. However, the exact mechanisms of the beneficial effects of inosine remain controversial.

Recently it has been discovered that purines in general and inosine in particular (but not adenosine) inhibit poly(ADP-ribose) polymerase (PARP) activation and modulate cell death [8]. PARP is an abundant nuclear enzyme of eukarotic cells that has been implicated in response to DNA injury and oxidant-induced cell death (see overview in Ref. [9]). We and others [10–12] previously showed that PARP-inhibition reduces ischemia–reperfusion injury.

In contrast to adenosine which mainly acts via surface purine receptors, inosine might have more direct effect on intracellular signaling. We hypothesized that inosine may also exert cytoprotective effects by interfering with the PARP activation pathway. This assumption is based on the structural similarity of inosine to part of NAD+, the substrate of PARP. The aim of the present study was to investigate the effects of inosine on ischemia/reperfusion injury and whether inosine influences the PARP pathway during ischemia/reperfusion.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1 Heterotopic heart transplantation
The experimental model was described elsewhere [10]. Briefly, donor hearts were explanted from Lewis rats. After 1 h of ischemic preservation at 4 °C, the hearts were implanted intraabdominally anastomosing the aorta and the pulmonary artery of the donor heart with the abdominal aorta or the vena cava of the recipient rat, respectively.

All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society of 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 No. 86-23, revised 1996).

2.2 Functional measurements in the graft
Left ventricular systolic (LVSP) and end-diastolic pressure (LVEDP), rate of pressure development (dP/dt), and relaxation time constant ({tau}) were measured by a Millar micromanometer (Millar Instruments Inc., Houston, TX, USA) at different LV volumes using an intraventricular balloon. Total coronary blood flow (CBF) was measured by a perivascular ultrasonic flow probe on the donor aorta. After baseline measurement, the endothelium-dependent vasodilator acetylcholine (ACH, 1 nM, 0.2 ml) and bradykinin (BK 0.1 nM, 0.2 ml) as well as the endothelium-independent vasodilator sodium-nitroprusside (SNP, 10 nM, 0.2 ml) were administered directly into the coronary arteries of the graft via the donor aorta. Between the infusions, CBF was allowed to return to baseline levels. Vasodilator response was expressed as maximum percent change of CBF from baseline.

2.3 Determination of high energy phosphates
Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) contents were assessed with standard photometry using an enzyme-kinetic assay [10]. Energy charge potential was calculated as (ATP + 0.5ADP)/(ATP + ADP + AMP).

2.4 Immunohistochemistry
Formalin-fixed cryostat-fixed sections were stained by primary mouse monoclonal anti-poly(ADP-ribose) antibody (Alexis, San Diego, CA, USA) to detect the product (poly(ADP-ribose)) of PARP activity [12,13]. Quantitative histomorphologic assessment was performed by the COLIM software package (Pictron Ltd., Budapest, Hungary) based on the intensity and distribution of labeling. The results were expressed with a grading system of 0 (no staining) to 4 (extensive staining) based on the measured intensity and area of positive labelings [10,12].

2.5 Experimental protocol
Four transplant groups were studied (n = 6 for each group). Immediately before releasing the aortic clamp, the slow injection of either saline (control group) or the inosine (100 mg/kg) was started and continued during the first 5 min of the reperfusion period. This dose was chosen based on in vitro and in vivo studies [8], previous efficacy data with the compound in various models of inflammation and vascular injury and pilot transplant experiments. In Group A (control) and Group B (inosine) the measurements of systolic and diastolic function and CBF were performed after 1 h of reperfusion. In Group C (control) and Group D (inosine) the abdominal cavity was closed and the animals were allowed to recover from the anesthesia. During the following 24 h, the animals of both groups received the same standard diet and normal drinking water. After 24 h the animals were reanesthetized and the abdominal cavity was reopened. The grafts were instrumented and the measurements were performed as in Groups A and B. After the functional measurements the hearts were excised for histologic analysis.

In a separate series of experiments, four groups (n = 6 for each group) of hearts were transplanted and treated with either inosine or saline vehicle similarly to the above mentioned protocol. After either 1 or 24 h of reperfusion, the grafts were excised to determine high energy phosphate contents.

2.6 Statistical analysis
All values were expressed as mean ± standard error of the mean (SEM). Individual means between the groups were compared by one-way analysis of variance followed by an unpaired t-test with a Bonferroni correction for multiple comparisons and the post hoc Scheffe's test. A value of p < 0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1 Early reperfusion (Groups A and B)
The hemodynamic parameters and CBF after 60 min of reperfusion are shown in Table 1 . The recipient's heart rate and aortic pressure were same in all groups. Systolic functional recovery was significantly better in the inosine group in comparison to control. LVSP and peak positive dP/dt were significantly (p < 0.05) higher in the inosine group. Systolic cardiac function curves showed a significant leftward shift in the inosine group in comparison to the vehicle-treated group (Fig. 1 ). Peak negative dP/dt was significantly higher (p < 0.05) and {tau} significantly lower (p < 0.05) in the inosine group indicating a better myocardial relaxation (Table 1, Fig. 2 ). LVEDP did not differ between the groups. The diastolic compliance curves (end-diastolic pressure–volume relationships) were similar in all groups (Fig. 2). CBF was significantly higher (p < 0.05) in the inosine group in comparison to control after 60 min (Table 1). Endothelium-independent vasodilatation after SNP (Fig. 2) was similar in both groups. In contrast, endothelium-dependent vasodilatation after ACH and BK was significantly (p < 0.05) better in the inosine group than in the vehicle-treated transplant group (Fig. 3 ).


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  		Table 1. Functional parameters
 

Figure 1
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  		Fig. 1. Left ventricular peak systolic pressure (LVSP)-volume (LVV) (left) and maximum pressure development (dP/dt max)-LVV (B, right) and left ventricular end-diastolic pressure (LVEDP)-LVV (C) relationships after 1 and 24 h of reperfusion. All values are given as mean ± SEM, * p < 0.05 versus other groups.

 

Figure 2
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  		Fig. 2. Myocardial relaxation ({tau}, left) and left ventricular end-diastolic pressure (LVEDP)-LVV (right) relationships after 1 and 24 h of reperfusion. All values are given as mean ± SEM, * p < 0.05 inosine versus control at a given time point, {dagger} p < 0.05, 24 h versus 60 min.

 

Figure 3
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  		Fig. 3. Vasodilator response after application of the endothelium-dependent vasodilator bradykinin (0.1 nM, left) and acetylcholine (1 nM, mid) and the endothelium independent vasodilator sodium nitroprusside (10 nM, right). All values are given as mean ± SEM. * p < 0.05 inosine versus control at a given time point, {dagger} p < 0.05, 24 h versus 60 min.

 
Myocardial high energy phosphate content especially ATP-content as well as energy charge potential were better preserved by inosine treatment during heart transplantation (Fig. 4 ).


Figure 4
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  		Fig. 4. Energy charge potential (left) and total adenylate pool (right). All values are given as mean ± SEM. * p < 0.05 inosine versus control at a given time point.

 
Histologic findings reveal a slight edema and in some cases a scare inflammatory perivascular infiltrate composed predominantly of polymorphonuclear neutrophils and lymphocytes in the transplanted heart which was more pronounced in the control group. Immunohistochemical staining showed increased immunoreactivity for poly(ADP-ribose) (PAR) – indicative of enhanced activation of PARP – in the vehicle-treated transplant group. PAR positive staining was observed in the nucleus of the myocytes and in some cases in the cytosol as an indicator of myocyte cell necrosis. Furthermore, endothelial cell nuclei also showed a strong PAR staining (Fig. 5 ). The staining for PAR was nearly absent in the inosine group (Fig. 5).


Figure 5
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  		Fig. 5. Immunohistological staining against poly(ADP-ribose), a marker of poly(ADP-ribose) polymerase activation after 1 h of reperfusion. Top panels: low magnification (160x) bottom panels: high magnification (400x). The control specimens (A, C) showed positive dark staining in the nuclei of the myocytes and in the capillary endothelium. The inosine group (B, D) showed completely negative staining.

 
3.2 Late reperfusion (Groups C and D)
After 24 h of reperfusion, there were no differences in LVSP, peak positive and negative dP/dt, {tau}, and LVEDP between the vehicle- and the inosine-treated transplant groups (Table 1). In the vehicle-treated transplant group, all these parameters showed a significant improvement in comparison to the values after 60 min of reperfusion (p < 0.05). In the inosine-treated transplant group, there were no significant differences in comparison to the values of 60 min of reperfusion. Systolic cardiac function curves and diastolic compliance curves of the control and the inosine group were nearly identical (Figs. 1 and 2). Baseline CBF was also similar in both groups. After 24 h, endothelium-dependent vasodilatation was significantly increased (p < 0.05) in both groups in comparison to the 60 min of reperfusion values. Endothelium-dependent vasodilatation after both ACH and BK was also significantly higher in the inosine group in comparison to vehicle-treated transplant group (Fig. 3).

After 24 h, total adenylate pool showed no significant differences between the groups; however, ATP content was still slightly higher in the inosine-treated animals without reaching the level of significance (Fig. 4).

Immunohistochemical staining showed almost no activation of PARP in both groups (not shown).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In this study, the benefits of the application of inosine during reperfusion were assessed after reversible hypothermic ischemia in a heterotopic rat heart transplantation model. Heterotopic heart transplantation was used to simulate the clinical conditions in terms of whole blood reperfusion and to allow an observation time of 24 h, which is impossible in isolated organ models. Furthermore, the heterotopic situation also allows to assess myocardial function independently from the actual loading conditions. We also demonstrated that cardiac preservation (global deep hypothermic ischemia) followed by reperfusion leads to a significant activation of PARP which was blocked by inosine.

The modulation of the ATP degradation pathway at different levels is an important strategy to reduce ischemia–reperfusion [14]. During the past years, beneficial effects of adenosine [14,15], adenosine analogues [16], adenosine uptake, and desaminase inhibitors [17] have been described. In contrast, the role of other purine nucleotides is poorly investigated. An increase of contractile force and coronary blood flow in response to inosine has been demonstrated as early as the late 70s [5]. Inosine was supposed to block the desensitizing action of cyclic AMP on the reaction between calcium ions and contractile proteins [18]. Furthermore, it was found that inosine infusion resulted in a nonmetabolically coupled coronary vasodilatation in dogs [19]. In subsequent studies, inosine exerted beneficial effects after hypoxia-reoxygenation [20] and ischemia/reperfusion [6] which is in concert with our data.

The mechanism of action of inosine is multiple and not completely understood. It has been shown previously that intermediate periods of ischemia induce a severe loss of cellular NAD+ and ATP levels. The loss of cellular energetic pools, in turn, importantly affects myocardial function [10]. We demonstrated that a major action of inosine is the preservation of myocardial of ATP contents during reperfusion. This is in accordance with a 31P magnetic resonance spectroscopic study in which significantly higher levels of ATP was detected after ischemia/reperfusion in crystalloid perfused isolated hearts after application of inosine [21].The increase of coronary blood flow during reperfusion contribute also to the improvement of cardiac function. Previous studies [6,21] demonstrated that inosine increase coronary flow dose dependently and, as a consequence, the function of the reperfused heart. These effects are also comparable with that of adenosine: Galinanes and Hearse [15] showed in a similar model of heterotopic transplantation that after 8 h of cardiac preservation and 1 h of reperfusion, that adenosine significantly improved coronary blood flow and myocardial function. Interestingly they did not found any difference in high energy phosphate contents which implicate that increased coronary blood flow is an independent factor of enhanced functional recovery.

Similar to our previous studies, endothelial function was severely impaired after 1 h of reperfusion and was sustained after 24 h. The present study is the first which demonstrates that inosine improves not only myocardial but also endothelial function. This effect is comparable to those with application of nitric oxide donors [22], endothelin receptor antagonists [23], or PARP-inhibitors [9,10,12]. How inosine protects the endothelium remains not completely understood. Previous data suggest that energy depletion severely impairs endothelial function [10]. As inosine restores ATP levels, this may contribute to improved endothelial function. If inosine has a direct effect on nitric oxide synthesis remains to be clarified.

Neutrophil–endothelial interaction is a central step during the development of reperfusion injury which leads to endothelial and subsequent myocardial injury. Novel studies implicate that purin nucleotides in general and inosine in particular may reduce neutrophil-mediated injury. In isolated cell cultures, inosine dose-dependently inhibited LPS-induced monocyte activation [24]. In a rodent model of endotoxin shock, inosine improved vascular function and reduced neutrophil accumulation in selected organs [13]. Recently, it has been shown that inosine-monophosphate, an intermediate metabolite of the AMP-inosine degredation pathway and inosine itself inhibits neutrophil rolling and trafficking into the reperfused tissue [25].

A very important new finding of the present study that inosine acts as an endogen PARP inhibitor. The immunhistologic examinations indicated extensive PARP activation in the vehicle-treated group, which is in accordance with our previous studies [9,10]. Inosine treatment almost completely abolished PARP activation. Recently we were able to demonstrate in vitro that inosine (and other purine nucleotides such as hypoxanthine) reduce cellular PARP activity in peroxynitrite-treated macrophages and improves mitochondrial respiration.

The activation of PARP is currently described to be a final common effector in various types of tissue injury including systemic inflammation, circulatory shock, and ischemia/reperfusion (see Section 1). Both genetic disruption and pharmacologic inhibition of the PARP pathway effectively protect against oxygen radical and nitric oxide toxicity in different cell cultures, attenuate regional myocardial ischemia/reperfusion and global hypoxia-reoxygenation injury [5,9]. The pathomechanisms of PARP inhibition are discussed in detail elsewhere [9]. Briefly, PARP-inhibitors exert their beneficial effects at multiple levels by preservation of cellular ATP, downregulation of adhesion molecules, improvement of mitochondrial respiration, and regulation of necrosis and apoptosis. The observed changes after inosine treatment are in concert with previous studies using PARP inhibitors in similar models of ischemia/reperfusion [10]. The current results are the first to demonstrate that an endogenous molecule (other than nicotinamide), namely inosine, inhibits PARP activation in vivo and therefore modulates oxidant-induced cell death [8]. We propose the hypothesis that inosine appears to work, at least in the currently used model systems, as nonprofessional, but reasonably potent inhibitor of PARP activation; it modulates cell death in a fashion that is entirely consistent with its PARP inhibitory effect. Nevertheless, further studies are necessary to elucidate the exact mode of action of inosine treatment.


   Acknowledgments
 
This work was supported by Forschungsschwerpunkt Transplantation of the University of Heidelberg to G.S. and, in part, by grants from the National Institutes of Health (HL59266 and GM 60915) to C.S.


   Footnotes
 
{star} Presented at the joint 19th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 13th Annual Meeting of the European Society of Thoracic Surgeons, Barcelona, Spain, September 25–28, 2005.


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

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  11. Zingarelli B, Cuzzocrea S, Zsengellér Zs, Salzman AL, Szabó C. Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly(ADP ribose) synthetase. Cardiovasc Res 1997;36:205-215.[Abstract/Free Full Text]
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