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Ann Thorac Surg 2000;70:901-905
© 2000 The Society of Thoracic Surgeons

Original articles: cardiovascular

Myocardial protection using diadenosine tetraphosphate with pharmacological preconditioning

Ismayil Ahmet, MDa, Yoshiki Sawa, MDa, Motonobu Nishimura, MDa, Takahiro Yamaguchi, MDa, Masafumi Kitakaze, MDb, Hikaru Matsuda, MDa

a First Department of Surgery, Osaka University Medical School, Osaka, Japan
b First Department of Medicine, Osaka University Medical School, Osaka, Japan

Address reprint requests to: Dr Sawa, First Department of Surgery, Osaka University Medical School, Yamadaoka 2–2, Suita, Osaka 565, Japan
e-mail: ismayilt{at}surg1.med.osaka-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. We have reported a similar cardioprotective effect and mechanism of diadenosine tetraphosphate (AP4A) and ischemic preconditioning in rat hearts. In this study, the applicability of AP4A administration to cardiac surgery was tested by using a canine cardiopulmonary bypass model.

Methods. Hearts underwent 60 minutes of cardioplegic arrest (34°C) by a single dose of cardioplegia. Cardioplegia contained either AP4A (40 µmol/L; n = 6) or saline (n = 6). Beagles were weaned from cardiopulmonary bypass 30 minutes after reperfusion, and left ventricular function was evaluated after another 30 minutes by using the cardiac loop analysis system.

Results. Administration of AP4A significantly improved the postischemic recovery of cardiac function and reduced the leakage of serum creatine kinase compared with saline. Systemic vascular resistance, mean aortic blood pressure, and the electrocardiographic indices were not significantly altered by AP4A administration.

Conclusions. Administration of AP4A was cardioprotective without apparent adverse effects. Because the cardioprotective mechanism may be similar to that of ischemic preconditioning, the addition of AP4A into cardioplegia may be a novel safe method for clinical application of preconditioning cardioprotection.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Diadenosine tetraphosphate (AP4A) is a major representative of the diadenosine polyphosphates that are a novel class of high-energy endogenous nucleotides with recently discovered intracellular actions but yet unknown physiologic roles. Diadenosine tetraphosphate has been found at low concentrations in many living cells [1] and is known to increase significantly in circulating blood during stressful conditions [2]. Hilderman and coworkers [3] reported the presence of a specific membrane receptor for AP4A with the greatest density in cardiac tissue, which supports the notion that circulating AP4A is a modulator of myocardial function, presumably during stressful conditions such as ischemia. Recently, it was reported that preischemic administration of AP4A mimics the cardioprotective effect of ischemic preconditioning (PC) to limit the postischemic myocardial infarct size in canine hearts [4] and that the cardioprotective effect of AP4A was partly diminished by the blockade of either adenosine receptors or purine 2y receptors. We also found that administration of AP4A before ischemia, during ischemia, or during hypothermic heart storage effectively protected the myocardium against ischemia-reperfusion injury in isolated perfused rat hearts [5–7]. This protective effect seemed to occur by activating the protein kinase C (PKC) and the adenosine triphosphate–sensitive potassium channel (KATP channel), which are two of the main protective mechanisms of PC. That finding supported the application of AP4A as a novel pharmacologic preconditioning agent to cardiac surgery.

Administration of AP4A induced vasodilation in coronary arteries by activating the adenosine receptors, purine 2y receptors [2], and KATP channels [8]. Intravenous administration of AP4A also induced hypotension, which was reported in canine models [9]. Because AP4A is rapidly degraded into adenosine in whole blood (the half-life is about 2 to 6 minutes [10]), the adenosine production of AP4A might also induce hypotension and atrioventricular conduction block (AV block) by activating adenosine receptors. Therefore, hypotension and AV block might be the main adverse effect of AP4A.

In this study, we used an open-chest canine cardiopulmonary bypass (CPB) model to test the cardioprotective effect of AP4A cardioplegia by simulating clinical open heart procedures. We added AP4A to St. Thomas’ cardioplegic solution and studied the effect of AP4A cardioplegia on the recovery of postischemic left ventricular (LV) contractile properties and on the hemodynamic indices and cardiac conduction system.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Study design
Sixteen adult female beagles (9.6 ± 0.7 kg) were used in this study. The dogs were put on a total vented CPB, and the hearts underwent 60 minutes of cardioplegic arrest at 34°C with antegrade administration of St. Thomas’ cardioplegic solution with or without AP4A. The dogs were weaned from CPB 30 minutes after unclamping the aorta, and cardiac function was evaluated again after another 30 minutes. Four animals were used in dose-response studies of AP4A, and the others were divided into two groups, the AP4A group (n = 6), which received cardioplegia containing 40 µmol/L of AP4A, and the control group (n = 6), which received cardioplegia only.

Surgical procedures
All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication no. 86-23, revised 1985). Beagles were anesthetized with ketamine (8 mg/kg intramuscularly) and pentobarbital (30 mg/kg intravenously), then intubated and ventilated (Ventilator 710, Siemens-Elema AB, Solna, Sweden). Anesthesia was maintained with inhalation of sevoflurane (2% v/v). The right femoral artery and vein were cannulated for pressure monitoring of mean aortic blood pressure and central venous blood pressure. An electrocardiogram (ECG) was recorded continuously by a polygraph system (San-ei 361, NEC, Tokyo, Japan). After bilateral transverse thoracotomy was done through the fifth intercostal space, the pericardium was incised and tented. After systemic heparinazation, a 7F conductance catheter (Cordis Europe, Roden NA, The Netherlands) and a 5F micromanometer (MPC-500; Millar, Houston, TX) were inserted into the left ventricle (LV) through the apex to measure LV instantaneous pressures and volumes.

A perfusion cannula was placed in the left femoral artery, and a venous drainage cannula was inserted into the right atrium. A left arterial vent was inserted from the left arterial appendage. After preischemic LV function was measured, animals were placed on total vented CPB using a centrifugal blood pump (Bio-console 540; Medtronic, Eden Prairie, MN) and a membrane oxygenator (Minimax Plus CB3381; Medtronic). The CPB circuit was primed with 600 mL of Ringer’s lactate solution, and the blood temperature was kept at approximately 34°C. An intravenous infusion of Ringer’s lactate solution was given during CPB, if required. The arterial oxygen pressure (PO2) was maintained at a level of more then 300 mm Hg and carbon dioxide pressure (PCO2) was 30 to 45 mm Hg. Sodium bicarbonate was used to counteract acidemia, and pH was maintained between 7.38 and 7.42.

A catheter was inserted into the ascending aorta for delivery of cardioplegia, and an aortic clamp was applied 10 minutes after starting CPB. A 15 mL/kg dose of St. Thomas’ solution (110 mmol/L NaCl, 10 mmol/L NaHCO3, 1.2 mmol/L CaCl2, 16 mmol/L MgCl2, 16 mmol/L KCl, 1 mmol/L lidocaine) at 34°C was infused within 3 minutes at a pressure of 100 cm H2O to obtain cardioplegic arrest. A myocardial temperature probe (model 3529; Tsuruga Inc, Tokyo, Japan) was inserted into the interventricular septum to monitor myocardial ischemic temperature. After 60 minutes of ischemia, the aortic cross-clamp was removed and the hearts were reperfused. A direct electrical counter shock (5 J) was applied if necessary. The dogs were weaned from bypass at 30 minutes after reperfusion, and the postischemic LV function was evaluated after another 30 minutes.

Acquisition and analysis of cardiac function
To measure the LV systolic function (preload recruitable stroke work, PRSW; and the slope of end-systolic pressure-volume relationship, Emax) and diastolic function (the slope of end-diastolic pressure-volume relationship, Eed), a cardiac loop analysis computer system (Signal Processor-1000; NEC, Tokyo, Japan) was used. The LV volume data were acquired during a 15-second period of respiratory apnea by transiently occluding the inferior vena cava with a snare and calculated by a volumetric system (Sigma 5; Leycom, Oegstgeest, The Netherlands). The calculation of LV pressure-volume data was done as previously described [11]. The percentage recoveries of postischemic PRSW, Emax and Eed were calculated from preischemic values of each index.

Evaluation of hemodynamic indices
The central venous and mean aortic blood pressures and pump blood flow rate were monitored and recorded continuously. Systemic vascular resistance was calculated from those indices.

Diagnosis on electrocardiography
The measurements and diagnosis on ECG were taken from the standard electrocardiographic criteria. The heart rate was calculated from P-p duration. The time to electrical arrest was defined as the time to absence of ECG signals from the aortic cross-clamping. The reperfusion-induced arrhythmia (ventricular tachycardia and fibrillation) was determined during the reperfusion period. Ventricular tachycardia was defined as four or more consecutive ventricular premature beats and ventricular fibrillation as a signal in which individual QRS complexes could not be distinguished from one another. Analysis of atrioventricular conduction intervals and diagnosis of AV block were taken from the duration of p wave and PQ segment.

Measurements of blood creatine kinase leakage and AP4A and adenosine concentrations
Venous blood samples were drawn from the femoral vein for measurements of cardiac enzyme activity of creatine kinase (CK-MB). Arterial blood samples were drawn from the femoral artery for measurements of the serum concentration of AP4A and adenosine. The serum concentration of adenosine was assessed by using the radioimmunoassay method, which was first described by Ballard and associates [12]. The amount of AP4A was determined by the method of Ogilvie [13] using high performance liquid chromatography.

Statistical analysis
All values are expressed as mean ± standard deviation. For normally distributed data (mean aortic blood pressure, systemic vascular resistance, and blood adenosine concentration), comparisons were performed using one-way analysis of variance followed by the Bonferroni least significant difference test. Other data (cardiac functional indices, CK-MB content, and ECG indices) were compared by paired Student t test. A p value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Dose-response study
Cardioplegia containing 10, 20, 40, and 80 µmol/L of AP4A was used in four animals in the dose-response study. The postischemic percentage recovery of PRSW was 72%, 80%, 98%, and 98% at doses of 10, 20, 40, and 80 µmol/L AP4A, respectively. The best recovery was noted at 40 and 80 µmol/L. The recovery of Emax and Eed showed a result similar to that of PRSW. Therefore, the 40 µmol/L dose of AP4A was selected for the following studies.

Postischemic recovery of cardiac function
Table 1 shows the LV systolic and diastolic functions before and after ischemia. A good recovery of PRSW and Emax was observed in the AP4A group, with values statistically significantly better than in the control group. Postischemic values of Eed, a measurement of LV diastolic function, were also significantly better in the AP4A group than in the control group.


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  		Table 1. Left Ventricle Systolic and Diastolic Function

 
Effect of AP4A administration on hemodynamic and electrocardiographic indices
Mean aortic blood pressure was not significantly different between groups during CPB, but after weaning from CPB it was significantly higher in the AP4A group than in the control group (p = 0.019, 0.003, and 0.001 at 10, 20, and 30 minutes after cessation of CPB) (Fig 1). Systemic vascular resistance was not significantly different between two groups before, during, and after cardioplegia administration (Fig 2).



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  		Fig 1. Effect of diadenosine tetraphosphate (AP4A) cardioplegia on mean aortic blood pressure (MAP). The whiskers represent standard deviation. (* p < 0.05 versus control group; AoX = aortic cross-clamping; CPB = cardiopulmonary bypass.)

 


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  		Fig 2. Effect of diadenosine tetraphosphate (AP4A) cardioplegia on the systemic vascular resistance (SVR). The whiskers represent standard deviation. Abbreviations as in Figure 1. (* p < 0.05 versus control group).

 
The time to electrical arrest was not significantly different between groups (211 ± 117 seconds in the control group and 164 ± 68 seconds in the AP4A group). Reperfusion-induced arrhythmia (ventricular tachycardia or ventricular fibrillation) was observed in two of six hearts in both groups, and all these ventricular tachycardias and ventricular fibrillations were successfully converted into sinus rhythm by the direct current cardioversion. There was no detectable AV block on the ECG records during reperfusion in both groups. Heart rate was not significantly different between groups during reperfusion. No significant change in ST segment was observed in both groups (Table 2).


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  		Table 2. Electrocardiographic Diagnosisa

 
Creatine kinase leakage and blood adenosine and AP4A concentrations
The amount of serum CK-MB at the end of reperfusion was significantly lower in the AP4A group (1634 ± 345 IU/L; p = 0.019) than in the control group (2398 ± 403 IU/L). The blood adenosine concentration was significantly higher during cardioplegia administration in the AP4A group and rapidly returned to the preadministration level at 10 minutes after cessation of cardioplegia administration. The maximum level of blood adenosine concentration in the AP4A group was 69.5 ± 10.5 nmol/L (Fig 3). Throughout the experiment, AP4A was not detected in arterial blood samples in either group.



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  		Fig 3. Blood adenosine concentration during and after cardioplegia administration. The whiskers represent standard deviation. (* p < 0.05 versus control group)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
The results of this study showed that addition of AP4A into crystalloid cardioplegic solution remarkably enhanced the postischemic recovery of cardiac function and reduced the cardiac enzyme leakage in canine hearts. According to ECG and hemodynamic indices, AP4A cardioplegia had minimal effects on cardiac rhythm and systemic vascular resistance.

Although the intracellular or extracellular physiologic roles of AP4A are still unknown, AP4A exists physiologically in a variety of living cells [1]. Finding the intracellular emergency actions of AP4A under stressful conditions improved the possibility that AP4A might participate in the cellular self-defense actions, such as PC, during stressful conditions [14–17]. Subsequent studies have confirmed the cardioprotective effect of AP4A administration in postischemic myocardial infarction in canine hearts [4] and in postischemic contractile dysfunction in rat hearts [5–7]. This effect of AP4A administration is similar to that of PC with regard to the magnitude of protection and the role of KATP channel and PKC in rat hearts [5]. Addition of AP4A into hyperkalemic cardioplegia mimics the effect of PC by opening the KATP channels in rat hearts [6]. Although the cardioprotective mechanism of AP4A and its relation to PC are not fully understood yet, the results of our experiment showed that the addition of AP4A into cardioplegia prevented ischemia-reperfusion injury as effectively as preischemic administration of AP4A. Despite species differences, it could be speculated that the protective effect of AP4A cardioplegia might be regulated by KATP channel and PKC in canine hearts as well as in rat hearts. Thereby, AP4A cardioplegia could mimic the effect of PC in canine hearts.

Considering that the KATP channel and PKC mimicked the possible protective mechanism of AP4A, preischemic administration of AP4A might be the best way to mimic the effect of PC. However, from the clinical standpoint, it is still worrisome that intravenous administration of AP4A induced hypotension (and AV block), which limits widespread use of this agent. This shortcoming of AP4A is common to adenosine [18, 19] and most previously developed cardioprotective agents [20, 21]. In our previous studies, we tested the effect of preischemic administration of AP4A by using the same canine CPB model. Intravenous administration of AP4A (10–80 µg · kg-1 · min-1 for 10 minutes) resulted in marked decrease in mean aortic blood pressure (approximate change of 10% to 40%). Although preischemic administration of AP4A (80 µg · kg-1 · min-1) significantly improved postischemic recovery of cardiac indices, and its effect on aortic blood pressure abated within 5 minutes after cessation of AP4A administration (unpublished data), preischemic administration is still considered problematic for clinical use. In contrast, addition of the AP4A into cardioplegia effectively protected the myocardium, decreased the amount of drug needed, prolonged the reaction time, and had fewer effects on other organs. Therefore, the addition of the AP4A into cardioplegia may be a simple, effective, and safe method for clinical application.

Compared with intravenous administration of AP4A, the addition of AP4A into cardioplegia had a milder effect on hemodynamic indices and cardiac rhythm. AP4A cardioplegia did not reduce arterial blood pressure throughout the experiment. Also, there was no detectable AV block or other abnormality in ECG records when AP4A cardioplegia was used. The possible reason for this minimum adverse effect of AP4A is that AP4A might be metabolized rapidly within the myocardial circulates. For this reason, AP4A had its effect mostly on the heart and not on the whole body. In fact, AP4A was not detected in arterial blood, and the blood adenosine content in the AP4A group was 69.5 nmol/L at most. It was much lower than 25 µmol/L, the maximum blood adenosine level reported by Fremes and colleagues [22] that had no adverse effects on hemodynamic indices and the cardiac conduction system. Considered the optimal dose of adenosine for adenosine cardioplegia (range, 200 µmol/L to 2 mmol/L [23–25]), the cardioprotective effect of AP4A cardioplegia might be independent of its own adenosine production in our experiments.

Addition of AP4A into crystalloid cardioplegia had a remarkable cardioprotective effect without any adverse effects on ECG and hemodynamic indices. Because of several experimental limitations, there was no critical study of the cardioprotective mechanism of AP4A in this model. However, we speculate that the mechanism may be similar to that of PC. Thus, AP4A cardioplegia could be a novel and safe method for myocardial protection instead of PC in cardiac operations.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Garrison P.N., Barnes L.D. Determination of dinucleoside polyphosphates. In: Mclennan A.G., ed. Ap4A and other dinucleoside polyphosphates. Boca Raton, Florida: CRC Press, 1992:42-50.
  2. Kitakaze M., Sekine A., Yamaura T., Nakajima H., Hori M. A novel endogenous vasoactive substance, diadenosine tetraphosphate (AP4A), produced in the ischemic heart as a new vasodilatory mediator. Circulation 1995;92:I238.
  3. Hilderman R.H., Martin M., Zimmerman J.K., Pivorun E.P. Identification of a unique membrane receptor for adenosine 5',5''', P1, P4-tetraphosphate. J Biol Chem 1991;266:6915-6918.[Abstract/Free Full Text]
  4. Node K., Funaya H., Sekine A., Yamamura T. A novel endogenous adenine nucleotide, diadenosine tetraphosphate (AP4A), mediates cardioprotection against ischemia and reperfusion injury in the canine heart. Circulation 1995;92:I524.
  5. Ahmet I., Sawa Y., Nishimura M., Ichikawa H., Matsuda H. Diadenosine tetraphosphate (AP4A) mimics cardioprotective effect of ischemic preconditioning in the rat heart. Basic Res Cardiol 2000;95:235-242.[Medline]
  6. Ahmet I, Sawa Y, Nishimura M, Matsuda H. Cardioprotective effect of diadenosine tetraphosphate (AP4A) cardioplegia in isolated rat hearts. Heart Vessels 2000; in press.
  7. Ahmet I., Sawa Y., Nishimura M., Matsuda H. Cardioprotective effect of diadenosine tetraphosphate (AP4A) preservation in hypothermic storage and its relation with mitochondrial ATP-sensitive potassium channels. Transplantation 2000;69:16-20.[Medline]
  8. Nakae I., Takahashi M., Takaoka A., et al. Coronary effects of diadenosine tetraphosphate resemble those of adenosine in anesthetized pigs. J Cardiovasc Pharmacol 1996;28:124-130.[Medline]
  9. Kikuta Y., Sekine A., Tezuka S., Okada K., Yamaura T., Nakajima H. Intravenous diadenosine tetraphosphate in dogs. Acta Anaesthesiol Scand 1994;38:284-288.[Medline]
  10. Luthje J., Ogilvie A. Catabolism of Ap4A and Ap3A in whole blood. Eur J Biochem 1988;173:241-245.[Medline]
  11. Ahmet I., Fukushima N., Sawa Y., et al. The effects of a new ultra-short-acting beta–adrenergic blocker, ONO-1101, on cardiac function during and after cardiopulmonary bypass. Surg Today 1999;29:248-254.[Medline]
  12. Ballard K.D., Eller T.D., Webb J.G., Newman W.H., Knapp D.R., Knapp R.G. Quantitative analysis of adenosine. Biomed Environ Mass Spectrom 1986;13:667-673.[Medline]
  13. Ogilvie A. Determination of diadenosine tetraphosphate (Ap4A) levels in subpicomole quantities by a phosphodiesterase luciferin–luciferase coupled assay. Anal Biochem 1981;115:302-307.[Medline]
  14. Lee P.C., Bochner B.R., Ames B.N. AppppA, heat shock stress, and cell oxidation. Proc Natl Acad Sci U S A 1983;80:7496-7500.[Abstract/Free Full Text]
  15. Varshavsky A. Diadenosine 5', 5'''-P1, P4-tetraphosphate. Cell 1983;34:711-712.[Medline]
  16. Rapaport E., Zamecnik P.C. Presence of diadenosine 5',5''' -P1, P4-tetraphosphate (Ap4A) in mammalian cells in levels varying widely with proliferative activity of the tissue. Proc Natl Acad Sci U SA 1976;73:3984-3988.[Abstract/Free Full Text]
  17. Vogel P.D., Cross R.L. Adenine nucleotide-binding sites on mitochondrial F1-ATPase. J Biol Chem 1991;266:6101-6105.[Abstract/Free Full Text]
  18. Cohen G., Feder-Elituv R., Iazetta J., et al. Phase 2 studies of adenosine cardioplegia. Circulation 1998;98:II225-II233.
  19. Cohen M.V., Thornton J.D., Thornton C.S., Sato H., Miki T., Downey J.M. Intravenous co-infusion of adenosine and norepinephrine preconditions the heart without adverse hemodynamic effects. J Thorac Cardiovasc Surg 1997;114:236-242.[Abstract/Free Full Text]
  20. Yamashita T., Masuda Y., Kawamura N., Fujikura N., Tanaka S. Comparative study of vasodilator effects of the potassium channel openers NIP-121 and levcromakalim in dogs and rats. Jpn J Pharmacol 1995;68:145-152.[Medline]
  21. Lawton J.S., Sepic J.D., Allen C.T., Hsia P.W., Damiano R.J., Jr Myocardial protection with potassium-channel openers is as effective as St. Thomas’ solution in the rabbit heart. Ann Thorac Surg 1996;62:31-38.[Abstract/Free Full Text]
  22. Fremes S.E., Levy S.L., Christakis G.T., et al. Phase 1 human trial of adenosine-potassium cardioplegia. Circulation 1996;94:II370-II375.
  23. O S.J., Zellner J.L., Cox M.H., et al. Contributory mechanisms for the beneficial effects of myocyte preconditioning during cardioplegic arrest. Circulation 1996;94:II389-II397.
  24. Van der Lee C., Huizer T., Janssen M., et al. Adenosine, added to St. Thomas’ Hospital cardioplegic solution, improves functional recovery and reduces irreversible myocardial damage. Cardioscience 1994;5:269-275.[Medline]
  25. Mentzer R.M., Jr, Rahko P.S., Molina-Viamonte V., et al. Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery. Am J Cardiol 1997;79:38-43.[Medline]
Accepted for publication April 1, 2000.




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