HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): S Fehmi Katirciolu Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ulus, A T. Articles by Katirciolu, S F. Search for Related Content PubMed Articles by Ulus, A T. Articles by Katirciolu, S F.

Beneficial Effects of Aminophylline on Ischemia-Reperfusion in Isolated Rabbit Heart

A Tulga Ulus, MD, Perran Gökçe, PhD^,1, Eser Özgencil, PhD^,1, Ülkü Yildiz, MD, Erdogan Ibriim, MD^,2, S Fehmi Katirciolu, MD

Department of Cardiovascular Surgery Türkiye Yüksek htisas Hospital Ankara, Turkey 1 The Veterinary Faculty University of Ankara Ankara, Turkey 2 Department of Cardiovascular Surgery Süleyman Demirel University Isparta, Turkey

For reprint information contact: A Tulga Ulus, MD Tel: 90 312 310 3080 Fax: 90 312 229 5868 email: ulus{at}escortnet.com Nigde sok Ulus ap. 20/6, Dikmen, Ankara 06460, Turkey.

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Eighteen rabbit hearts were arrested for 3 hours with cardioplegic solution at 4°C, followed by reperfusion with oxygenated perfusion solution at 37°C for 2 hours. Six control hearts received no drug during arrest or reperfusion (group 1). Six hearts received 3 mg•L^–1 aminophylline during the arrest period (group 2). Six hearts received 3 mg•L^–1 aminophylline during the reperfusion period (group 3). Effects of aminophylline were evaluated in terms of the pressure-volume relationship, coronary flow, myocardial oxygen extraction, and lactate release before cardioplegic arrest and after 1 and 2 hours of reperfusion. End-diastolic pressure at constant volume after 2 hours of reperfusion was 19 ± 2.63 mm Hg in group 1, 14 ± 1.7 mm Hg in group 2, and 19 ± 2.55 mm Hg in group 3 (p < 0.05 for group 2 versus groups 1 and 3). End-systolic pressure at constant volume after 2 hours of reperfusion was 81 ± 3.55 mm Hg in group 1, 90 ± 2.95 mm Hg in group 2, and 84 ± 3.47 mm Hg in group 3 (p < 0.05 for group 2 versus groups 1 and 3). Oxygen extraction was significantly higher and release of lactate was significantly lower in group 2 compared to groups 1 and 3. The results indicate that aminophylline administration during cardioplegic arrest improved systolic and diastolic function and had a beneficial effect on metabolic recovery.

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Hypothermia and cardioplegic solutions limit myocardial damage during periods of ischemia in cardiac operations. However, recovery of the myocardium after hypothermic cardioplegic arrest requires further improvement and greater cost effectiveness. Approaches to modifying cardioplegic solutions are based on reversal of metabolic dysfunction and inhibition of the toxic effects of metabolites during reperfusion, which play a role in augmenting ischemic cell damage. Various agents have been used to overcome these problems.^1–3 Most of the additives are effective in eliminating oxygen free radicals and contribute to the resumption of cardiac metabolic activity.

Reduced enzymatic activity due to hypothermic cardioplegic arrest may impair intracellular calcium transport during reperfusion. Calcium loading of myocardial cells leads to a reduction in contractile activity. An increase in intracellular cyclic adenosine mono-phosphate may reverse the deterioration of contractile activity and intracellular enzymatic activity. For this reason, we postulated that phosphodiesterase inhibitors might ameliorate the adverse effects on the myocardium of cardioplegic arrest.⁴ In this study, we evaluated the effects of aminophylline during cardioplegic arrest and reperfusion on myocardial hemodynamics and metabolism.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The isolated rabbit heart model was used in this study. Hearts were obtained from 18 healthy white New Zealand rabbits weighing approximately 1 kg. Animal care was provided by veterinary staff. Xylazine and ketamine were used for sedation and anesthesia as described previously.⁵ Heparin (100 U) was used for anticoagulation. After achieving anesthesia, the hearts were excised rapidly via a parasternal incision and placed on a Langendorff perfusion system. Retrograde aortic perfusion with an oxygenated solution was established at a pressure of 75 mm Hg and the perfusate was not recirculated. A saline-filled latex balloon connected by a catheter to a Statham pressure transducer was inserted into the left ventricle via the left atrium. The temperature of the perfusion fluid was maintained at 37°C. After a 30-minute stabilization period, the hearts were arrested by infusing 30 mL cardioplegic solution at a pressure of 75 mm Hg and a temperature of 4°C. The hearts were removed from the rig and placed in a container of Ringer's lactate solution at 4°C. After 3 hours, the hearts were reperfused with oxygenated perfusion fluid at 37°C for a period of 2 hours.

The perfusion fluid was oxygenated with 95% O₂ and 5% CO₂ and contained 118 mmol•L^–1 NaCl, 5.4 mmol•L^–1 KCl, 1.2 mmol•L^–1 MgCl₂, 25 mmol•L^–1 NaHCO₃, 2.4 mmol•L^–1 CaCl₂, 1 mmol•L^–1 KH₂PO₄, and 10 mmol•L^–1 glucose. The components of the cardioplegic solution were 92 mmol•L^–1 NaCl, 15 mmol•L^–1 KCl, 15 mmol•L^–1 MgCl₂, 25 mmol•L^–1 NaHCO₃, 1 mmol•L^–1 KH₂PO₄, 1.2 mmol•L^–1 CaCl₂. The pH of both solutions was 7.6 and the mean oxygen tension was 145 mm Hg.

Six hearts (group 1) served as controls and did not receive aminophylline at any stage. The 6 hearts in group 2 received 3 mg•L^–1 aminophylline in the cardioplegic solution. A further 6 hearts (group 3) were treated with 3 mg•L^–1 aminophylline added to the reperfusion fluid. Coronary flow, myocardial oxygen extraction, lactate release, end-diastolic pressure, and end-systolic pressure were measured at the end of the first and second hours of reperfusion. Coronary flow was determined by collecting the perfusate from the venous system in a measuring tube over a period of one minute. Oxygen saturation in the solutions was measured with an OSM 2 Hemoxymeter (Radiometer, Copenhagen, Denmark). Myocardial O₂ extraction was calculated as the difference between the O₂ saturation of the perfusion fluid in the aortic cannula and the O₂ saturation in the perfusate from the venous system, as a percentage of the aortic O₂ saturation. The sample for lactate analysis was placed immediately in perchloric acid and stored for spectro-photometric determination on the same day.⁶ Samples for biochemical analysis were obtained when the intraventricular balloon volume was adjusted to 0.5 mL because at this volume, myocardial metabolism was found to be maximal (maximal pressure/volume ratio). Two sequential measurements of left ventricular end-systolic and end-diastolic pressures were measured as the balloon volume was increased in 0.1 mL increments from 0.1 mL to 0.5 mL.

Analysis of variance was used to compare the changes in left ventricular end-systolic and end-diastolic pressures at various volume loadings. The groups were compared on the basis of volume-pressure and metabolic data by two-way analysis of variance. The Mann-Whitney U test was used to compare the groups in terms of end-diastolic pressure and end-systolic pressure. A p value of less than 0.05 was considered statistically significant. Results were expressed as mean ± standard deviation.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
After cardioplegic arrest and reperfusion, the hearts in all groups showed some degree of deterioration. In group 1, coronary blood flow did not show any significant change but end-diastolic pressure was elevated and end-systolic pressure was depressed after 1 and 2 hours of reperfusion, myocardial lactate release was significantly raised after the second hour of reperfusion (Tables 1 and 2). In group 2, coronary blood flow did not change. End-diastolic pressure in this group was lower than the other groups at most volume settings (Tables 1 and 2) and peak end-systolic pressures were achieved with lower end-diastolic pressures than in the other groups. Myocardial oxygen extraction was significantly higher in group 2 compared to the other groups and lactate release was significantly lower. In group 3, the presence of aminophylline during 2 hours of reperfusion did not significantly change the pressure and metabolic characteristics compared to group 1 (Tables 1 and 2). The hearts in group 2 that received aminophylline during arrest showed better performance compared with the other groups. Thus, at a left ventricular volume of 0.5 mL, left ventricular end-systolic pressure was 81 ± 3.55 mm Hg in group 1, 90 ± 2.95 mm Hg in group 2, and 84 ± 2.47 mm Hg in group 3 after reperfusion for 2 hours (p < 0.05 for group 2 versus groups 1 and 3).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

Isolated heart studies have demonstrated that cardioplegic arrest is associated with decreased left ventricular compliance. The extent of shortening and the velocity of lengthening is impaired after hypothermic cardioplegic arrest followed by rewarming.¹¹ The shortening depends on the rate of cross-bridge formation and calcium release by the sarcoplasmic reticulum. The velocity of lengthening is determined by an adenosine triphosphate-dependent processes. Myocyte beta-adrenergic responsiveness is also blunted after hyperkalemic arrest. Activation of the beta-adrenergic system through binding of beta agonists to receptors stimulates cyclic adenosine monophosphate (cAMP) production with a subsequent increase in intracellular calcium concentration during myocyte depolarization.^10–13 In the light of these findings, it could be expected that treatment of left ventricular dysfunction after elective cardiac arrest with beta-adrenergic agonists in the acute postoperative period, may not be effective. We speculated that after cardioplegic arrest, cAMP-dependent enzymes may not function very effectively and there may be a reduction of cAMP below the level required to activate the enzymes responsible for intra-cellular calcium transport.

The findings in this study suggest that the presence of aminophylline during the anoxic arrest period reduced the deterioration of myocardial metabolism. In previous studies, it was shown that aminophylline and prostacyclin protected the heart from protamine cardiotoxicity by elevating the cAMP level.^14,15 The most marked effects of aminophylline were observed during the early reperfusion period in terms of volume-pressure relationship and myocardial metabolism. In group 2 under maximal volume loading conditions, there was better contractile activity, increased oxidative activity, and less lactate release compared with the other groups, indicating reduced injury. If a heart is metabolically stable, the expected response to volume loading is an increase in oxidative metabolism with more oxygen extraction and less lactate release.

Aminophylline has also been shown to increase blood flow in the more vulnerable subendocardium during ischemia.¹⁶ In addition to this alteration in the flow pattern by aminophylline, it has other beneficial effects such as reduction of calcium influx and phosphodiesterase inhibition.^17–20 The benefit of aminophylline in the cardioplegic solution in terms of the pressure-volume relationship and myocardial metabolism found in this study may have been related to increased subendocardial flow and improved calcium metabolism. It must be kept in mind that the volume-pressure data observed in this study might have been influenced by various experimental factors such as intracellular or extracellular edema. However, this experimental model is useful in determining factors relevant to the protection of the heart during storage prior to transplantation. Our data support the suggestion that phosphodiesterase inhibition during anoxic cardiac arrest improves post-cardioplegic recovery. Further studies on intact animal models are warranted to investigate the potential usefulness of adding aminophylline to the cardioplegic solution during cardiac surgery.

	References

TOP Abstract Introduction Materials and Methods Results Discussion References

 

1. Ferreira R, Burgos M, Milei J, Llesuy S. Effects of supplementing cardioplegic solution with deferoxamine on reperfused human myocardium. J Thorac Cardiovasc Surg 1990;100:708–14.[Abstract]

2. Geffin GA, Reynolds TR, Titus JS, O'Keefe DD, Daggett WM. Relation of myocardial protection to cardioplegic solution pH: modulation by calcium and magnesium. Ann Thorac Surg 1991;52:955–64.[Abstract]

3. Rosenhranz ER, Okamoto F, Buckberg GD, Robertson JN. Safety of prolonged aortic cross-clamping with blood cardioplegia. J Thorac Cardiovasc Surg 1986;91:428–53.[Abstract]

4. Caldarone CA, Krukenkamp IB, Burns PG, Misare BD, Gaudette GR, Levitsky S. Ischemia-dependent efficacy of phosphodiesterase inhibition. Ann Thorac Surg 1994; 57:540–5.[Abstract]

5. Katirciog lu SF, Küçükaksu DS, Küplülü S, Vuran R, Bayazit M, Tademir O, et al. Effects of prostacyclin on spinal cord ischemia. An experimental study. Surgery 1992;25:13–7.

6. Henry RJ. Clinical chemistry. Principles and techniques. New York: Academic Press, 1968:664–8.

7. Handy JR, Spinale FG, Mukherjee R, Crawford FA. Hypothermic potassium cardioplegia impairs myocytes recovery of contractility and inotropy. J Thorac Cardiovasc Surg 1994;107:1050–8.[Abstract/Free Full Text]

8. Roberts AJ, Spies SM, Sanders JH. Serial assessment of left ventricular performance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 1981;81:69–84.[Abstract]

9. Weng ZC, Nicolosi AC, Detwiler PW. Effects of crystalloid, blood, and University of Wisconsin perfusates on weight, water content, and left ventricular compliance in edema-prone isolated porcine heart model. J Thorac Cardiovasc Surg 1992;103:504–13.[Abstract]

10. Rosenblum HM, Haasler GB, Spotnitz WD, Lazar HL, Spotnitz HM. Effects of simulated clinical cardiopulmonary bypass and cardioplegia on mass of the canine left ventricle. Ann Thorac Surg 1985;39:139–48.[Abstract]

11. Tsutsiu H, Urabe Y, Mann DL. Effects of chronic mitral regurgitation on diastolic function in isolated cardiocytes. Circ Res 1993;72:1110–23.[Abstract/Free Full Text]

12. White HD, Antman EM, Glynn MA. Efficacy and safety of timolol for prevention of supraventricular tachy-arrhythmias after coronary artery bypass surgery. Circulation 1984;70:479–84.[Abstract/Free Full Text]

13. Creswell LL, Schuessler RB, Rosenbloom M, Cox LL. Hazards of postoperative atrial arrhythmias. Ann Thorac Surg 1993;56:539–49.[Abstract]

14. Katirciog lu SF, Küçükaksu DS, Dalva C, Mavita B, Zorlutuna Y, Tademir O, et al. Beneficial effects of aminophylline administration on heparin reversal with protamine. Jpn J Surg 1994;24:99–102.

15. Katirciog lu SF, Küçükaksu DS, Bozdayi M, Saydam G, Zolutuna Y, Tademir O, et al. Effects of prostacyclin on heparin reversal with protamine. Vasc Surg 1992;8:464–72.

16. Crea F, Gaspardone A, Araujo L, Silva RD, Kaski JC, Davies G, et al. Effects of aminophylline on cardiac function and regional myocardial perfusion: implications regarding its anti-ischemic action. Am Heart J 1994;127:817–24.[Medline]

17. Burnstock G. Vascular control by purines with emphasis on the coronary system. Eur Heart J 1989;10:15–21.

18. Kalsner S, Few RD, Smith GM. Mechanism of methylxanthine sensitization of norepinephrine responses in a coronary artery. Am J Physiol 1975;228:1702–7.

19. Kalsner S. Mechanism of potentiation of contractor responses to catecholamines by methylxanthines in aortic strips. Br J Pharmacol 1971;43:379–88.[Medline]

20. Rutherford JD, Vatner SF, Braundwald E. Effects and mechanism of action of aminophylline on cardiac function and regional blood flow distribution in conscious dogs. Circulation 1981;63:37

This article has been cited by other articles:

				W.-J. Luo, J.-F. Qian, and H.-H. Jiang Pretreatment with aminophylline reduces release of Troponin I and neutrophil activation in the myocardium of patients undergoing cardioplegic arrest Eur. J. Cardiothorac. Surg., March 1, 2007; 31(3): 360 - 365. [Abstract] [Full Text] [PDF]

				S. Kaplan, K. Ozisik, J. A. Morgan, and R. Dogan Measurement of Troponin T and I to detect cardioprotective effect of aminophylline during coronary artery bypass grafting Interactive CardioVascular and Thoracic Surgery, September 1, 2003; 2(3): 310 - 315. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): S Fehmi Katirciolu Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ulus, A T. Articles by Katirciolu, S F. Search for Related Content PubMed Articles by Ulus, A T. Articles by Katirciolu, S F.