- 作者：Anwar Saad Abd-Elfattah ; Gert E. Tuchy ; Michael E. Jessen ; David R. Salter ; Jacques P. Goldstein ; Louis A. Brunsting III ; Andrew S. Wechsler
- 关键词：ATP ; adenosine triphosphate ; EHNA ; erythro-9-[2-hydroxy-3-nonyl]adenine ; es-ENT1 ; equilibrative-p-nitrobenzylthioinosine&ndash ; sensitive type of the equilibrative nucleoside transport 1 ; HPLC ; high-performance liquid chromatography ; NBMPR ; p-nitrobenzylth
- 刊名：The Journal of Thoracic and Cardiovascular Surgery
- 出版年：2013
- 出版时间：October, 2013
- 年：2013
- 卷：146
- 期：4
- 页码：961-970.e3
- 全文大小：1066 K
Objective
Simultaneous inhibition of the cardiac equilibrative-p-nitrobenzylthioinosine (NBMPR)-sensitive (es) type of the equilibrative nucleoside transport 1 (ENT1) nucleoside transporter, with NBMPR, and adenosine deaminase, with erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA), prevents release of myocardial purines and attenuates myocardial stunning and fibrillation in canine models of warm ischemia and reperfusion. It is not known whether prolonged administration of hypothermic cardioplegia influences purine release and EHNA/NBMPR-mediated cardioprotection in acutely ischemic hearts.Methods
Anesthetized dogs (n?=?46), which underwent normothermic aortic crossclamping for 20 minutes on-pump, were divided to determine (1) purine release with induction of intermittent antegrade or continuous retrograde hypothermic cardioplegia and reperfusion, (2) the effects of postischemic treatment with 100 ¦ÌM EHNA and 25 ¦ÌM NBMPR on purine release and global functional recovery, and (3) whether a hot shot and reperfusion with EHNA/NBMPR inhibits purine release and attenuates ventricular dysfunction of ischemic hearts. Myocardial biopsies and coronary sinus effluents were obtained and analyzed using high-performance liquid chromatography.
Results
Warm ischemia depleted myocardial adenosine triphosphate and elevated purines (ie, inosine?>?adenosine) as markers of ischemia. Induction of intermittent antegrade or continuous retrograde hypothermic (4¡ãC) cardioplegia releases purines until the heart becomes cold (<20¡ãC). During reperfusion, the levels of hypoxanthine and xanthine (free radical substrates) were >90 % of purines in coronary sinus effluent. Reperfusion with EHNA/NBMPR abolished ventricular dysfunction in acutely ischemic hearts with and without a hot shot and hypothermic cardioplegic arrest.
Conclusions
Induction of hypothermic cardioplegia releases purines from ischemic hearts until they become cold, whereas reperfusion induces massive purine release and myocardial stunning. Inhibition of cardiac es-ENT1 nucleoside transporter abolishes postischemic reperfusion injury in warm and cold cardiac surgery.