title: Hot shot induction and reperfusion with a specific blocker of the es-ENT1 nucleoside transporter before and after hypothermic cardioplegia abolishes myocardial stunning in acutely ischemic hearts despite metabolic derangement: hot shot drug delivery before hypothermic cardioplegia.
abstract: 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 μM EHNA and 25 μM 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°C) cardioplegia releases purines until the heart becomes cold (<20°C). 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.
authors: Cardiovascular Research Laboratories, Division of Cardiothoracic Surgery, Department of Surgery, VCU Medical Center, Richmond, Va. Electronic address: anwar@vcu.edu.
authors: Anwar Saad
authors: AS
authors: Abd-Elfattah
authors: Gert E
authors: GE
authors: Tuchy
authors: Michael E
authors: ME
authors: Jessen
authors: David R
authors: DR
authors: Salter
authors: Jacques P
authors: JP
authors: Goldstein
authors: Louis A
authors: LA
authors: Brunsting
authors: Andrew S
authors: AS
authors: Wechsler
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D050377:Cold Ischemia; D004195:Disease Models, Animal; D004285:Dogs; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006324:Heart Arrest, Induced / Q000009:adverse effects; D007036:Hypothermia, Induced / Q000009:adverse effects; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D017682:Myocardial Stunning / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D020127:Recovery of Function; D013868:Thioinosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D052096:Warm Ischemia
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D013868:Thioinosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D000255:Adenosine Triphosphate; C001789:4-nitrobenzylthioinosine; D000225:Adenine
keywords: 16; 17; 18; 31; ATP; EHNA; HPLC; NBMPR; adenosine triphosphate; equilibrative-p-nitrobenzylthioinosine–sensitive type of the equilibrative nucleoside transport 1; erythro-9-[2-hydroxy-3-nonyl]adenine; es-ENT1; high-performance liquid chromatography; p-nitrobenzylthioinosine