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

Anwar Saad Abd-Elfattah, Gert E. Tuchy, Michael E Jessen, David R. Salter, Jacques P. Goldstein, Louis A. Brunsting, Andrew S. Wechsler

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of Thoracic and Cardiovascular Surgery
Volume146
Issue number4
DOIs
StatePublished - Oct 2013

Fingerprint

Nucleoside Transport Proteins
Myocardial Stunning
Induced Heart Arrest
Purines
Nucleosides
Reperfusion
Pharmaceutical Preparations
Ventricular Dysfunction
Warm Ischemia
Coronary Sinus
Inosine
Adenosine Deaminase
Reperfusion Injury
Adenosine
Thoracic Surgery
9-(2-hydroxy-3-nonyl)adenine
4-nitrobenzylthioinosine
Canidae
Ischemia
Adenosine Triphosphate

Keywords

  • adenosine triphosphate
  • ATP
  • EHNA
  • equilibrative-p-nitrobenzylthioinosine-sensitive type of the equilibrative nucleoside transport 1
  • erythro-9-[2-hydroxy-3-nonyl]adenine
  • es-ENT1
  • high-performance liquid chromatography
  • HPLC
  • NBMPR
  • p-nitrobenzylthioinosine

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

@article{f36c9021ea8d40b49a1191d7960e6e6f,
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.",
keywords = "adenosine triphosphate, ATP, EHNA, equilibrative-p-nitrobenzylthioinosine-sensitive type of the equilibrative nucleoside transport 1, erythro-9-[2-hydroxy-3-nonyl]adenine, es-ENT1, high-performance liquid chromatography, HPLC, NBMPR, p-nitrobenzylthioinosine",
author = "Abd-Elfattah, {Anwar Saad} and Tuchy, {Gert E.} and Jessen, {Michael E} and Salter, {David R.} and Goldstein, {Jacques P.} and Brunsting, {Louis A.} and Wechsler, {Andrew S.}",
year = "2013",
month = "10",
doi = "10.1016/j.jtcvs.2012.10.054",
language = "English (US)",
volume = "146",
journal = "Journal of Thoracic and Cardiovascular Surgery",
issn = "0022-5223",
publisher = "Mosby Inc.",
number = "4",

}

TY - JOUR

T1 - 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

T2 - Hot shot drug delivery before hypothermic cardioplegia

AU - Abd-Elfattah, Anwar Saad

AU - Tuchy, Gert E.

AU - Jessen, Michael E

AU - Salter, David R.

AU - Goldstein, Jacques P.

AU - Brunsting, Louis A.

AU - Wechsler, Andrew S.

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - adenosine triphosphate

KW - ATP

KW - EHNA

KW - equilibrative-p-nitrobenzylthioinosine-sensitive type of the equilibrative nucleoside transport 1

KW - erythro-9-[2-hydroxy-3-nonyl]adenine

KW - es-ENT1

KW - high-performance liquid chromatography

KW - HPLC

KW - NBMPR

KW - p-nitrobenzylthioinosine

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U2 - 10.1016/j.jtcvs.2012.10.054

DO - 10.1016/j.jtcvs.2012.10.054

M3 - Article

VL - 146

JO - Journal of Thoracic and Cardiovascular Surgery

JF - Journal of Thoracic and Cardiovascular Surgery

SN - 0022-5223

IS - 4

ER -