On-pump inhibition of es-ENT1 nucleoside transporter and adenosine deaminase during aortic crossclamping entraps intracellular adenosine and protects.

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On-pump inhibition of es-ENT1 nucleoside transporter and adenosine deaminase during aortic crossclamping entraps intracellular adenosine and protects against reperfusion injury: Role of adenosine A1 receptor Anwar Saad Abd-Elfattah, MS, PhD, FAHA, AFSTS, Mai Ding, MD, Michael E. Jessen, MD, FACS, FSTS, FAHA, Andrew S. Wechsler, MD, FSTS, FACS The Journal of Thoracic and Cardiovascular Surgery Volume 144, Issue 1, Pages 243-249.e1 (July 2012) DOI: 10.1016/j.jtcvs.2011.09.073 Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Effect of 8-(p-sulfophenyl)theophyline (SPT) and 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) on myocardial adenosine triphosphate (ATP) levels. ATP was measured in myocardial biopsies before and after saline (control) or drug administration and at the end of ischemia and during reperfusion. No significant differences between groups were seen with respect to the time of sampling (analysis of variance, F = 0.04). ∗Statistically significant versus baseline. E/N, ENHA/NBMPR; ENHA, erythro-9 (2-hydroxy-3-nonyl)-adenine; NBMPR, p-nitro-benzylthioinosine. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 243-249.e1DOI: (10.1016/j.jtcvs.2011.09.073) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Effect of 8-(p-sulfophenyl)theophyline (SPT) and 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) on myocardial adenine nucleoside levels. Adenine nucleosides, A, adenosine and B, inosine, were measured in myocardial biopsies before and after saline (control) or drug administration and at the end of ischemia and during reperfusion. Statistically significant differences were found between groups with respect to the time of sampling (P < .001, analysis of variance, F = 11.8 and F = 8.8). ∗Statistically significant versus baseline. E/N, ENHA/NBMPR; ENHA, erythro-9 (2-hydroxy-3-nonyl)-adenine; NBMPR, p-nitro-benzylthioinosine. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 243-249.e1DOI: (10.1016/j.jtcvs.2011.09.073) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Effect of 8-(p-sulfophenyl)theophyline (SPT) and 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) on left ventricular (LV) performance. A, Plot showing the slope of the relationship between the stroke work/end-diastolic dimensions of the left ventricle at each point, except during ischemic arrest. Statistically significant differences seen between groups with respect to the time of sampling (P < .05, analysis of variance, F = 4.18). ∗Statistically significant versus baseline. B, Effect of SPT and DPCPX on the differences between recovery of LV performance. The differences between the percentage of recovery were identical in series A and B, suggesting that the contribution of extracellular adenosine is identical. E/N, ENHA/NBMPR; ENHA, erythro-9 (2-hydroxy-3-nonyl)-adenine; NBMPR, p-nitro-benzylthioinosine. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 243-249.e1DOI: (10.1016/j.jtcvs.2011.09.073) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure E1 Adenosine triphosphate (ATP) and purine metabolism during ischemia and reperfusion. Massive ATP depletion occurs at the onset of myocardial ischemia. The es-NT1 nucleoside transporter allows the release of both adenosine and inosine on reperfusion more effectively than during ischemia. On reperfusion, nucleosides are released and converted to hypoxanthine and xanthine, both substrates of xanthine oxidase and free radical production3 and oxidized to free radicals. A, Noncardiac ATP co-released from nerve endings with neurotransmitters is also degraded by ecto (external active site)-ATPases, ecto-nucleotidases, and adenosine deaminae, elevating the levels of extracellular adenosine and inosine, leading to activation of adenosine A1 receptor-mediated signaling mechanisms. B, Erythro-9 (2-hydroxy-3-nonyl)-adenine (EHNA)/p-nitro-benzylthioinosine (NBMPR) inhibits intracellular and extracellular adenosine deaminase activity and blocks es-NT1 transport system, allowing intracellular accumulation of mainly adenosine during ischemia and reperfusion, limiting hypoxanthine and xanthine formation and free radical production. C, Administration of selective or nonselective adenosine receptor antagonists blocked the action of extracellular adenosine but not the action of intracellular adenosine, interrupting adenosine receptor-mediated signaling mechanisms. ADP, Adenosine diphosphate; AMP, adenosine monophosphate; ADA, adenosine deaminase; A1R, adenosine A1 receptor; IPLase, inosine phosphorylase; es-ENT1, es-ENT1 transporter 1. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 243-249.e1DOI: (10.1016/j.jtcvs.2011.09.073) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions