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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.

ABSTRACT: The inhibition of adenosine deaminase with erythro-9 (2-hydroxy-3-nonyl)-adenine (EHNA) and the es-ENT1 transporter with p-nitro-benzylthioinosine (NBMPR), entraps myocardial intracellular adenosine during on-pump warm aortic crossclamping, leading to a complete recovery of cardiac function and adenosine triphosphate (ATP) during reperfusion. The differential role of entrapped intracellular and circulating adenosine in EHNA/NBMPR-mediated protection is unknown. Selective (8-cyclopentyl-1,3-dipropyl-xanthine) or nonselective [8-(p-sulfophenyl)theophyline] A1 receptor antagonists were used to block adenosine A1-receptor contribution in EHNA/NBMPR-mediated cardiac recovery.Anesthetized dogs (n = 45), instrumented to measure heart performance using sonomicrometry, were subjected to 30 minutes of warm aortic crossclamping and 60 minutes of reperfusion. Three boluses of the vehicle (series A) or 100 ?M EHNA and 25 ?M NBMPR (series B) were infused into the pump at baseline, before ischemia and before reperfusion. 8-Cyclopentyl-1,3-dipropyl-xanthine (10 ?M) or 8-(p-sulfophenyl)theophyline (100 ?M) was intra-aortically infused immediately after aortic crossclamping distal to the clamp in series A and series B. The ATP pool and nicotinamide adenine dinucleotide was determined using high-performance liquid chromatography.Ischemia depleted ATP in all groups by 50%. The adenosine/inosine ratios were more than 10-fold greater in series B than in series A (P < .001). ATP and function recovered in the EHNA/NBMPR-treated group (P < .05 vs control group). 8-Cyclopentyl-1,3-dipropyl-xanthine and 8-(p-sulfophenyl)theophyline partially reduced cardiac function in series A and B to the same degree but did not abolish the EHNA/NBMPR-mediated protection in series B.In addition to the cardioprotection mediated by activation of the adenosine receptors by extracellular adenosine, EHNA/NBMPR entrapment of intracellular adenosine provided a significant component of myocardial protection despite adenosine A1 receptor blockade.

SUBMITTER: Abd-Elfattah AS

PROVIDER: S-EPMC3355204 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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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.

Abd-Elfattah Anwar Saad AS Ding Mai M Jessen Michael E ME Wechsler Andrew S AS

The Journal of thoracic and cardiovascular surgery 20120209 1

<h4>Objective</h4>The inhibition of adenosine deaminase with erythro-9 (2-hydroxy-3-nonyl)-adenine (EHNA) and the es-ENT1 transporter with p-nitro-benzylthioinosine (NBMPR), entraps myocardial intracellular adenosine during on-pump warm aortic crossclamping, leading to a complete recovery of cardiac function and adenosine triphosphate (ATP) during reperfusion. The differential role of entrapped intracellular and circulating adenosine in EHNA/NBMPR-mediated protection is unknown. Selective (8-cyc ...[more]

PMID: 22325325

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Project description:To determine the role of the p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 (es-ENT1) in postmyocardial infarction reperfusion injury-mediated ventricular fibrillation and regional dysfunction. We used erythro-9 (2-hydroxy-3-nonyl)-adenine and p-nitrobenzylthioinosine to inhibit both adenosine deamination and transport in a canine model of off pump acute myocardial infarction.Anesthetized adult dogs (n = 37), instrumented to monitor the percentage of systolic segmental shortening and wall thickening using sonomicrometry, underwent 90 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion. Myocardial coronary blood flow, adenosine triphosphate pool, infarct size, and the incident of ventricular fibrillation and cardioversion were also measured. The dogs received an intravenous infusion of the vehicle (control) or 100 ?M of erythro-9 (2-hydroxy-3-nonyl)-adenine and 25 ?M p-nitrobenzylthioinosine before ischemia (preconditioning group) or just before reperfusion (postconditioning group).In the control group, adenosine triphosphate depletion was associated with the accumulation of more inosine than adenosine during ischemia and washed out during reperfusion. Myocardial adenosine and inosine were the major nucleosides in the pre- and postconditioning groups during ischemia and remained detectable during reperfusion. In both groups, recovery of systolic segmental shortening and wall thickening and a reduction in the incidence of ventricular fibrillation (P < .05 vs the control group) coincided with retention of myocardial nucleosides. The infarct size in the 3 groups was not significantly different, independent of myocardial blood flow during ischemia.Preconditioning or postconditioning with erythro-9 (2-hydroxy-3-nonyl)-adenine/p-nitrobenzylthioinosine significantly reduced the incidence of ventricular fibrillation and cardioversion and attenuated regional contractile dysfunction mediated by postmyocardial infarction reperfusion injury. It is concluded that p-nitrobenzylthioinosine-sensitive equilibrative nucleoside transporter 1 played a major role in these events.

Project description:Activation of A(1) adenosine receptors (ARs) protects against renal ischemia-reperfusion (I/R) injury by reducing necrosis, apoptosis, and inflammation. However, extrarenal side effects (bradycardia, hypotension, and sedation) may limit A(1)AR agonist therapy for ischemic acute kidney injury. Here, we hypothesized that an allosteric enhancer for A(1)AR (PD-81723) protects against renal I/R injury without the undesirable side effects of systemic A(1)AR activation by potentiating the cytoprotective effects of renal adenosine generated locally by ischemia. Pretreatment with PD-81723 produced dose-dependent protection against renal I/R injury in A(1)AR wild-type mice but not in A(1)AR-deficient mice. Significant reductions in renal tubular necrosis, neutrophil infiltration, and inflammation as well as tubular apoptosis were observed in A(1)AR wild-type mice treated with PD-81723. Furthermore, PD-81723 decreased apoptotic cell death in human proximal tubule (HK-2) cells in culture, which was attenuated by a specific A(1)AR antagonist (8-cyclopentyl-1,3-dipropylxanthine). Mechanistically, PD-81723 induced sphingosine kinase (SK)1 mRNA and protein expression in HK-2 cells and in the mouse kidney. Supporting a critical role of SK1 in A(1)AR allosteric enhancer-mediated renal protection against renal I/R injury, PD-81723 failed to protect SK1-deficient mice against renal I/R injury. Finally, proximal tubule sphingosine-1-phosphate type 1 receptors (S1P(1)Rs) are critical for PD-81723-induced renal protection, as mice selectively deficient in renal proximal tubule S1P(1)Rs (S1P(1)R(flox/flox) PEPCK(Cre/-) mice) were not protected against renal I/R injury with PD-81723 treatment. Taken together, our experiments demonstrate potent renal protection with PD-81723 against I/R injury by reducing necrosis, inflammation, and apoptosis through the induction of renal tubular SK1 and activation of proximal tubule S1P(1)Rs. Our findings imply that selectively enhancing A(1)AR activation by locally produced renal adenosine may be a clinically useful therapeutic option to attenuate ischemic acute kidney injury without systemic side effects.

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Dataset Information

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.

Publications

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.

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