Myocardial protection in beating heart cardiac surgery: I: Pre- or postconditioning with inhibition of es-ENT1 nucleoside transporter and adenosine deaminase attenuates post-MI reperfusion-mediated ventricular fibrillation and regional contractile dysfunction

Abstract

Objectives To determine the role of the es-ENT1 nucleoside transporter in post-MI reperfusion injury-mediated ventricular fibrillation (VFib) and regional dysfunction. We used erythro-9 (2-hydroxy-3-nonyl)-adenine (EHNA) and p-nitrobenzylthioinosine (NBMPR) to inhibit both adenosine deamination and transport in a canine model of off pump acute MI. Methods Anesthetized adult dogs (n= 37), instrumented to monitor systolic segmental shortening (SS %) and wall thickening (WT %) using sonomicrometry, underwent 90 minutes of LAD coronary artery occlusion and 120 minutes reperfusion. Myocardial coronary blood flow, ATP pool, infarct size and the incidents of ventricular fibrillation and cardioversions were also measured. Animals received an intravenous infusion of the vehicle (Control) or 100μM of EHNA and 25 μM NBMPR before ischemia (preconditioning, PreC group) or just before reperfusion (postconditioning, PostC group). Results In the control group, ATP depletion was associated with accumulation of more inosine than adenosine during ischemia and washed out during reperfusion. Myocardial adenosine and inosine were the major nucleosides in the PreC- and Post-C groups during ischemia and remained detectable during reperfusion, respectively. In both groups, recovery of systolic SS% and WT%, and reduction in the incidence of VFib (p<0.05 vs. Control group) coincided with retention of myocardial nucleosides. Infarct sizes in the three groups were not significantly different, independent of myocardial blood flow during ischemia. Conclusion PreC-or PostC with EHNA/NBMPR significantly reduced the incidence of ventricular fibrillation and cardioversions and attenuated regional contractile dysfunction mediated by post-MI reperfusion injury and that es-ENT1 plays a major role in these events.

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

“…This is in line with the important role that ADO plays in regulation of the embryonic cardiovascular function (35). It should be noticed that the ratio INO/ADO of 4 under normoxia is close to the ratio INO/ADO Ͼ3 found in hypoxic embryonic and adult cardiomyocytes (1,27) and that INO can also alter cardiac activity in an autocrine/paracrine manner as we recently showed (41). In the present work, the timedependent myocardial accumulation of ADO under hypoxia with no effect on INO level ( Fig.…”

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

“…3,4 Binding kinetics studies have demonstrated identification of es-ENT1 binding sites in myocardial preparations of different species, including humans. Gene deletion of es-ENT1 proved to be protective in an isolated mouse heart model of ischemia and reperfusion, thus supporting our previous 2–4,8,9,13–15 and current findings that the es-ENT1 nucleoside transporter plays a major role in postischemic reperfusion injury.…”

“…2–4,8,9,13–15 Furthermore, we demonstrated that pre- and postischemic inhibition of the equilibrative-p-nitrobenzylthioinosine (NBMPR)–sensitive (es) type of the equilibrative nucleoside transport 1 (ENT1) nucleoside transport with NBMPR and adenosine deaminase activity with erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA) blocks release of purines and attenuates ventricular dysfunction and fibrillation. 2–4,8,9,13–15 The inhibitory effects of EHNA/NBMPR are site specific and are limited to the ischemic myocardium. 4 Although we have demonstrated the efficacy of EHNA/NBMPR intervention in various models of warm ischemia and reperfusion, it is not known whether prolonged infusion of hypothermic cardioplegia affects purine release from ischemic hearts and subsequently influences cardioprotection offered by EHNA/NBMPR treatment.…”

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

“…A unique aspect of ENT4 is the enhancement of substrate flux in acidic conditions, such as those associated with vascular ischemia‐reperfusion injury (Barnes et al, 2006; Tandio et al, 2019; Zhou, Duan, Engel, Xia, & Wang, 2010). ENT4 has been implicated in regulating 5‐HT levels in rat heart, particularly during the reperfusion stage of ischemia‐reperfusion (Sonobe, Akiyama, Du, & Pearson, 2019), and modulation of adenosine actions in the vasculature has long been proposed as a therapy to attenuate ischemia‐reperfusion injury (Abd‐Elfattah, Aly, Hanan, & Wechsler, 2012; Abd‐Elfattah et al, 2013; Hirai & Ashraf, 1998; Rose et al, 2010; Van Belle, 1995; Yang & Leung, 2015). Therefore, ENT4 may prove to be a novel drug target for therapeutic intervention in ischemia‐reperfusion injury.…”