Blockade of Nucleoside Transport Is Required for Delivery of Intraarterial Adenosine Into the Interstitium

Abstract

Background-Adenosine, a known mediator of preconditioning, has been infused into the coronary circulation to induce therapeutic preconditioning, eg, in preparation for angioplasty. However, results have been disappointing. We tested the hypothesis that endothelial nucleoside transporter acts as a barrier impeding the delivery of intravascular adenosine into the underlying myocardium and that this can be overcome with dipyridamole, a nucleoside transporter blocker. Methods and Results-We infused saline or adenosine (0.125 and 0.5 mg/min) into the brachial artery while monitoring forearm blood flow (FBF) and interstitial adenosine levels with microdialysis probes implanted in the flexor digitorum superficialis of the forearm in 7 healthy volunteers during intravenous administration of saline or dipyridamole (loading dose, 0.142 mg/kg per min for 5 minutes followed by 0.004 mg/kg per min). Adenosine produced near maximal forearm vasodilation, increasing FBF from 4.0Ϯ0.7 to 10.4Ϯ1.9 and 13.1Ϯ1.6 mL/100 mL per min for the low and high doses, respectively, but did not increase muscle dialysate adenosine concentration (from 88Ϯ21 to 65Ϯ23 and 85Ϯ26 nmol/L). Intravenous dipyridamole enhanced resting muscle dialysate adenosine (from 77Ϯ25 to 147Ϯ50 nmol/L), adenosineinduced increase in FBF (from 4.1Ϯ0.8 to 12.6Ϯ3 and 15.1Ϯ3 mL/100 mL per min for the low and high dose, respectively), and the delivery of adenosine into the interstitium (to 290Ϯ80 and 299Ϯ143 nmol/L for the low and high dose, respectively, Pϭ0.04). Key Words: adenosine Ⅲ ischemia Ⅲ endothelium Ⅲ blood flow A denosine is an intermediate product in the breakdown of ATP and accumulates in the interstitium of metabolically active tissues when oxygen demands exceed supply, eg, during ischemia. 1,2 Adenosine is considered a retaliatory autacoid, whose main function is to protect tissues against ischemia-related injury. Many of its actions are indeed consistent with such a role. Adenosine contributes to reactive hyperemia and produces maximal coronary vasodilation, inhibits norepinephrine and renin release, and inhibits neutrophil activation and platelet aggregation. Conclusions-IntravascularAdenosine is also considered an important mediator of ischemic preconditioning, a phenomenon by which an initial brief period of ischemia protects the tissue from the damage produced by a subsequent more intense ischemic episode. It is believed that during transient coronary occlusion, adenosine and other mediators are released and initiate a cascade of intracellular events involving protein kinase C activation that are responsible for the protective effect to subsequent ischemia. [3][4][5][6] There has been interest, therefore, in replicating ischemic preconditioning by infusing adenosine and using this pharmacological preconditioning as a therapeutic approach for cardiac protection. A situation where this approach may be of practical relevance is angioplasty, where ischemia may be induced transiently during the procedure. Indeed, adenosine has been infused into the coronary ...

Role of Adenosine Receptors in the Regulation of Angiogenic Factors and Neovascularization in Hypoxia

“…We used a sensitive and specific ion-pair liquid chromatographic electrospray ionization tandem mass spectrometry assay to measure adenosine concentrations as described previously (Gamboa et al, 2003). HMEC-1 were placed in hypoxic chambers and incubated in serum-free DMEM containing 5 M EHNA under normoxic or hypoxic conditions for 1 h. Cell culture media were collected by centrifugation at 12,000g for 1 min at 4°C, diluted 10-fold with water containing 10 nM [U-13 C 10 -U-15 N 5 ]adenosine as an internal standard and precleared by filtration through Amicon Ultrafree-MS centrifugal filters (Millipore Corporation, Bedford, MA).…”

Tissue Distribution of Concentrative and Equilibrative Nucleoside Transporters in Male and Female Rats and Mice

“…Dipyridamole and nitrobenzylthioinosine, the two inhibitors of ENTs, protect the heart from ischemia/reperfusion-induced toxicity by increasing the concentration and efficacy of adenosine. Recently, Gamboa et al (2003) reported that inhibitor-sensitive nucleoside transporters (ENTs) may function as an efflux barrier to prevent intravascular adenosine into the interstitium of heart or blood vessels. Currently, there is no report regarding gender-related information on expression of nucleoside transporters in human heart.…”

Skeletal Muscle Mitochondrial Function in Peripheral Arterial Disease: Usefulness of Muscle Biopsy

“…PC via PKC and postconditioning via gradual restoration of pH at reperfusion up-regulate RISK and preserve viable part of the ischemic region. In order to confer pharmacological protection, novel therapeutic strategies, based on the knowledge of the ligands, of the receptors and of the intracellular signaling pathways have emerged (Addison et al, 2003;Gamboa et al, 2003;Martou et al, 2006;Andreadou et al, 2008b). Adenosine, nicorandil, tempol, coenzyme Q and other agents (Addison et al, 2003;Gamboa et al, 2003;Martou et al, 2006;Thaveau et al, 2010) have been already used as pharmacological mimetics of ischemic preconditioning.…”

“…In order to confer pharmacological protection, novel therapeutic strategies, based on the knowledge of the ligands, of the receptors and of the intracellular signaling pathways have emerged (Addison et al, 2003;Gamboa et al, 2003;Martou et al, 2006;Andreadou et al, 2008b). Adenosine, nicorandil, tempol, coenzyme Q and other agents (Addison et al, 2003;Gamboa et al, 2003;Martou et al, 2006;Thaveau et al, 2010) have been already used as pharmacological mimetics of ischemic preconditioning. Furthermore, agents that increase RISK or directly prevent mPTP are also under investigation as postconditioning analogues (Andreadou et al, 2008a;Tsubota et al, 2010;Tran et al, 2011).…”