title: Inhibition of glucose uptake in murine cardiomyocyte cell line HL-1 by cardioprotective drugs dilazep and dipyridamole.
abstract: Inhibition of adenosine reuptake by nucleoside transport inhibitors, such as dipyridamole and dilazep, is proposed to increase extracellular levels of adenosine and thereby potentiate adenosine receptor-dependent pathways that promote cardiovascular health. Thus adenosine can act as a paracrine and/or autocrine hormone, which has been shown to regulate glucose uptake in some cell types. However, the role of adenosine in modulating glucose transport in cardiomyocytes is not clear. Therefore, we investigated whether exogenously applied adenosine or inhibition of adenosine transport by S-(4-nitrobenzyl)-6-thioinosine (NBTI), dipyridamole, or dilazep modulated basal and insulin-stimulated glucose uptake in the murine cardiomyocyte cell line HL-1. HL-1 cell lysates were subjected to SDS-PAGE and immunoblotting to determine which GLUT isoforms are present. Glucose uptake was measured in the presence of dipyridamole (3-300 microM), dilazep (1-100 microM), NBTI (10-500 nM), and adenosine (50-250 microM) or the nonmetabolizable adenosine analog 2-chloro-adenosine (250 microM). Our results demonstrated that HL-1 cells possess GLUT1 and GLUT4, the isoforms typically present in cardiomyocytes. We found no evidence for adenosine-dependent regulation of basal or insulin-stimulated glucose transport in HL-1 cardiomyocytes. However, we did observe a dose-dependent inhibition of glucose transport by dipyridamole (basal, IC(50) = 12.2 microM, insulin stimulated, IC(50) = 13.09 microM) and dilazep (basal, IC(50) = 5.7 microM, insulin stimulated, IC(50) = 19 microM) but not NBTI. Thus our data suggest that dipyridamole and dilazep, which are widely used to specifically inhibit nucleoside transport, have a broader spectrum of transport inhibition than previously described. Moreover, these data may explain previous observations, in which dipyridamole was noted to be proischemic at high doses.
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3.
authors.forename: Irina
authors.initials: I
authors.lastname: Shuralyova
authors.forename: Panteha
authors.initials: P
authors.lastname: Tajmir
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.forename: Imogen R
authors.initials: IR
authors.lastname: Coe
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D003847:Deoxyglucose / Q000493:pharmacokinetics*; D004109:Dilazep / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007700:Kinetics; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D013868:Thioinosine; D004176:Dipyridamole; D003847:Deoxyglucose; D004109:Dilazep; C001789:4-nitrobenzylthioinosine; D005947:Glucose; D000241:Adenosine