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Inhibition of glucose uptake in murine cardiomyocyte cell line HL-1 by cardioprotective drugs dilazep and dipyridamole

¹Department of Biology, York University, Toronto M3J 1P3; and ²Department of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8

Submitted 7 July 2003 ; accepted in final form 1 October 2003

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 µM), dilazep (1–100 µM), NBTI (10–500 nM), and adenosine (50–250 µM) or the nonmetabolizable adenosine analog 2-chloro-adenosine (250 µM). 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, IC₅₀ = 12.2 µM, insulin stimulated, IC₅₀ = 13.09 µM) and dilazep (basal, IC₅₀ = 5.7 µM, insulin stimulated, IC₅₀ = 19 µM) 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.

adenosine; equilibrative nucleoside transporters; regulation

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