title: [3H]adenosine transport in DDT1 MF-2 smooth muscle cells: inhibition by metabolites of propentofylline.
abstract: Adenosine receptor signal transduction mechanisms have previously been characterized in Syrian hamster smooth muscle DDT1 MF-2 cells but adenosine transport in these cells has not. DDT1 MF-2 cells possess a high density (370,000 sites/cell) of high affinity (Kd value of 0.26 nM) binding sites for [3H]nitrobenzylthioinosine, a marker for the equilibrative and inhibitor-sensitive subtype of nucleoside transporters. Transport of [3H]adenosine was insensitive to Na+ and was inhibited by the nucleoside transport inhibitors nitrobenzylthioinosine, dilazep and dipyridamole with IC50 values of 1, 13 and 270 nM, respectively. Propentofylline, a neuroprotective compound that can inhibit nucleoside transporters, is rapidly metabolized in vivo to the racemate (+/-)-A720287. Based on recent findings that some transport inhibitors exhibit marked stereoselectivity, we tested the degree to which individual stereoisomers of (+/-)-A720287 affect adenosine transport. Propentofylline inhibited [3H]adenosine transport in DDT1 MF-2 cells with an IC50 value of 24 microM. (+/-)-A720287 and the individual stereoisomers (+)-833791 and (-)-844261 had similar potency to propentofylline for inhibition of [3H]adenosine transport in DDT1 MF-2 cells as well as in clonal mouse leukemia L1210/B23.1 cells, cells which possess only the equilibrative and inhibitor-sensitive subtype of nucleoside transporters. Thus, the neuroprotective effects of propentofylline may be due, in part, to the primary metabolites of propentofylline.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
authors.forename: F E
authors.initials: FE
authors.lastname: Parkinson
authors.forename: K
authors.initials: K
authors.lastname: Mukherjee
authors.forename: J D
authors.initials: JD
authors.lastname: Geiger
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D006224:Cricetinae; D004109:Dilazep / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D005834:Genital Neoplasms, Male / Q000378:metabolism; D007700:Kinetics; D007890:Leiomyosarcoma / Q000378:metabolism; D007939:Leukemia L1210 / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013868:Thioinosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014970:Xanthines; D013868:Thioinosine; C032114:propentofylline; D004176:Dipyridamole; D004109:Dilazep; C001789:4-nitrobenzylthioinosine; D000241:Adenosine