[3H]Adenosine transport in DDT1 MF-2 smooth muscle cells: Inhibition by metabolites of propentofylline

Fiona E. Parkinson, Kallol Mukherjee, Jonathan D. Geiger

Research output: Contribution to journalArticle

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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 (K(d) 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 μM. (±)-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.

Original languageEnglish (US)
Pages (from-to)97-102
Number of pages6
JournalEuropean Journal of Pharmacology
Volume308
Issue number1
DOIs
StatePublished - Jul 11 1996

Fingerprint

Adenosine
Smooth Muscle Myocytes
Nucleoside Transport Proteins
Stereoisomerism
Inhibitory Concentration 50
Dilazep
Leukemia L1210
Purinergic P1 Receptors
Dipyridamole
propentofylline
Mesocricetus
Neuroprotective Agents
Nucleosides
Smooth Muscle
Signal Transduction
Binding Sites

Keywords

  • Adenosine
  • Nitrobenzylthioinosine
  • Nucleoside transport
  • Propentofylline

ASJC Scopus subject areas

  • Pharmacology

Cite this

[3H]Adenosine transport in DDT1 MF-2 smooth muscle cells : Inhibition by metabolites of propentofylline. / Parkinson, Fiona E.; Mukherjee, Kallol; Geiger, Jonathan D.

In: European Journal of Pharmacology, Vol. 308, No. 1, 11.07.1996, p. 97-102.

Research output: Contribution to journalArticle

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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 (K(d) 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 μM. (±)-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.",
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