Inhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells

Rachel Wai Sum Li, Sai Wang Seto, Alice Lai Shan Au, Yiu Wa Kwan, Shun Wan Chan, Simon Ming Yuen Lee, Chung Ming Tse, George Pak Heng Leung

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


It is generally accepted that the clinical efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) arises mainly from the inhibition of cyclooxygenase (COX). However, more evidence has suggested that certain pharmacological actions of NSAIDs may be mediated by COX-independent mechanisms. The present study investigated the effects of NSAIDs on adenosine uptake in human aortic smooth muscle cells (HASMCs). Among the NSAIDs tested (all at 100 μM), aspirin, ibuprofen and naproxen had no effect on [3H]adenosine uptake. Piroxicam inhibited [3H]adenosine uptake by 30%, while etodolac, indomethacin, ketoprofen, mefenamic acid and sulindac inhibited [3H]adenosine by 13-18%. Sulindac sulfide, an active metabolite of sulindac, inhibited [3H]adenosine uptake and [3H]nitrobenzylmercaptopurine ribonucleoside (NBMPR) binding of HASMCs with IC50 values of 40.67 ± 4.82 and 24.19 ± 3.76 μM, respectively. Kinetic studies revealed that sulindac sulfide was a competitive inhibitor of adenosine uptake. Using the nucleoside-transporter-deficient PK15NTD cells that stably express equilibrative nucleoside transport (ENT) 1 and ENT2, it was found that the inhibitory effect of sulindac sulfide on ENT1 was greater than that on ENT2. Sulindac sulfide increased the extracellular adenosine level. In addition, it inhibited the proliferation of HASMCs and this anti-proliferative effect could be abolished by adenosine A2B receptor antagonist. Our results suggest that sulindac sulfide may exert pharmacological effects through the inhibition of adenosine uptake, which modulates the availability of adenosine in the vicinity of adenosine receptors.

Original languageEnglish (US)
Pages (from-to)15-20
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number1-3
StatePublished - Jun 10 2009


  • Adenosine transport
  • Smooth muscle cell
  • Sulindac

ASJC Scopus subject areas

  • Pharmacology


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