title: Inhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells.
abstract: 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 microM), aspirin, ibuprofen and naproxen had no effect on [(3)H]adenosine uptake. Piroxicam inhibited [(3)H]adenosine uptake by 30%, while etodolac, indomethacin, ketoprofen, mefenamic acid and sulindac inhibited [(3)H]adenosine by 13-18%. Sulindac sulfide, an active metabolite of sulindac, inhibited [(3)H]adenosine uptake and [(3)H]nitrobenzylmercaptopurine ribonucleoside (NBMPR) binding of HASMCs with IC(50) values of 40.67+/-4.82 and 24.19+/-3.76 muM, 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 A(2B) 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.
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.
authors.forename: Rachel Wai-Sum
authors.initials: RW
authors.lastname: Li
authors.forename: Sai-Wang
authors.initials: SW
authors.lastname: Seto
authors.forename: Alice Lai-Shan
authors.initials: AL
authors.lastname: Au
authors.forename: Yiu-Wa
authors.initials: YW
authors.lastname: Kwan
authors.forename: Shun-Wan
authors.initials: SW
authors.lastname: Chan
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Tse
authors.forename: George Pak-Heng
authors.initials: GP
authors.lastname: Leung
mesh_terms: D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017308:Etodolac / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007660:Ketoprofen / Q000494:pharmacology; D007700:Kinetics; D008528:Mefenamic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010894:Piroxicam / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013696:Temperature; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013868:Thioinosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D010894:Piroxicam; D013467:Sulindac; D017308:Etodolac; D008528:Mefenamic Acid; D013868:Thioinosine; C025462:sulindac sulfide; D007660:Ketoprofen; C022616:thiazolyl blue; C001789:4-nitrobenzylthioinosine; D000241:Adenosine; D007213:Indomethacin