TY - JOUR
T1 - Inhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells
AU - Li, Rachel Wai Sum
AU - Seto, Sai Wang
AU - Au, Alice Lai Shan
AU - Kwan, Yiu Wa
AU - Chan, Shun Wan
AU - Lee, Simon Ming Yuen
AU - Tse, Chung Ming
AU - Leung, George Pak Heng
N1 - Funding Information:
This study is supported by the RGC Earmarked Grants of Hong Kong SAR (project code: 769607) and Seed Funding for basic Research (The University of Hong Kong).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2009/6/10
Y1 - 2009/6/10
N2 - 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.
AB - 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.
KW - Adenosine transport
KW - Smooth muscle cell
KW - Sulindac
UR - http://www.scopus.com/inward/record.url?scp=65549129242&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2009.04.017
DO - 10.1016/j.ejphar.2009.04.017
M3 - Journal article
C2 - 19379728
AN - SCOPUS:65549129242
SN - 0014-2999
VL - 612
SP - 15
EP - 20
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -