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 journalArticle

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 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
Volume612
Issue number1-3
DOIs
StatePublished - Jun 10 2009

Fingerprint

Vascular Smooth Muscle
Adenosine
Smooth Muscle Myocytes
Anti-Inflammatory Agents
Pharmaceutical Preparations
Sulindac
Prostaglandin-Endoperoxide Synthases
Adenosine A2 Receptor Antagonists
Etodolac
Nucleoside Transport Proteins
Mefenamic Acid
Pharmacology
Ribonucleosides
Piroxicam
Ketoprofen
Naproxen
Purinergic P1 Receptors
Ibuprofen
Nucleosides
Indomethacin

Keywords

  • Adenosine transport
  • Smooth muscle cell
  • Sulindac

ASJC Scopus subject areas

  • Pharmacology

Cite this

Li, R. W. S., Seto, S. W., Au, A. L. S., Kwan, Y. W., Chan, S. W., Lee, S. M. Y., ... Leung, G. P. H. (2009). Inhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells. European Journal of Pharmacology, 612(1-3), 15-20. https://doi.org/10.1016/j.ejphar.2009.04.017

Inhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells. / Li, Rachel Wai Sum; Seto, Sai Wang; Au, Alice Lai Shan; Kwan, Yiu Wa; Chan, Shun Wan; Lee, Simon Ming Yuen; Tse, Chung Ming; Leung, George Pak Heng.

In: European Journal of Pharmacology, Vol. 612, No. 1-3, 10.06.2009, p. 15-20.

Research output: Contribution to journalArticle

Li, Rachel Wai Sum ; Seto, Sai Wang ; Au, Alice Lai Shan ; Kwan, Yiu Wa ; Chan, Shun Wan ; Lee, Simon Ming Yuen ; Tse, Chung Ming ; Leung, George Pak Heng. / Inhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells. In: European Journal of Pharmacology. 2009 ; Vol. 612, No. 1-3. pp. 15-20.
@article{9bfaf6cc109649d9a6a2fb29eee999c4,
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 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.",
keywords = "Adenosine transport, Smooth muscle cell, Sulindac",
author = "Li, {Rachel Wai Sum} and Seto, {Sai Wang} and Au, {Alice Lai Shan} and Kwan, {Yiu Wa} and Chan, {Shun Wan} and Lee, {Simon Ming Yuen} and Tse, {Chung Ming} and Leung, {George Pak Heng}",
year = "2009",
month = "6",
day = "10",
doi = "10.1016/j.ejphar.2009.04.017",
language = "English (US)",
volume = "612",
pages = "15--20",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",
number = "1-3",

}

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

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

UR - http://www.scopus.com/inward/citedby.url?scp=65549129242&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2009.04.017

DO - 10.1016/j.ejphar.2009.04.017

M3 - Article

C2 - 19379728

AN - SCOPUS:65549129242

VL - 612

SP - 15

EP - 20

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1-3

ER -