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

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TitleInhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells
AuthorsLi, RWS1
Seto, SW1
Au, ALS1
Kwan, YW1
Chan, SW3
Lee, SMY2
Tse, CM4
Leung, GPH1
KeywordsAdenosine transport
Smooth muscle cell
Sulindac
Issue Date2009
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar
CitationEuropean Journal Of Pharmacology, 2009, v. 612 n. 1-3, p. 15-20 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ejphar.2009.04.017
AbstractIt 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 IC 50 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 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. © 2009 Elsevier B.V. All rights reserved.
ISSN0014-2999
2011 Impact Factor: 2.516
2011 SCImago Journal Rankings: 0.199
DOIhttp://dx.doi.org/10.1016/j.ejphar.2009.04.017
ISI Accession Number IDWOS:000267150900003
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLi, RWS
dc.contributor.authorSeto, SW
dc.contributor.authorAu, ALS
dc.contributor.authorKwan, YW
dc.contributor.authorChan, SW
dc.contributor.authorLee, SMY
dc.contributor.authorTse, CM
dc.contributor.authorLeung, GPH
dc.date.accessioned2010-05-31T03:52:30Z
dc.date.available2010-05-31T03:52:30Z
dc.date.issued2009
dc.description.abstractIt 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 IC 50 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 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. © 2009 Elsevier B.V. All rights reserved.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationEuropean Journal Of Pharmacology, 2009, v. 612 n. 1-3, p. 15-20 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.ejphar.2009.04.017
dc.identifier.doihttp://dx.doi.org/10.1016/j.ejphar.2009.04.017
dc.identifier.epage20
dc.identifier.hkuros157519
dc.identifier.isiWOS:000267150900003
dc.identifier.issn0014-2999
2011 Impact Factor: 2.516
2011 SCImago Journal Rankings: 0.199
dc.identifier.issue1-3
dc.identifier.openurl
dc.identifier.pmid19379728
dc.identifier.scopuseid_2-s2.0-65549129242
dc.identifier.spage15
dc.identifier.urihttp://hdl.handle.net/10722/59548
dc.identifier.volume612
dc.languageeng
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/ejphar
dc.publisher.placeNetherlands
dc.relation.ispartofEuropean Journal of Pharmacology
dc.relation.referencesReferences in Scopus
dc.rightsEuropean Journal of Pharmacology. Copyright © Elsevier BV.
dc.subjectAdenosine transport
dc.subjectSmooth muscle cell
dc.subjectSulindac
dc.titleInhibitory effect of nonsteroidal anti-inflammatory drugs on adenosine transport in vascular smooth muscle cells
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong
  2. University of Macau
  3. Hong Kong Polytechnic University
  4. The Johns Hopkins School of Medicine