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
Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.
Eur J Pharmacol. 2009 Jun 10;612(1-3):15-20. doi: 10.1016/j.ejphar.2009.04.017. Epub 2009 Apr 18.
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.
一般认为，非甾体抗炎药（NSAIDs）的临床疗效主要源于对环氧化酶（COX）的抑制作用。然而，越来越多的证据表明，NSAIDs的某些药理作用可能由COX非依赖性机制介导。本研究调查了NSAIDs对人主动脉平滑肌细胞（HASMCs）中腺苷摄取的影响。在所测试的NSAIDs中（均为100 microM），阿司匹林、布洛芬和萘普生对[³H]腺苷摄取没有影响。吡罗昔康抑制[³H]腺苷摄取30%，而依托度酸、吲哚美辛、酮洛芬、甲芬那酸和舒林酸抑制[³H]腺苷摄取13 - 18%。舒林酸的活性代谢产物舒林酸硫化物抑制HASMCs的[³H]腺苷摄取和[³H]硝基苄基巯基嘌呤核糖核苷（NBMPR）结合，IC₅₀值分别为40.67±4.82和24.19±3.76 μM。动力学研究表明，舒林酸硫化物是腺苷摄取的竞争性抑制剂。使用稳定表达平衡核苷转运体（ENT）1和ENT2的核苷转运体缺陷型PK15NTD细胞，发现舒林酸硫化物对ENT1的抑制作用大于对ENT2的抑制作用。舒林酸硫化物增加细胞外腺苷水平。此外，它抑制HASMCs的增殖，并且这种抗增殖作用可被腺苷A₂B受体拮抗剂消除。我们的数据表明，舒林酸硫化物可能通过抑制腺苷摄取发挥药理作用，这调节了腺苷在腺苷受体附近的可利用性。
