Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice.
Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice.
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DOI：
10.1186/ar3372
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发表时间：
2011-06-20
影响因子：
4.9
通讯作者：
Schulz S
中科院分区：
文献类型：
--
作者：
Imhof AK;Glück L;Gajda M;Bräuer R;Schaible HG;Schulz S
内皮素参与组织炎症、疼痛、水肿和细胞迁移。我们的全基因组微阵列分析显示，内皮素-1（ET-1）和内皮素-2（ET-2）在关节炎急性期的背根神经节中表现出明显的上调。因此，我们研究了内皮素受体拮抗剂对单关节炎小鼠关节炎和炎性疼痛的发展的影响。基因表达检测在腰背根神经节两天后，诱导抗原诱导的关节炎（AIA），使用mRNA微阵列分析。通过反复评估AIA期间的关节肿胀、疼痛相关行为和组织病理学表现来确定药物治疗的效果。每日口服ETA和ETB内皮素受体拮抗剂波生坦混合物可显著减轻膝关节肿胀和炎症，其程度与地塞米松相当。此外，波生坦可减少炎性机械性痛觉过敏。波生坦长期给药还可抑制关节肿胀，并在AIA突发反应期间保护关节免受炎症和关节破坏。相比之下，ETA选择性拮抗剂安立生坦未能促进任何可检测的镇痛或抗伤害感受活性。因此，本研究揭示了内皮素系统在关节炎和关节炎疼痛的发展中的关键作用。我们表明，内皮素受体拮抗剂可以有效地控制炎症，疼痛和关节炎过程中的关节破坏。我们的研究结果表明波生坦的镇痛和抗伤害作用主要通过ETB受体介导。
Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice. Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA. Daily oral administration of the mixed ETA and ETB endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ETA-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity. Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ETB receptor.
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影响因子：
7.3
作者：
Piovezan, AP;D'Orléans-Juste, P;Rae, GA
通讯作者：
Rae, GA
影响因子：
3.6
作者：
Menéndez, L;Lastra, A;Baamonde, A
通讯作者：
Baamonde, A
DOI：
10.1124/jpet.103.063990
发表时间：
2004-08-01
影响因子：
3.5
作者：
Verri, WA;Schivo, IRS;Cunha, FQ
通讯作者：
Cunha, FQ
影响因子：
2.5
作者：
Hamamoto, Darryl T.;Khasabov, Sergey G.;Simone, Donald A.
通讯作者：
Simone, Donald A.
影响因子：
--
作者：
Boettger, Michael K.;Hensellek, Susanne;Schaible, Hans-Georg
通讯作者：
Schaible, Hans-Georg