Differential regulation of oxidative stress and cytokine production by endothelin ET_A and ET_B receptors in superoxide anion-induced inflammation and pain in mice

The present study investigated whether endothelin-1 acts via ET_A or ET_B receptors to mediate superoxide anion-induced pain and inflammation. Mice were treated with clazosentan (ET_A receptor antagonist) or BQ-788 (ET_B receptor antagonist) prior to stimulation with the superoxide anion donor, KO₂. Intraplantar treatment with 30 nmol of clazosentan or BQ-788 reduced mechanical hyperalgesia (47% and 42%), thermal hyperalgesia (68% and 76%), oedema (50% and 30%); myeloperoxidase activity (64% and 32%), and overt-pain like behaviours, such as paw flinching (42% and 42%) and paw licking (38% and 62%), respectively. Similarly, intraperitoneal treatment with 30 nmol of clazosentan or BQ-788 reduced leukocyte recruitment to the peritoneal cavity (58% and 32%) and abdominal writhing (81% and 77%), respectively. Additionally, intraplantar treatment with clazosentan or BQ-788 decreased spinal (45% and 41%) and peripheral (47% and 47%) superoxide anion production as well as spinal (47% and 47%) and peripheral (33% and 54%) lipid peroxidation, respectively. Intraplantar treatment with clazosentan, but not BQ-788, reduced spinal (71%) and peripheral (51%) interleukin-1 beta as well as spinal (59%) and peripheral (50%) tumor necrosis factor-alpha production. Therefore, the present study unveils the differential mechanisms by which ET-1, acting on ET_A or ET_B receptors, regulates superoxide anion-induced inflammation and pain.