title: Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion-induced pain and inflammation in mice.
abstract: Bosentan is a mixed endothelin receptor antagonist widely used to treat patients with pulmonary arterial hypertension, and the emerging literature suggests bosentan as a potent anti-inflammatory drug. Superoxide anion is produced in large amounts during inflammation, stimulates cytokine production, and thus contributes to inflammation and pain. However, it remains to be determined whether endothelin contributes to the inflammatory response triggered by the superoxide anion. The present study investigated the effects of bosentan in a mouse model of inflammation and pain induced by potassium superoxide, a superoxide anion donor. Male Swiss mice were treated with bosentan (10-100 mg/kg) by oral gavage, 1 h before potassium superoxide injection, and the inflammatory response was evaluated locally and at spinal cord (L4-L6) levels. Bosentan (100 mg/kg) inhibited superoxide anion-induced mechanical and thermal hyperalgesia, overt pain-like behavior (abdominal writhings, paw flinching, and licking), paw edema, myeloperoxidase activity (neutrophil marker) in the paw skin, and leukocyte recruitment in the peritoneal cavity. Bosentan also inhibited superoxide anion-induced interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) production, while it enhanced IL-10 production in the paw skin and spinal cord. Bosentan inhibited the reduction of antioxidant capacity (reduced glutathione, ferric reducing antioxidant power, and ABTS radical scavenging ability) induced by the superoxide anion. Finally, we demonstrated that intraplantar injection of potassium superoxide induces the mRNA expression of prepro-endothelin-1 in the paw skin and spinal cord. In conclusion, our results demonstrated that superoxide anion-induced inflammation, pain, cytokine production, and oxidative stress depend on endothelin; therefore, these responses are amenable to bosentan treatment.
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, Londrina, Paraná, 86057-970, Brazil.
authors.forename: Karla G G
authors.initials: KG
authors.lastname: Serafim
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, Londrina, Paraná, 86057-970, Brazil.
authors.forename: Suelen A
authors.initials: SA
authors.lastname: Navarro
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, Londrina, Paraná, 86057-970, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, Londrina, Paraná, 86057-970, Brazil.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, Londrina, Paraná, 86057-970, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Fattori
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Hospital Universitário, Universidade Estadual de Londrina, Av. Robert Koch, 60, Londrina, Paraná, 86038-350, Brazil.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, Londrina, Paraná, 86057-970, Brazil. waldiceujr@yahoo.com.br.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077300:Bosentan; D016207:Cytokines / Q000276:immunology; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D010529:Peritoneal Cavity / Q000166:cytology; D009195:Peroxidase / Q000276:immunology; D012867:Skin / Q000187:drug effects / Q000276:immunology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013481:Superoxides
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D013481:Superoxides; C039316:potassium superoxide; D009195:Peroxidase; D000077300:Bosentan
keywords: Bosentan; Endothelin; Inflammation; Oxidative stress; Pain; Superoxide