Role of nitric oxide, bradykinin B2 receptor, and TRPV1 in the airway alterations caused by simvastatin in rats.

Mayara Alves Amorim, Janiana Raíza Jentsch Matias de Oliveira, Vitor Hélio Souza Oliveira, Daniela Almeida Cabrini, Michel Fleith Otuki, Eunice André

European journal of pharmacology 2021 Dec 05

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Dry cough has been reported in patients receiving statin therapy. However, the underlying mechanism or other possible alterations in the airways induced by statins remain unknown. Thus, the aim of this study was to evaluate whether simvastatin promotes alterations in airways, such as bronchoconstriction and plasma extravasation, as well as the mechanism involved in these events. Using methods to detect alterations in airway resistance and plasma extravasation, we demonstrated that simvastatin [20 mg/kg, intravenous (i.v.)] caused plasma extravasation in the trachea (79.8 + 14.8 μg/g/tissue) and bronchi (73.3 + 8.8 μg/g/tissue) of rats, compared to the vehicle (34.2 + 3.6 μg/g/tissue and 29.3 + 5.3 μg/g/tissue, respectively). NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg, intraperitoneal), a nitric oxide (NO) synthase inhibitor, Icatibant [HOE 140, 10 nmol/50 μl, intratracheal (i.t.)], a bradykinin B2 antagonist, and capsazepine (100 nmol/50 μl, i.t.), a TRPV1 antagonist, attenuated simvastatin-induced plasma extravasation. Simvastatin (5, 10 and 20 mg/kg) did not cause bronchoconstriction per se, but exacerbated the bronchoconstrictive response to bradykinin (30 nmol/kg, i.v.), a B2 agonist (0.7 + 0.1 ml/H2O), or capsaicin (30 nmol/kg, i.v.), a TRPV1 agonist (0.8 + 0.1 ml/H2O), compared to the vehicle (0.1 + 0.04 ml/H2O and 0.04 + 0.01 ml/H2O, respectively). The bronchoconstriction elicited by bradykinin (100 nmol/kg, i.v.) in simvastatin non-treated rats was inhibited by L-NAME. The exacerbation of bronchoconstriction induced by bradykinin or capsaicin in simvastatin-treated rats was inhibited by L-NAME, HOE 140 or capsazepine. These results suggest that treatment with simvastatin promotes the release of bradykinin, which, via B2 receptors, releases NO that can then activate the TRPV1 to promote plasma extravasation and bronchoconstriction. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Mayara Alves Amorim, Janiana Raíza Jentsch Matias de Oliveira, Vitor Hélio Souza Oliveira, Daniela Almeida Cabrini, Michel Fleith Otuki, Eunice André. Role of nitric oxide, bradykinin B2 receptor, and TRPV1 in the airway alterations caused by simvastatin in rats. European journal of pharmacology. 2021 Dec 05;912:174591