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

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.

The role of TRPA1 and TRPV4 channels in bronchoconstriction and plasma extravasation in airways of rats treated with captopril.

Angiotensin-converting enzyme inhibitors (ACEis) may cause adverse airway events, such as cough and angioedema, due to a reduction in bradykinin breakdown and consequent activation of bradykinin type 2 receptor (B2 receptor). Recent studies have shown that bradykinin can also sensitize pro-inflammatory receptors such as the transient receptor potential ankyrin 1 (TRPA1) and vanilloid 4 (TRPV4), which are implicated in several inflammatory airway diseases. Based on these considerations, the aim of this study was to understand the role of TRPA1 and TRPV4 channels in the bronchoconstrictive response and plasma extravasation in the trachea of rats pretreated with captopril. Using methods to detect alterations in airway resistance and plasma extravasation, we found that intravenous (i.v.) administration of bradykinin (0.03-0.3 µmol/kg, B2 receptor agonist), allyl isothiocyanate (100-1000 µmol/kg, TRPA1 agonist) or GSK1016790A (0.01-0.1 µmol/kg, TRPV4 agonist), but not des-arg9-bradykinin (DABK; 100-300 µmol/kg, B1 receptor agonist), induced bronchoconstriction in anaesthetized rats. In doses that did not cause significant bronchoconstriction, bradykinin (0.03 µmol/kg) or allyl isothiocyanate (100 µmol/kg), but not GSK1016790A (0.01 µmol/kg) or DABK (300 µmol/kg) induced an increased bronchoconstrictive response in rats pretreated with captopril (2.5 mg/kg, i.v.). On the other hand, in rats pretreated with captopril (5 mg/kg, i.v.), an increased bronchoconstrictive response to GSK1016790A (0.01 µmol/kg) was observed. The bronchoconstrictive response induced by bradykinin in captopril-pretreated rats was inhibited by intratracheal treatment (i.t.) with HC030031 (300 µg/50 µl; 36 ± 9%) or HC067047 (300 µg/50 µl; 35.1 ± 16%), for TRPA1 and TRPV4 antagonists, respectively. However, the co-administration of both antagonists did not increase this inhibition. The bronchoconstriction induced by allyl isothiocyanate in captopril-pretreated rats (2.5 mg/kg) was inhibited (58.3 ± 8%) by the B2 receptor antagonist HOE140 (10 nmol/50 µl, i.t.). Similarly, the bronchoconstriction induced by GSK1016790A in captopril-pretreated rats (5 mg/kg) was also inhibited (84.2 ± 4%) by HOE140 (10 nmol/50 µl, i.t.). Furthermore, the plasma extravasation induced by captopril on the trachea of rats was inhibited by pretreatment with HC030031 (47.2 ± 8%) or HC067047 (38.9 ± 8%). Collectively, these findings support the hypothesis that TRPA1 and TRPV4, via a B2 receptor activation-dependent pathway, are involved in the plasma extravasation and bronchoconstriction induced by captopril, making them possible pharmacological targets to prevent or remediate ACEi-induced adverse respiratory reactions.