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 mu mol/kg, B2 receptor agonist), allyl isothiocyanate (100-1000 mu mol/kg, TRPA1 agonist) or GSK1016790A (0.01-0.1 mu mol/kg, TRPV4 agonist), but not des-arg9-bradykinin (DABK; 100-300 mu mol/kg, B1 receptor agonist), induced bronchoconstriction in anaesthetized rats. In doses that did not cause significant bronchoconstriction, bradykinin (0.03 mu mol/kg) or allyl isothiocyanate (100 mu mol/kg), but not GSK1016790A (0.01 mu mol/kg) or DABK (300 mu mol/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 mu mol/kg) was observed. The bronchoconstrictive response induced by bradykinin in captopril-pretreated rats was inhibited by intratracheal treatment (i.t.) with HC030031 (300 mu g/50 mu l; 36 +/- 9%) or HC067047 (300 mu g/ 50 mu l; 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 captoprilpretreated rats (2.5 mg/kg) was inhibited (58.3 +/- 8%) by the B2 receptor antagonist HOE140 (10 nmol/50 mu l, 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 mu l, 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 activationdependent 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.