Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung

ABSTRACT

To determine whether bronchoconstriction can be mediated via the tachykinin NK₃ receptors, isolated guinea pig lungs were challenged with the exogenous tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B ([MePhe⁷]-NKB) and senktide. [MePhe⁷]-NKB induced bronchoconstriction (EC₅₀ = 11.8 ± 1.7 μM) that was significantly inhibited by the tachykinin NK₃-receptor antagonist SB 223412 at 10 μM (EC₅₀ = 24.4 ± 4.5 μM). Senktide also induced bronchoconstriction (EC₅₀ = 96.2 ± 20.3 μM) and the bronchoconstriction was significantly reduced by SB 223412 at 1 and 10 μM (EC₅₀ = 270.8 ± 78.9 μM and 388.3 ± 105.5 μM, respectively). Although the authors demonstrated that SB 223412, [MePhe⁷]-NKB, and senktide are potent and selective for the tachykinin NK3 receptors in binding and functional (Ca²⁺ mobilization) assays, the tachykinin NK₁-receptor antagonist CP 99,994 at 1 μM (EC₅₀ = 32.7 ± 8.5 μM) produced inhibition of [MePhe⁷]-NKB–induced bronchoconstriction, whereas the tachykinin NK₂-receptor antagonist SR 48968 at 0.1 μM (EC₅₀ = 213.2 ± 42.9 μM) blocked senktide-induced bronchoconstriction. These data suggest that [MePhe⁷]-NKB and senktide caused bronchoconstriction in guinea pig through activation of the tachykinin NK₃-receptors but the tachykinin NK₁- and/or NK₂-receptors are also involved in the response.

KEYWORDS :

• isolated guinea pig lung
• tachykinin NK₃-receptors
• [MePhe⁷]-neurokinin B
• senktide
• SB 223412