Effect of thiorphan on response of the guinea-pig gallbladder to tachykinins

Abstract

Tachykinins produced a concentration-related contraction of the isolated guinea-pig gallbladder, with a rank order of potency neurokinin A (NKA) > Arg-neurokinin B = neurokinin B (NKB) > substance P (SP). Only the effect of SP was potentiated by thiorphan (0.1–10 μM). A significant enhancement of the response to SP was also produced by captopril (1 μM). [Nle 10]NKA-(4–10) and [β-Ala 8]NKA-(4–10), selective NK-2 receptor agonists, were active, whereas [Pro 9]SP sulfone (selective NK-1 agonist) was almost ineffective. [MePhe 7]NKB (selective NK-3 agonist) had some activity but only at high concentrations. Septide was almost ineffective and DiMeC 7 had an action comparable to that of [MePhe 7]NKB. None of the effects induced by these synthetic tachykinin analogs were significantly potentiated by thiorphan. Capsaicin (10 μM) produced a contraction which was unaffected by thiorphan. Both capsaicin and NKA-induced contractions were antagonized by Spantide at concentrations (5–10 μM) which had no effect against the atropine-sensitive contractions produced by electrical field stimulation. Capsaicin (1 μM) produced a consistent release of SP-like immunoreactivity (SP-LI) and a second application of the drug had no further effect, indicating complete desensitization. SP-LI release by capsaicin was almost doubled in the presence of thiorphan. These findings indicate that NK-2 and possibly some NK-3 receptors mediate the contractile response of the guinea-pig gallbladder to tachykinins. Both exogenous and endogenous (released by capsaicin) SP were degraded to a significant extent in this organ via a thiorphan-sensitive mechanism, the identity of which remains to be established.