Effect of thiorphan on response of the guinea-pig gallbladder to tachykinins.
Tachykinins produced a concentration-related contraction of the isolated guinea-pig gallbladder, with a rank order of potency neurokinin A (NKA) greater than Arg-neurokinin B = neurokinin B (NKB) greater than substance P (SP). Only the effect of SP was potentiated by thiorphan (0.1-10 microM). A significant enhancement of the response to SP was also produced by captopril (1 microM). [Nle10]NKA-(4-10) and [beta-Ala8]NKA-(4-10), selective NK-2 receptor agonists, were active, whereas [Pro9]SP sulfone (selective NK-1 agonist) was almost ineffective. [MePhe7]NKB (selective NK-3 agonist) had some activity but only at high concentrations. Septide was almost ineffective and DiMeC7 had an action comparable to that of [MePhe7]NKB. None of the effects induced by these synthetic tachykinin analogs were significantly potentiated by thiorphan. Capsaicin (10 microM) produced a contraction which was unaffected by thiorphan. Both capsaicin and NKA-induced contractions were antagonized by Spantide at concentrations (5-10 microM) which had no effect against the atropine-sensitive contractions produced by electrical field stimulation. Capsaicin (1 microM) 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.
Maggi
C A
CA
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Patacchini
R
R
Renzi
D
D
Santicioli
P
P
Regoli
D
D
Rovero
P
P
Drapeau
G
G
Surrenti
C
C
Meli
A
A
D000818:Animals; D002216:Captopril / Q000494:pharmacology; D005704:Gallbladder / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D015288:Neurokinin A / Q000494:pharmacology; D010446:Peptide Fragments; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011863:Radioimmunoassay; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology*
D010446:Peptide Fragments; D015320:Tachykinins; D013373:Substance P; C054725:septide; D015288:Neurokinin A; D002216:Captopril; D015244:Thiorphan; D011761:Pyrrolidonecarboxylic Acid