Effect of newly developed tachykinin agonist and antagonists on the guinea pig isolated gallbladder.
The present study was undertaken to assess the activity of the neurokinin-2 (NK2) tachykinin receptor-selective antagonists MEN 10,376, L 659,877 and R 396 along with the NK2 receptor-selective ligand, MDL 28,564 on the isolated guinea pig gallbladder. None of the antagonists tested inhibited the response to the peptide CCK-8, although they competitively antagonized the contractile effect produced by NKA in the above tissue. The following rank order of potency was observed: MEN 10,376 (pKB = 6.77) greater than L 659,877 (pKB = 6.29) greater than R396 (pKB = 5.26). MEN 10,376 also antagonized the response to the NK3-selective agonist [MePhe7].NkB (10 microM), showing that the agonist activity of this peptide is due to NK2 receptor stimulation. On the other hand, MDL 28,564 had an agonist effect in the isolated gallbladder, its maximal effect approaching 58% of that to NKA. The results obtained using the above NK2 receptor-selective drugs in the guinea pig gallbladder was similar to that observed in other mammalian tissues bearing the NK2A receptor subtype, such as the endothelium-denuded rabbit pulmonary artery, the guinea pig bronchus and the circular muscle of the human colon and ileum. Therefore, we conclude that in the isolated guinea pig gallbladder tachykinins exert their contractile effect by activating NK2 receptors, which seem to belong to the NK2A receptor subtype.
Patacchini
R
R
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Maggi
C A
CA
D000595:Amino Acid Sequence; D000818:Animals; D005704:Gallbladder / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D018039:Receptors, Tachykinin
D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C066015:MDL 28564; C069192:neurokinin A(4-10), Tyr(5)-Trp(6,8,9)-Lys(10)-; D015288:Neurokinin A