[Ala5, beta-Ala8]-Neurokinin A (4-10)

Analogs of NKA(4-10) which are selective tachykinin NK2 receptor agonists have been tested as anti-secretory and anti-ulcer agents in 2-h pylorus ligation in rats. Peripheral (500 micrograms/kg s.c.) or central (5 micrograms/rat i.c.v.) administration of Ala5NKA(4-10), but not NKA(4-10) or Ala5[beta Ala8]NKA(4-10), inhibited gastric ulcer and secretion. The same effective doses of Ala5NKA(4-10) did not influence gastric emptying. The anti-secretory and anti-ulcer effects of Ala5NKA(4-10) were antagonized by pretreatment with the tachykinin NK2 receptor antagonist MEN 10,627 at a dose (250 micrograms/kg s.c.) which did not affect gastric secretion and ulcers. These findings provide the first evidence that activation of central and peripheral tachykinin NK2 receptors affords protection against gastric ulcers induced by 2 h pylorus ligation in rats, by reducing gastric acid secretion.

Background:Tachykinins (TKs) have been shown to be involved in the excitatory enteric motor pathway. This study aimed to examine the direct and nerve-mediated effect of specific NK1, NK2 and NK3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC).Materials and methods:Cumulative concentrations of Sar9Met(O2)11 substance P (selective NK1 receptor agonist), [Ala5,beta-Ala8]-neurokinin A (4-10) (selective NK2 receptor agonist) and [MePhe7]-neurokinin B (selective NK3 receptor agonist) were tested on colonic circular muscle strips to evaluate the direct drug effects. In addition, in the presence of atropine, the role of TKs in the off-contraction that follows the typical inhibitory response evoked by low frequencies of electrical field stimulation (0.5--10 Hz, 20 V, 1 ms pulse trains lasting 1 min) was investigated.Results:In control preparations, the rank order of potency was: NK2 receptor-selective agonist > NK3 receptor-selective agonist > NK1 receptor-selective agonist. The off-contraction was found to be reduced by about 30--40% in colonic circular muscle from ICC patients with respect to controls. Incubation with the NK1 receptor agonist did not modify the off-contraction measurements in either control or ICC preparations. Conversely, both NK2 and NK3 receptor agonists significantly (P < 0.01) increased the off-contraction in ICC preparations only. This increased response was fully antagonized by MEN-10627, a NK2 and NK3 receptor antagonist depending on the dose.Conclusions:We may conclude that ICC is hyporesponsive to TKs and that the contractile reflex to distension is greatly reduced in ICC disease, but can be restored by incubation with NK2 and NK3 receptor agonists.

The tachykinins [Ala5,beta-Ala8]neurokinin A-(4-10) {[Ala5,beta-Ala8]NKA-(4-10)} and NKA-(4-10) dose dependently protected against ethanol-induced gastric mucosal damage in rats (half-maximal inhibitory dose, 46 and 48 nmol/kg, respectively). These effects were abolished by primary afferent nerve denervation, calcitonin gene-related peptide (CGRP) immunoneutralization, the CGRP receptor antagonist human (h) hCGRP-(8-37), and inhibition of nitric oxide (NO) biosynthesis by NG-nitro-L-arginine methyl ester. Tachykinin-induced protection occurred despite marked depression of gastric mucosal blood flow and was not associated with increased acid secretion. NK2-receptor blockade antagonized the protective effects of [Ala5,beta-Ala8]NKA-(4-10) and NKA-(4-10), whereas NK1-receptor blockade was ineffective. Blockade of NK2 but not NK1 receptors prevented by 65% the protection evoked by topical capsaicin without affecting capsaicin-induced hyperemia. We conclude that the increase in gastric mucosal resistance evoked by tachykinins is NK2 receptor-mediated and involves primary afferent neurons, CGRP, and NO. Gastric mucosal hyperemia and increased acid secretion do not participate in the effect. Tachykinins activating NK2 receptors contribute to the increase in gastric mucosal resistance but not the increment in mucosal blood flow after primary afferent nerve stimulation by capsaicin.