Defensive and pathological functions of the gastrointestinal NK3 receptor.

In general, normal gut functions are unaffected by selective NK(3) receptor antagonists such as talnetant (SB-223412), osanetant (SR 142901) or SB-235375. However, NK(3) receptors may mediate certain defensive or pathological intestinal processes. The precise mechanisms, by which this role is achieved, are not fully understood. In summary, intense stimulation of the intrinsic primary afferent neurones (IPANs) of the enteric nervous system is thought to release tachykinins from these neurones, to induce slow excitation (slow EPSPs) of connecting IPANs. This is hypothesised to cause hypersensitivity and disrupt intestinal motility, at least partly explaining why NK(3) receptor antagonism can reduce the level of disruption caused by supramaximal distension pressures in vitro. Tachykinin release from IPANs may also increase C-fibre sensitivity, directly or indirectly. Thus, NK(3) receptor antagonists can inhibit nociception associated with intestinal distension, in normal animals or after pre-sensitisation by restraint stress. Importantly, such inhibition has been found with SB-235375, a peripherally restricted antagonist. SB-235375 can also reduce a visceromotor response to brief colorectal distension without affecting similar responses to skin pinch, providing additional evidence for intestinal-specific activity. NK(3) receptor biology is, therefore, revealing a novel pathway by which disruptions in intestinal motility and nociception can be induced.

Pharmacological characterization of endothelin receptors-mediated contraction in the mouse isolated proximal and distal colon.

The study investigated the role of endothelin (ET) and the ET receptor subtypes ET(A) and ET(B) in mediating longitudinal contraction in the mouse proximal and distal colon. Cumulative concentration-response curves to a range of ET agonists (ET-1, ET-2, ET-3, (Ala(1,3,11,13)) ET and IRL 1620) were established by administering concentrations ranging from 0.01 nM to 0.3 microM. Concentration-response curves to ET-1, which exhibits a high affinity for both ET(A) and ET(B) receptor subtypes, were also established in the presence of the ET(A) antagonist BMS 182874 and the ET(B) antagonist IRL1038. The addition of the selective ET(A) receptor antagonist BMS 182874 caused a rightward shift of the concentration-response curve to ET-1 in both sections of the colon. The ET(B) receptor antagonist IRL1038 (0.3-1 microM) did not significantly effect the response to ET-1 in the proximal colon but caused a significant decrease in response towards higher concentrations ranges (>or=3 nM) in the distal colon. A comparison of the concentration-response curves to ET-1, ET-2 and ET-3 showed a rank order of potency ET-1>or=ET-2>>ET-3 in the proximal colon and ET-1>or=ET-2>or=ET-3 in the distal colon. The selective ET(B) receptor agonists, (Ala(1,3,11,13)) ET and IRL 1620 did not produce any response in the proximal sections of the colon but produced a smaller contraction in the distal segments. The data indicate that ET can contract the proximal tissues of the mouse colon predominantly via ET(A) receptors and in the distal tissues via ET(A) and ET(B) receptors.

5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum.

The study was undertaken to investigate the 5-HT receptor mediating the inhibitory effect of 5-HT on peristalsis in the guinea-pig isolated ileum. The facilitatory and inhibitory effects were measured as the decrease and increase, respectively, in the intraluminal pressure required to trigger peristalsis. In the presence of 5-HT(2/3&4) receptor antagonists ketanserin (0.1 micro M), granisetron (1 micro M) and SB-204070 (1 micro M), a cumulative addition (0.1-100 micro M) of 5-HT or 5-carboxamidotryptamine, but not 2-methyl-5-HT produced a concentration-dependent increase in the threshold required to trigger peristalsis. The 5-HT(7) receptor selective antagonist SB-269970-A (0.01-1 micro M) or methiothepin (0.01-0.1 micro M) concentration-dependently antagonised this response to 5-HT. SB-269970-A (1 micro M) and methiothepin (1 micro M) were also able to restore peristalsis in tissues in which peristalsis was inhibited by a prior addition of 30 micro M of 5-HT. The results indicate an involvement of 5-HT(7) receptors in the inhibitory effect of 5-HT on peristalsis in the guinea-pig ileum.