Antisecretory and Relaxatory Effects of Tachykinin Antagonists in the Guinea-pig Intestinal Tract

Abstract

Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by beta-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion. Using these models the potency of therapeutically useful compounds was determined. NK1 and NK2 activation directly contracted smooth muscle, while NK1-mediated secretion was nerve-mediated. NK3 stimulation of contraction and secretion was neurally mediated, involving cholinergic nerves and 5-HT release. NK1-mediated contraction and secretion were antagonized by SR140333 (pD'2 = 9.29 and pKb = 8.53); NK2-mediated contraction was antagonised by SR48968 (pD'2 = 8.35) and NK3-mediated contraction and secretion were antagonized by SB223412 (pKb = 8.97 and 8.79). The mixed antagonist MDL103392 blocked NK1- and NK2-mediated contraction with pKb values of 7.92 and 6.71 respectively and NK1-mediated secretion with a pKb value of 6.57. This data characterizes existing tachykinin antagonists, and should orientate the development of improved compounds as therapies for intestinal disease.

An Endogenous Tachykinergic NK2/NK3 Receptor Cascade System Controlling the Release of Serotonin from Colonic Mucosa

“…1 , the enhancing effect of senktide on 5-HT release was prevented by both TTX and the NK 2 receptor-selective antagonist SR48968, thus suggesting that senktide stimulates the release of neuronal TKs, which in turn enhances 5-HT release via mucosal NK 2 receptors. This agrees with previous findings in guinea-pig colon where NK 3 receptor activation releases TKs and 5-HT [ 13 , 14 ]. The 5-HT-releasing action of senktide was also inhibited by hexamethonium, and was not seen in myenteric plexus-free mucosal preparations, thus suggesting that myenteric cholinergic interneurons also participate in the mechanism for NK 3 receptor-triggered 5-HT release [ 8 ].…”

Loperamide Inhibits Tachykinin NK3-Receptor-Triggered Serotonin Release Without Affecting NK2-Receptor-Triggered Serotonin Release From Guinea Pig Colonic Mucosa

“…These observations imply that the suppressant effect of loperamide on the NK 3 -receptor-triggered 5-HT release is not due to a direct action on colonic enterocytes because tetrodotoxin prevented the NK 3 -receptor-triggered 5-HT release without affecting the NK 2 -receptor-triggered 5-HT release (13). 5-HT is an important mediator of intestinal water and electrolyte secretion (2,18), and the activation of tachykinin NK 3 receptors induces a neurally mediated (involving 5-HT release) Cl − secretion by guinea pig colonic mucosa (19). Therefore, the suppressant effect of loperamide on the NK 3 -receptor-triggered 5-HT release contributes to the antisecretory effect of loperamide.…”

The mechanisms for tachykinin‐induced contractions of the rabbit corpus cavernosum

“…The effect of SR 140333 (an NK 1 receptor selective antagonist) was apparently non‐competitive, because this antagonist reduced the tachykinin‐induced maximum contractions. The non‐competitive nature of the inhibition by SR 140333 toward smooth muscle contraction induced by tachykinins is in good agreement with the previous studies (Emonds‐Alt et al ., 1993; Goldhill et al ., 1999). Although SR 48968 (an NK 2 receptor selective antagonist) alone did not influence the contractile responses to tachykinins, it potentiated the inhibitory effects of SR 140333 on the tachykinin‐induced contractions (Figure 3).…”