Leukotriene D4 excitation of rabbit distal colon arises in the region of the muscularis mucosae.

We previously have demonstrated in vivo that intra-arterial administration of leukotriene D4 (LTD4) causes increased myoelectric and mechanical activity in the rabbit distal colon. The aim of this study was to use both in vivo and in vitro techniques to try to elucidate the mechanism underlying this effect. In vivo the excitatory response of the rabbit distal colon to LTD4 was abolished by pretreatment with atropine (0.1 mg/kg iv) or hexamethonium (5 mg/kg iv) or the LTD4 receptor antagonist SK&F 102922 (0.8 micrograms/kg ia). In vitro neither the longitudinal nor the circular muscle layer responded to LTD4 (10(-10) to 10(-7) M) with a contractile response. Over the same concentration range, LTD4 caused contractions of the muscularis mucosae that were attenuated by either SK&F 102922 (10(-9) to 10(-7) M) or indomethacin (10(-6) M) but were unaffected by atropine (10(-6) M), pyrilamine (10(-6) M), or tetrodotoxin (10(-6) M). Full thickness segments of longitudinal muscle, circular muscle, and muscularis mucosae did not contract to LTD4. These data imply that LTD4-induced excitation of the rabbit distal colon in vivo arises as a result of the excitation of LTD4 receptors in the region of the muscularis mucosae and that this leads ultimately to the release of acetylcholine onto the muscularis propria. It is proposed that one possible mechanism leading to the latter effect is an increased excitability of intrinsic nerves resulting from a prostaglandin-induced depression of norepinephrine release from nerves impinging on the submucosal plexus.