The present study was undertaken to investigate neural control of mouse small intestinal longitudinal muscle. Electrical field stimulation evoked acetylcholine- and neurokinin A-mediated contractile responses, whereas nitric oxide-mediated neurotransmission resulted in relaxation. The inflammatory mediators, histamine and leukotriene D4, contracted the longitudinal muscle preparation. Histamine-evoked contractions resulted from binding to histamine H1 receptors on non-neural cells of the small intestine. Leukotriene D4 played a role in neurokinin A-mediated excitation as the leukotriene D4 receptor antagonist, WY 48,252, reduced the response to nerve stimulation under noncholinergic conditions by almost 80%. In contrast, WY 48,252 had no effect on the response to exogenous neurokinin A, indicating that the response to this neurotransmitter is not mediated by leukotriene D4 release. Subthreshold concentrations of leukotriene D4 did not modify the response to neurokinin A, ruling out a synergistic relationship between these two agonists. Leukotriene D4 did not cause synaptic transmitter release through ganglionic stimulation, because its contractile effect was tetrodotoxin insensitive, and did not contribute to noncholinergic excitation through stimulation of neurokinin A release, as the neurokinin2 receptor antagonist, MEN 10,376, did not alter the response to leukotriene D4. Instead leukotriene D4 may modulate the release of neurokinin A from nerve endings during nerve stimulation.