Modulation of cholinergic and substance P-like neurotransmission by nitric oxide in the guinea-pig ileum.

1. The role of endogenous nitric oxide (NO) as a modulator of enteric neurotransmission was investigated in longitudinal muscle myenteric plexus (LMMP) preparations of guinea-pig isolated ileum. 2. In tissues previously incubated with [3H]-choline, exogenous NO inhibited electrically-evoked [3H]-choline overflow as well as responses to exogenous agonists, indicating that NO has the potential of neuromodulation both pre- and postjunctionally. 3. A series of NO synthase inhibitors enhanced contractile responses to nerve stimulation indicating inhibitory neuromodulation by endogenous NO. 4. The potency order of the NO synthase inhibitors and their consistent effects after dexamethasone, on responses to nerve stimulation, indicate action on a constitutive NO synthase. 5. Responses enhanced by NO synthase inhibitors were inhibited by the substance P receptor antagonist, spantide, suggesting a neuromodulatory influence on substance P-like neurotransmission by the endogenous NO. 6. NO synthase inhibition did not modify contractile responses to application of acetylcholine or substance P, or [3H]-choline overflow, indicating that endogenous NO mainly has a prejunctional inhibitory action on substance P-like neurotransmission. Nor did it modify responses to direct electrical muscle stimulation in the presence of tetrodotoxin. This suggests a prejunctional enhancing effect by NO synthesis inhibition. 7. Evidence for endogenous NO modulation of acetylcholine release was obtained when NO synthase inhibition modified atropine-sensitive, nerve-mediated contractile responses. However, [3H]-choline overflow was unaltered by NO synthase inhibition. 8. NO synthase inhibition did not modify responses to inhibitory neurotransmission. 9. The findings suggest that endogenous NO inhibits substance P-like motor neurotransmission, probably via prejunctional mechanisms. Cholinergic transmission may also be reduced by endogenous NO, acting prejunctionally.