The effects of three substance P (SP) antagonists on the inferior mesenteric ganglion of the guinea-pig were studied using intracellular recording techniques, and the possible role of SP as a transmitter for the non-cholinergic slow excitatory post-synaptic potential (e.p.s.p.) was examined. The SP antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP, exerted a depolarizing action on the ganglion cells when applied by perfusion at a concentration of 3-16 microM or by pressure ejection from a micropipette. This depolarizing action is probably due to a release of endogenous histamine because it was abolished by treatment with a histamine antagonist, mepyramine (1-3 microM), or by a repeated application of the antagonist. When applied by pressure ejection, SP at 0.5-1 microM depolarized the ganglion cells. In the presence of mepyramine, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP suppressed the SP-induced depolarization by 41% at a concentration of 8 microM and by 75% at 16 microM. By contrast the SP antagonist did not affect the depolarizing action of angiotensin II on the ganglion cells. The non-cholinergic slow e.p.s.p. evoked in the ganglion cells by repetitive stimulation of the lumbar splanchnic nerves was suppressed by [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP at 8 or 16 microM. The degrees of suppression of both the non-cholinergic slow e.p.s.p. and the SP-induced depolarization by the SP antagonist were approximately equal. The cholinergic fast e.p.s.p. evoked by preganglionic nerve stimulation was not affected by the SP antagonist. [D-Pro2, D-Trp7,9]SP exhibited the properties of an SP antagonist similar to, but slightly weaker than [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP. [D-Pro2, D-Phe7, D-Trp9] at a concentration of 16 microM had a depolarizing action on the ganglion cells, which was not blocked by mepyramine. The peptide exerted hardly any antagonistic action against the SP-induced depolarization of the ganglion cells. Stimulation of the other preganglionic (intermesenteric) nerves and the post-ganglionic (colonic and hypogastric) nerves produced a non-cholinergic slow e.p.s.p. in the inferior mesenteric ganglion cells. The non-cholinergic slow e.p.s.p. evoked by both pre- and post-ganglionic nerve stimulation were depressed by [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP to similar extents. The present results show that [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP and [D-Pro2, D-Trp7,9]SP can serve as specific SP antagonists in the inferior mesenteric ganglion of the guinea-pig.(ABSTRACT TRUNCATED AT 400 WORDS)