The peptides, neurotensin and substance P, caused transient increases in transepithelial potential difference and short-cir-cuit current when added to the medium bathing the serosah surface of guinea-pig ileal mucosa mounted in vitro in Ussing chambers. Both peptides were ineffective when added to the mucosal bathing medium. Neurotensin caused a maximal in-crement of 41 A/cm2 in short-circuit current and a half-max-imal effect was produced by 3 x 1 O M neurotensin. Substance P caused a maximal increment of 63 A/cm2 in short-circuit current and a half-maximal effect occurred at a concen-tration of 3.5 x 1 0_8 M peptide. After addition of neurotensin or substance P, subsequent additions of the same peptide exhibited desensitization. After desensitization to neurotensin, the action of substance P was only slightly reduced. After desensitization to substance P, the effect of neurotensin was completely blocked Desensitization to neurotensin and sub-stance P was reversible. The effects of neurotensin or substance P were not blocked by atropine, indomethacin, diphen-hydramine, somatostatin or etorphine. The effects of neurotensin, but not substance P, were blocked by tetrodotoxin and epinephrine. Prior desensitization to serotonin partially blocked the effects of neurotensin or substance P. Prior desensitization to neurotensin or substance P partially blocked the effect of serotonin. Substitution of Cl and HCO3 in the Ringer’s solution by gluconate or SO4 inhibited the action of neurotensin and substance P, as did the replacement of Na with choline. Removal of Ca ions or addition of verapamil also blocked the effect of both peptides. It is hypothesized that neurotensin may stimulate intestinal secretion by a neuronal mechanism, possibly through the stimulation of substance P release from enteric neurons. Substance P, on the other hand, appears to stimulate intestinal secretion by a direct action on mucosal cells.

Substance P was discovered in 1930 by von Euler and Gaddum (1931) in extracts of equine gut. The structure of the molecule was eventually determined in 1970 when it was isolated from hypothalamic extracts by Chang and Leeman(1970)(table 1). During the purification of substance P, a second peptide named neurotensin was detected and isolated(table 2). Since its isolation, substance P has been found to be widely distributed in the peripheral nervous system, particularly in a class of primary sensory afferent fibers responsible for transmitting nociceptive information to the spinal cord (H#{246} kfelt et al., 1976). Innervation of the gut by substance P-containing neurons is extensive(Costa et al., 1980; Franco et al., 1979; Jessen et al., 1980; Schultzberg et al., 1978, 1980) and specific neuronal actions of the peptide have been demonstrated by iontophoresis in the myenteric plexus (Katayama and North, 1978; Katayama et al., 1979). Terminals containing substance