Neurohumoral control of ileal electrolyte transport. II. Neurotensin and substance P

The peptides, neurotensin and substance P, caused transient increases in transepithelial potential difference and short-circuit current when added to the medium bathing the serosal 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 increment of 41 μA/cm² in short-circuit current and a half-maximal effect was produced by 3 x 10^-9 M neurotensin. Substance P caused a maximal increment of 63 μA/cm² in short-circuit current and a half-maximal effect occurred at a concentration of 3.5 x 10^-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 substance P was reversible. The effects of neurotensin and substance P were not blocked by atropine, indomethacin, diphenhydramine, 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.