1 The effects of substance P (SP) on the membrane and contractile properties of the smooth muscle cell, or on neuro-effector transmission in the guinea-pig ileum were observed by means of microelectrodes, double sucrose gap and tension recording.2 SP (10(-13)-10(-10)M) induced a phasic contraction of longitudinal muscle strips, but did not change the muscle tone of circular muscle strips, in concentrations up to 10(-8)M.3 SP (10(-10)-10(-8)M) evoked three different membrane responses in longitudinal muscle cells: (i) bursts of spike discharges with no significant change in the membrane potential and input membrane resistance; (ii) bursts of spike discharges with a small but clear depolarization of the membrane and increase in the input membrane resistance; (iii) slow waves with no change in the membrane potential.4 In the circular muscle cells, low concentrations of SP (<10(-8)M) did not affect the membrane potential or the spikes, but SP (10(-7)M) increased the spike discharges with no significant change in the membrane potential.5 SP (10(-10)M) reduced the threshold depolarization required for the generation of action potentials with no change in membrane potential of the longitudinal muscle cells.6 Pretreatment with atropine (5 x 10(-6)M), tetrodotoxin (TTX 10(-6)M) or baclofen (4.7 x 10(-6)M) had no effect on the excitatory actions of SP on the smooth muscle cells of longitudinal and circular muscle strips.7 Excitatory actions of SP on the membrane potential or spike activities of longitudinal muscle cells were preserved in NaCl but not in Ca-deficient solution.8 SP (10(-10)-10(-9)M) enhanced the amplitude of the excitatory junction potentials (e.j.ps) evoked by electrical field stimulation in longitudinal muscle cells with no change in the membrane potential and input resistance. SP (10(-10)-10(-9)M), however, did not change the amplitude of inhibitory junction potentials (i.j.ps) recorded from the circular muscle cells.9 These results indicate that SP in relatively low concentrations acts on both smooth muscle cells and on excitatory neuro-effector transmission in the longitudinal muscle; the main site of the action of SP is probably the muscle membrane.