The Effects of Substance P on Smooth Muscle Cells and on Neuro‐effector Transmission in the Guinea‐pig Ileum

Abstract

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. 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. SP (1010‐10‐8M) 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. In the circular muscle cells, low concentrations of SP (< 10−8M) did not affect the membrane potential or the spikes, but SP (10−7M) increased the spike discharges with no significant change in the membrane potential. SP (10−10M) reduced the threshold depolarization required for the generation of action potentials with no change in membrane potential of the longitudinal muscle cells. Pretreatment with atropine (5 × 10−6M), tetrodotoxin (TTX 10−6M) or baclofen (4.7 × 10−6M) had no effect on the excitatory actions of SP on the smooth muscle cells of longitudinal and circular muscle strips. 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. SP (10−10‐10−9M) 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 (10−10‐10−9M), however, did not change the amplitude of inhibitory junction potentials (i.j.ps) recorded from the circular muscle cells. 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.

On the mechanism of contraction and desensitization induced by substance P in the intestinal muscle of the guinea‐pig.

“…The situation is, however, complicated by the finding of unidirectional cross-desen-sitization/sensitization between substance P and tetraethylammonium. Monitoring the efflux of 86Rb (as a measure of membrane K+ permeability; see Burgen & Spero, 1968;Bolton, 1981) showed that tetraethylammonium and substance P, in concentrations up to 100 times higher than those producing 50 0 maximal contraction, slightly increased the 86Rb efflux into the standard medium, but since tetraethylammonium as well as substance P depolarize the smooth muscle (Bolton, 1979;Fujisawa & Ito, 1982) it is not possible to draw any conclusion as to the effect on resting K+ permeability. To the contrary, in K+ depolarized strips both substance P and tetraethylammonium appreciably reduced the 86Rb efflux indicating a reduction of a potential-sensitive K+ conductance.…”

“…One of them is that the initial step by which substance P elicits contraction of intestinal muscle is binding to specific receptors which are constituents of the muscle cell membrane (Hanley & Iversen, 1980). Activation of the receptors by substance P depolarizes the muscle cell membrane, evokes slow waves, reduces the threshold depolarization required for generation of action potentials, and initiates or increases the frequency of action potentials (Fujisawa & Ito, 1982). There is circumstantial evidence that these effects are brought about by a reduction of the K+ permeability of the cell membrane, but the permeability for other ions, particularly Ca2+, Cl-and Na+, may also be changed (Bury & Mashford, 1976;Fujisawa & Ito, 1982;Holzer, 1982).…”

“…Tetrodotoxin was therefore used in all ion flux experiments to block propagated effects of substance P on neurones, but local effects may well have persisted. As to the direct effect of substance P on the smooth muscle, the presence of tetrodotoxin in only the ion flux experiments should not pose any problems for interpretation, since neither the membrane effects nor the contractile response to substance P in the smooth muscle are affected by tetrodotoxin (Fujisawa & Ito, 1982).…”

“…Activation of the receptors by substance P depolarizes the muscle cell membrane, evokes slow waves, reduces the threshold depolarization required for generation of action potentials, and initiates or increases the frequency of action potentials (Fujisawa & Ito, 1982). There is circumstantial evidence that these effects are brought about by a reduction of the K+ permeability of the cell membrane, but the permeability for other ions, particularly Ca2+, Cl-and Na+, may also be changed (Bury & Mashford, 1976;Fujisawa & Ito, 1982;Holzer, 1982). The conductance changes induced by substance P in intestinal smooth muscle seem to be similar to those induced in neurones (Katayama et al 1979;Konishi, Tsunoo & Otsuka, 1979; Hosli, H6sli, Zehntner & Landolt, 1981;Minota, Dun & Karczmar, 1981;Nowak & MacDonald, 1981).…”

“…The contractile effect of substance P on the longitudinal muscle of the guinea-pig small intestine is mainly due to a direct action on the muscle cells (among others Bury & Mashford, 1977;Rosell, Bjorkroth, Chang, Yamaguchi, Wan, Rackur, Fisher & Folkers, 1977;Franco et al 1979); however, release of acetylcholine seems to contribute to maintaining the contractile response to substance P Holzer, Emson, Iversen & Sharman, 1981). Circumstantial evidence indicates that the mechanism underlying the direct contractile effect of substance P is inactivation of the resting K+ conductance (Fujisawa & Ito, 1982); a similar mechanism, reduction of a potential-sensitive K+ conductance, has been proposed to account for the facilitatory effect of substance P on the phasic contractions of the rabbit small intestine (Holzer, 1982).…”