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

Abstract

SUMMARY1. The contractile effect of substance P on the longitudinal muscle of the isolated guinea-pig small intestine and the desensitization of the muscle which occurs on prolonged exposure to the peptide have been investigated. All experiments were performed in the presence of atropine.2. The response to a substance P concentration which produced a nearly maximal effect was not sustained but faded rapidly. It was found that not elimination of substance P from the bath, but desensitization of the muscle to substance P was the main cause for the fading of contraction.3. Desensitization of the muscle to substance P only developed if the muscle was exposed to the peptide for a certain time. The degree of and the time needed for recovery from desensitization were directly related to concentration of substance P and contact time.4. Tetraethylammonium (3 mM), which reduces the membrane conductance for K+, enhanced the potency of substance P in contracting the muscle and reduced the fading of contraction. Noradrenaline (295 nM), which increases the K+ conductance, produced opposite effects.5. Lowering the extracellular Ca2+ concentration to one-tenth decreased the potency of substance P in contracting the muscle, accelerated the fading of contraction, and reduced the ability of the muscle to respond to a second addition of substance P after the response to the first addition had faded away.6. Concentrations of substance P (22 nM) and tetraethylammonium (30 mM), which produced nearly maximal contractions, slightly enhanced the efflux of 86Rb from pre-loaded muscle strips. Both substances, however, caused a sustained reduction of 86Rb efflux from strips depolarized by high [K+], the effect of substance P being smaller than that of tetraethylammonium. The effect of substance P and tetraethylammonium on 86Rb efflux appeared independent of the extracellular [Ca2+].7. On exposure of the muscle to substance P (22 nM) for 8 min the intracellular uptake of 46Ca was first decreased and then increased while the 45Ca influx was instantly enhanced by tetraethylammonium (30 mM) or K+ (108 mM). The delayed increase in 45Ca influx caused by substance P was also observed in muscle strips depolarized with high [K+].-P. HOLZER AND U. PETSCHE 8. Taken together, the results suggest that there are two mechanisms of action by which substance P causes contraction of intestinal smooth muscle: reduction of a K+ conductance and a mechanism dependent on the extracellular [Ca2+]. Circumstantial evidence indicates that desensitization of the muscle to substance P arises from a block in excitation-contraction coupling and the hypothesis has been put forward that fading of the contractile response and desensitization reflect depletion of a Ca2+ store which is operated by the substance P receptor.

Substance P can contract the longitudinal muscle of the guinea‐pig small intestine by releasing intracellular calcium

“…Low, submaximally effective, concentrations of SP elicit a sustained contraction (Holzer & Lembeck, 1980), membrane depolarization (due to reduced GK+) and Ca2+ influx (Bury & Mashford, 1976;Szeli et al, 1977;Fujisawa & Ito, 1982;Holzer & Petsche, 1983). Higher concentrations of SP, producing a contraction that after reaching a maximum fades away (Holzer & Lembeck, 1980), may release Ca2+ from an intracellular store.…”

“…Desensitization to substance P in Ca2+-free medium In a previous study (Holzer & Petsche, 1983) it was suggested that the desensitization of the ileal longitudinal muscle to SP, which is observed during the Q Ye Y prolonged presence of high SP concentrations, might be due to a depletion of an intracellular Ca2+ store. This possibility was tested in the present experiments.…”

“…The bath fluid could be changed rapidly by overflow. The preparations were kept under a resting load of 0.5 g, and longitudinal contractions were recorded isotonically (for further details see Holzer & Petsche, 1983).…”

“…It has been argued that the contraction in response to SP involves the mobilization of Ca2+ from an intracellular store and that depletion of this store might be responsible for desensitization but there was no direct experimental support for this proposal. In addition, SP was found to alter the transmembrane movements of 45Ca2+, but the changes were so complex that they could not be fully explained (Holzer & Petsche, 1983). …”

Pardaxin produces postjunctional muscle contraction in guinea‐pig intestinal smooth muscle

“…However, neither PX nor Pardachirus secretion (Parness & Zlotkin, 1976) was affected by TTX. High concentrations of 5-HT and SP are known to produce desensitization to their respective effects (Huidobro-Toro & Foree, 1980;Holzer & Petsche, 1983). However, in preparations desensitized to 5-HT and SP, PX maintained its activity.…”