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

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Abstract
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 was investigated. All experiments were performed in the presence of atropine. The response to a substance P concentration which produced a nearly maximal effect was not sustained and faded rapidly. It was found that desensitization of the muscle to substance P was the main cause for the fading of contraction. Desensitization of the muscle 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. Tetraethylammonium [TEA] (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 [norepinephrine] (295 nM), which increases the K+ conductance, produced opposite effects. Lowering the extracellular Ca2+ concentration to 1/10 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 2nd addition of substance P after the response to the 1st addition had faded away. Concentrations of substance P (22 nM) and TEA (30 mM), which produced nearly maximal contractions, slightly enhanced the efflux of 86Rb from pre-loaded muscle strips. Both substances caused a sustained reduction of 86Rb efflux from strips depolarized by high [K+], the effect of substance P being smaller than that of TEA. The effect of substance P and TEA on 86Rb efflux appeared independent of the extracellular [Ca2+]. On exposure of the muscle to substance P (22 nM) for 8 min the intracellular uptake of 45Ca was 1st decreased and then increased while the 45Ca influx was instantly enhanced by TEA (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+]. These results suggest that there are 2 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.