Antagonist discrimination between subtypes of tachykinin receptors in the guinea-pig ileum

Abstract

The effects of substance P and eledoisin on spontaneous and electrically-evoked release of [3H]acetylcholine, and on smooth muscle were studied in the guinea-pig myenteric plexus-longitudinal muscle preparation preloaded with [3H]choline. Substance P and eledoisin caused transient increases in spontaneous release of [3H]-acetylcholine and in longitudinal muscle tone. Both tachykinins were equipotent in contracting the muscle, but eledoisin was more potent than substance P in eliciting [3H]acetylcholine release. The release caused by substance P was enhanced in the presence of naloxone and scopolamine which suggests that the release is modulated through opioid and muscarinic receptors. Substance P and eledoisin inhibited the release of [3H]acetylcholine evoked by electrical stimulation at 0.1 Hz. The inhibition was not due to an activation of alpha-adrenoceptors, histamine or opioid receptors. The substance P antagonists (D-Pro2, D-Trp7,9)SP (10 and 30 microM) and (Arg5, D-Trp7,9, Nle11)SP5-11 (1 and 10 microM) competitively antagonized both the contractile effects of substance P and eledoisin, and the inhibition by the tachykinins of the electrically-evoked release of [3H]acetylcholine. The increase in spontaneous [3H]acetylcholine release elicited by substance P and eledoisin was not prevented by the substance P antagonists. The results suggest that the neuronal receptor whose activation causes inhibition of acetylcholine release and the smooth muscle receptor correspond to the SP-P type, whereas the neuronal receptor mediating an increase in spontaneous acetylcholine release is of the SP-E type. The two antagonists, (D-Pro2, D-Trp7,9)SP and (Arg5, D-Trp7,9, Nle11)SP5-11, selectively block only the SP-P receptor.