A comparison of the effects of three substance P antagonists on tachykinin‐stimulated [³H]‐acetylcholine release in the guinea‐pig ileum

Abstract

Trp7'9,Leul ']SP( 1) and [D-Arg',D-Trp7 9'Leu' 'JSP(j Ij) (spantide) against eledoisin were examined in the guinea-pig ileum myenteric plexus, where a continuous superfusion system was employed to examine evoked release of [3H]-acetylcholine ([3H]-ACh]); effects on mechanical activity of the preparations were also measured. 2 Eledoisin was chosen as the standard tachykinin agonist since the rank order ofpotency observed in evoking release was eledoisin, kassinin, substance P, physalaemin; on this basis is may be presumed that an 'SP-E' type receptor was involved in the release process. 3 The two undecapeptide antagonists both significantly reduced the response to eledoisin (10 nM) as assessed by both [3H]-ACh release and mechanical activity which under these conditions was largely dependent on ACh release, and the response levels could be restored by increasing the concentration of eledoisin to 100 nM. The pA2 values for the two antagonists were estimated as 5. ,) being the most active in this respect, a 10 gM concentration producing 50% of the response seen with 10 nM eledoisin. 5 These findings are discussed both in relation to tachykinin receptor classifications and limitations in the use of such antagonists in the study of the role of tachykinins in neurotransmission.

Facilitation by tachykinins of neurotransmission in guinea‐pig pulmonary parasympathetic nerves

“…The rank order of potency for the augmentation of responses was NKA > eledoisin > SP, and this indicates that the neural effect is also mediated via an NK2 receptor. This correlates with findings in the guinea-pig gastrointestinal tract, in which an NK2 receptor is involved in modulating ACh release from the mesenteric plexus (Featherstone et al, 1986).…”

A tachykinin antagonist inhibits gastric emptying and gastrointestinal transit in the rat

“…The small contraction produced by Trp7' 1-substance P in the circular muscle of the rat gastric corpus may indicate a partial agonist activity, a property which has been previously described for some substance P antagonists on other preparations (Hawcock et al, 1982;Bailey & Jordan, 1984;Featherstone et al, 1986). Although the contractile effect of [D-Pro2, D-Trp7' 1-substance P was not further examined, it seems unlikely to be due to release of histamine, since histamine is ineffective in producing a contraction of this preparation.…”

“…These findings in the rat are consistent with previous findings in the guinea-pig intestine where concentrations of up to 80 ILM [D-Pro2, D-Trp7'1-substance P seem to be specific for substance P (Leander et al, 1981;Bartho et al, 1982). However, the finding that in the guinea-pig intestine [D-Pro2, D-Trp7'I-substance P and some related analogues are effective antagonists only at tachykinin receptors located on the smooth muscle and not on those located on enteric neurones (Nemeth et al, 1983;Costa et al, 1985;Kilbinger et al, 1986) needs to be taken into consideration, although this does not apply to all substance P antagonists (Featherstone et al, 1986).…”

Influence of perivascular peptides on endoneurial blood flow and microvascular resistance in the sciatic nerve of the rat.

“…Finally, it is possible that spantide activates an alternative receptor that mediates an overriding vasoconstriction or blocks the capsaicin receptor. The presence of more than one type of spantide-susceptible tachykinin receptor has been previously suggested (Chahl, 1985;Featherstone, Fosbraey & Morton, 1986;Buck & Shatzer, 1988;Nussbaumer, Yanagisawa & Otsuka, 1989).…”