A study of [D-Pro2, D-Phe7, D-Trp9]-substance P and [D-Trp7,9]-substance P as tachykinin partial agonists in the rat colon

Abstract

Two substance P (SP) analogues, [D-Pro2, D-Phe7, D-Trp9]-SP (DPDPDT) and [D-Trp7,9]-SP (DT79), previously described as tachykinin antagonists, have been shown to contract the rat colon muscularis mucosae preparation. The maximum response exhibited by these analogues was about 30% that of the SP maximum, suggesting that they were acting as partial agonists relative to SP. The responses to DPDPDT were unaffected by pretreatment with mepyramine, methysergide or [Sar1, Ile5, Ala8]-angiotensin II, which abolished the responses to histamine, 5-hydroxytryptamine (5-HT) and angiotensin II, respectively. Methysergide also did not affect the responses to DT79; the other antagonists were not tested against this analogue. Indomethacin and cimetidine also had no inhibitory effect. Atropine (2 microM) was present in all experiments to prevent indirect muscarinic effects. Phenoxybenzamine did not affect the dose-response curves to SP, eledoisin-related peptide (ERP), kassinin, eledoisin or physalaemin, nor did it affect the responses to individual doses of DPDPDT or DT79. However, in the absence of atropine, it shifted the carbachol dose-response curve markedly to the right, and reduced its maximum. The tachykinin antagonist [D-Pro4, D-Trp7,9,10]-SP4-11 reduced the responses to individual matched doses of DPDPDT, DT79 and SP to the same degree, whilst leaving responses to 5-HT or angiotensin II unaffected. This suggested that DPDPDT and DT79 were acting at the same receptor as SP. The inhibitory effects of DPDPDT on responses to SP, ERP and kassinin, and that of DT79 on responses to SP, were analysed. All four combinations yielded data compatible with an interaction at only one receptor, although DPDPDT appeared slightly more potent at inhibiting responses to kassinin. The results are discussed in the light of the proposed existence of multiple tachykinin receptor subtypes. The possible influence of differential metabolism of tachykinin analogues is also considered.