Studies on Effects of the Substance P Analogues [D-Pro2, D-Trp7,9]-substance P and [D-Arg1, D-Trp7,9, L-Leu11]-substance P Not Related to Their Antagonist Action

Two tachykinin antagonists, [D-Pro2, D-Trp7,9]-substance P (AP-2) and [D-Arg1, D-Trp7,9, L-Leu11]-substance P (spantide) were injected or infused intraarterially into the isolated perfused rabbit ear connected to the body via the nerve only. The effects of these antagonists on venous outflow, release of histamine, and on acetylcholine-induced reflex fall in blood pressure were recorded. The effect of spantide was also investigated on cholinergic "twitch" responses to the isolated field stimulated ileum of the guinea-pig. Bolus injections of AP-2 (6.6 nmol and 20 nmol) and spantide 20 nmol and 66 nmol i.a. caused a dose-dependent reduction in venous outflow, which could mainly be explained by the release of histamine since the histamine H1 receptor blocker mepyramine inhibited this effect; release of histamine was also directly demonstrated. Injections of AP-2 (20 nmol) and spantide (66 nmol) caused nociceptor stimulation which might in part result from the histamine release. The reflex fall in blood pressure due to nociceptor stimulation by acetylcholine was reduced by less than 30% by infusion of the tachykinin antagonists in a concentration of 12 mumol l-1 but not at 2.4 mumol l-1. Spantide (up to 100 mumol l-1) did not inhibit electrically evoked "twitch" responses of the guinea-pig ileum. The local anaesthetic drug procaine (4.2-42 mumol l-1) inhibited these contractions in a concentration-dependent manner. It is concluded that the tachykinin antagonists might show effects which are not related to their specific tachykinin antagonistic action as indicated by the findings in the rabbit ear.(ABSTRACT TRUNCATED AT 250 WORDS)