Tachykininergic transmission to the circular muscle of the guinea‐pig ileum: evidence for the involvement of NK 2 receptors

1 The effect of newly developed, receptor‐selective tachykinin antagonists (GR 71,251 for NK 1 receptors, MEN 10,376 and L 659,877 for NK 2 receptors) on noncholinergic transmission to the circular muscle of the guinea‐pig ileum has been investigated. 2 In circular muscle strips of the ileum, electrical field stimulation in the presence of atropine (2 μ m ) and apamin (0.1 μ m ) evoked a complex motor response. The tonic primary contraction in this response was reduced by GR 71,251 (10 μ m ) and MEN 10,376 (3–10 μ m ) but not by L 659,877 (up to 10 μ m ). The presence of apamin was necessary in this experimental arrangement to unmask an atropine‐resistant primary contraction, sensitive to tachykinin antagonists. The motor response was abolished by tetrodotoxin. 3 In circular strips of the ileum GR 71,251 (10 μ m ) inhibited the tonic contraction produced by [Sar 9 ] substance P sulphone, a selective NK 1 receptor agonist but not that produced by [β Ala 8 ] neurokinin A (4–10), a selective NK 2 receptor agonist. By contrast, MEN 10,376 antagonized the effect of the NK 2 agonist while leaving the response to the NK 1 agonist unaffected. 4 In whole segments of the ileum, distension of the gut wall by an intraluminal balloon placed at about 1 cm from the point of recording of mechanical activity of the circular muscle produced atropine‐sensitive phasic contractions (ascending enteric reflex). In the presence of atropine (2 μ m ), a noncholinergic response was elicited, which required larger volumes of distension that the cholinergic one. The atropine‐resistant ascending enteric reflex was enhanced by apamin (0.1 μ m ) and abolished by tetrodotoxin, either in the presence or absence of apamin. 5 MEN 10,376 (3–10 μ m ) inhibited the atropine‐resistant ascending enteric reflex in the presence of apamin while GR 71,251 or L 659,877 (10 μ m each) were ineffective. MEN 10,376 inhibited the atropine‐resistant ascending enteric reflex to a larger extent in the absence than in the presence of apamin and also slightly inhibited the ascending enteric reflex in the absence of atropine. 6 These findings provide evidence for an involvement of NK 2 tachykinin receptors in excitatory transmission to the circular muscle of the guinea‐pig ileum. NK 2 receptors are also involved in the physiological‐like circular muscle activation produced by stimulation of intramural neuronal pathways which subserve the atropine‐resistant ascending enteric reflex.