TACHYKININERGIC TRANSMISSION TO THE CIRCULAR MUSCLE OF THE GUINEA-PIGILEUM - EVIDENCE FOR THE INVOLVEMENT OF NK2 RECEPTORS

1 The effect of newly developed, receptor-selective tachykinin antagon ists (GR 71,251 for NK1 receptors, MEN 10,376 and L 659,877 for NK2 re ceptors) 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-mu-M) and apamin (0.1-mu-M) evoked a complex motor response. The ton ic primary contraction in this response was reduced by GR 71,251 (10-m u-M) and MEN 10,376 (3-10-mu-M) but not by L 659,877 (up to 10-mu-M). The presence of apamin was necessary in this experimental arrangement to unmask an atropine-resistant primary contraction, sensitive to tach ykinin antagonists. The motor response was abolished by tetrodotoxin. 3 In circular strips of the ileum GR 71,251 (10-mu-M) inhibited the to nic contraction produced by [Sar9] substance P sulphone, a selective N K1 receptor agonist but not that produced by [beta-Ala8] neurokinin A (4-10), a selective NK2 receptor agonist. By contrast, MEN 10,376 anta gonized the effect of the NK2 agonist while leaving the response to th e NK1 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 p roduced atropine-sensitive phasic contractions (ascending enteric refl ex). In the presence of atropine (2-mu-M), a noncholinergic response w as elicited, which required larger volumes of distension that the chol inergic one. The atropine-resistant ascending enteric reflex was enhan ced by apamin (0.1-mu-M) and abolished by tetrodotoxin, either in the presence or absence of apamin. 5 MEN 10,376 (3-10-mu-M) inhibited the atropine-resistant ascending enteric reflex in the presence of apamin while GR 71,251 or L 659,877 (10-mu-M each) were ineffective. MEN 10,3 76 inhibited the atropine-resistant ascending enteric reflex to a larg er extent in the absence than in the presence of apamin and also sligh tly inhibited the ascending enteric reflex in the absence of atropine. 6 These findings provide evidence for an involvement of NK2 tachykini n receptors in excitatory transmission to the circular muscle of the g uinea-pig ileum. NK2 receptors are also involved in the physiological- like circular muscle activation produced by stimulation of intramural neuronal pathways which subserve the atropine-resistant ascending ente ric reflex.