FACILITATORY EFFECTS OF SELECTIVE AGONISTS FOR TACHYKININ RECEPTORS ON CHOLINERGIC NEUROTRANSMISSION - EVIDENCE FOR SPECIES-DIFFERENCES

1 Exogenous tachykinins modulate cholinergic neurotransmission in rabb it and guinea-pig airways. We have investigated the effect of selectiv e tachykinin receptor agonists and antagonists bn cholinergic neurotra nsmission evoked by electrical field stimulation (EFS) of bronchial ri ngs in rabbit, guinea-pig and human airways in vitro to assess which t ype of tachykinin receptor is mediating this facilitatory effect. 2 Br onchial rings were set up for isometric tension recording. Contractile responses to EFS (60 V, 0.4 ms, 2 Hz for 10 s every min) and exogenou s acetylcholine (ACh) were obtained and the effects of selective tachy kinin agonists and antagonists were investigated. 3 In rabbit bronchi the endogenous tachykinins, substance P (SP) and neurokinin A (NKA) (1 0 nM) potentiated cholinergic responses to EFS (by 287.6 +/- 121%, P < 0.01 and 181.4 +/- 56.5%, P < 0.001 respectively). 4 The NK1 receptor selective agonist, [Sar(9)]SP sulphone (10 nM) evoked a maximal facil itatory action on cholinergic responses of 334.9 +/- 63% (P < 0.01) (p D(2) = 8.5 +/- 0.06) an effect which was blocked by the selective NK1- receptor antagonist, CP 96,345 (100 nM) (P < 0.05) but not by the NK2 receptor antagonist, MEN 10,376 (100 nM). The NK2 receptor selective a gonist, [beta Ala(8)]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD(2) = 8.7 + 0.1) an effect which was b locked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345. [MePhe( 7)]NKB, an NK3 receptor selective agonist was without effect. 5 The ra nk order of potency of NK2 receptor antagonists against enhancement of cholinergic responses by [beta Ala(8)]NKA(4-10) was MEN 10,376 > L 65 9,877> R 396. This pattern together with the observation of the full a gonist activity of MDL 28,564 indicates that the NK2 receptors in the rabbit bronchus are similar to those which are present in the rabbit p ulmonary artery. 6 Neither [Sar(9)]SP sulphone (5 nM) nor [beta Ala(8) ]NKA(4-10) (1 nM) had any effect on contractile responses to ACh (10 m u M) suggesting a pre-junctional mechanism of action. 7 By contrast, i n guinea-pig bronchi only the NK1-receptor agonist [Sar(9)]SP sulphone (3 nM) was effective in enhancing cholinergic neurotransmission but t he effect was relatively small (maximal enhancement 25.7 +/- 5.5%, P < 0.01). In human bronchial rings all the selective neurokinin agonists were without effect on cholinergic neurotransmission. 8 These results suggest that tachykinins may play an important role in modulating cho linergic neurotransmission in rabbit (via NK1 and NK2 receptors) and g uinea-pig airways (via NK1 receptor) but have no demonstrable effect o n human airways