Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences

Abstract

1 Exogenous tachykinins modulate cholinergic neurotransmission in rabbit and guinea-pig airways. We have investigated the effect of selective tachykinin receptor agonists and antagonists on cholinergic neurotransmission evoked by electrical field stimulation (EFS) of bronchial rings in rabbit, guinea-pig and human airways in vitro to assess which type of tachykinin receptor is mediating this facilitatory effect. 2 Bronchial rings were set up for isometric tension recording. Contractile responses to EFS (60 V, 0.4 ms, 2 Hz for lOs every min) and exogenous acetylcholine (ACh) were obtained and the effects of selective tachykinin agonists and antagonists were investigated. 3 In rabbit bronchi the endogenous tachykinins, substance P (SP) and neurokinin A (NKA) (10 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, [SarISP sulphone (10 nM) evoked a maximal facilitatory action on cholinergic responses of 334.9 ± 63% (P<0.01) (pD2 = 8.5 ± 0.06) an effect which was blocked by the selective NKI-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 agonist, [PAla8]NKA(4-10) (1O nM), produced a maximum enhancement of 278 ± 83.5% (P<0.01) (pD2 = 8.7 ± 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P <0. 7 By contrast, in guinea-pig bronchi only the NK,-receptor agonist [SarISP sulphone (3 nM) was effective in enhancing cholinergic neurotransmission but the 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 cholinergic neurotransmission in rabbit (via NKI and NK2 receptors) and guinea-pig airways (via NKI receptor) but have no demonstrable effect on human airways

Role of tachykinin NK1 and NK2 receptors in allergen‐induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs

“…With respect to the latter point, it is important to note that methacholine‐induced bronchoconstriction results from direct stimulation of airway smooth muscle, whereas histamine‐induced bronchoconstriction is partially mediated by stimulation of afferent vagal nerve endings, leading to additional reflex bronchoconstriction, which may be enhanced after allergen challenge [35]. Because tachykinins, predominantly via stimulation of NK 1 receptors, may facilitate cholinergic neurotransmission in guinea pig airways [36], the enhanced cholinergic contribution to histamine‐induced bronchoconstriction may involve exaggerated NK 1 receptor stimulation, which is inhibited by SR 140333.…”

Effects of two β3‐adrenoceptor agonists, SR 58611A and BRL 37344, and of salbutamol on cholinergic and NANC neural contraction in guinea‐pig main bronchi in vitro

“…Finally, it might have been expected that inhibition of the NANC response would result in some diminution of cholinergic response, since it has been demonstrated that tachykinins may lead to facilitation of the cholinergic response induced by direct vagal nerve stimulation or by electrical field stimulation of the guinea-pig airway (Watson et al, 1992;Belvisi et al, 1993), and capsaicin, which depletes sensory nerves, may lead to a decrease of the cholinergic response (Stretton et al, 1992). This was apparently not the case in our experiments since inhibition of the NANC response induced by P-adrenoceptor agonists resulted in no modification of the cholinergic response, in agreement with our previous results (Martin et al, 1992) where we demonstrated that SR 48968, a selective antagonist of NK2 receptors, did not modify the first cholinergic response, and atropine did not modify the second NANC response.…”

Neurogenic mechanisms in bronchial inflammatory diseases

“…The underlying processes can even be initiated without a prior neuronal depolarization. Sensory nerve fibers are also known to project to local intrinsic airway ganglia (23,27), which may depolarize in response to tachykinins (28,29). Therefore, peripheral activation of sensory nerve fibers with consecutive neuropeptide release may also lead to a significant modulation of centrally mediated medullary reflexes (30).…”