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The excitatory nonadrenergic noncholinergic (NANC) system, involving various neuropeptides of the tachykinin family, such as substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP), as transmitters, has now been well characterized. In airways, SP, NKA and CGRP are co-localized in the sensory unmyelinated C-fibres, which innervate all compartments of the airway wall from the trachea down to the bronchioles. C-fibre endings are found within the epithelium. They form a dense plexus in the subepithelial lamina propria, supply the glands, ramify within the smooth muscle layer and make direct contacts with postganglionic parasympathetic neurons, located in the local ganglion. In the trachea, this sensory innervation is almost exclusively derived from sensory vagal neurons, supplied by the jugular ganglion, whilst that of the lung is of mixed origin with a predominating vagal and a smaller spinal contribution [1][2][3][4][5]. The NANC system can be activated by different stimuli, which affect the chemosensitive C-fibre afferents in airways and lead to a local release of tachykinins that are responsible for several biological effects in the bronchopulmonary system: bronchospasm; increase in vascular permeability from postcapillary venules; stimulation of glandular secretion; facilitation of cholinergic neurotransmission; and recruitment and activation of some types of inflammatory cells. Sensory nerves also mediate respiratory defence reflexes, such as coughing, sneezing and secretion of mucus ( fig. 1).From these data, it has been hypothesized that abnormal stimulation of the sensory nerve terminals, e.g. induced by epithelial shedding as seen in asthma, results in enhanced release of tachykinins in the airway wall with subsequent exaggeration of inflammation. This concept of "neurogenic inflammation" introduces sensory nerve fibres as important components in the pathogenesis of asthma.The biological actions of tachykinins are mediated via three types of receptors, denoted neurokinins 1-3 (NK 1 , NK 2 and NK 3 ), which have the highest affinity for SP, NKA and NKB, respectively. This receptor classification has been established from receptor-binding and functional studies. It has now been recognized that the expression of tachykinin NK 3 receptors is confined mainly to the central and peripheral nervous system, whilst tachykinin NK 1 and tachykinin NK 2 receptors are expressed both in the central and peripheral nervous system and in target organs, including airways [5][6][7][8][9][10]. According Taken together, the results obtained with the various selective receptor antagonists provide pharmacological evidence that tachykinins play a role in delayed bronchopulmonary alterations and suggest that tachykinin receptor antagonists may be useful for investigating mechanisms and possibly reducing airway functional alterations in asthmatic patients. PHARMACOLOGICAL REVIEW

Sensitive afferent nerves and the neurokinins they release upon activation are considered to be important in controlling bronchomotor tone. Human isolated bronchi respond to neurokinin A (NKA), substance P (SP), and neurokinin B (NKB) with dose-dependent contractions. The order of potency of the three natural neurokinins is NKA greater than SP greater than NKB, suggesting the presence of NK-2 receptors. To further characterize the neurokinin receptors in human bronchi, we used selective agonists for each receptor type (i.e., NK-1, NK-2, and NK-3). In fact, NK-1 selective compounds, [Pro9]SP(1-11) sulfone and [beta-ala4,Sar9]SP(4-11) sulfone, did not induce significant contractions up to 10(-5) M. Similarly, the selective agonist for the NK-3 receptor, [MePhe7]NKB(4-10), was almost inactive. However, the NK-2 selective fragment [Nle]NKA(4-10) was a potent stimulant. The negative log of the peptide concentration that caused 50% of maximal effect (pD2) was 6.99 for NKA and 6.12 for [Nle10]NKA(4-10). Removal of the epithelium significantly enhanced the contractile responses to the three neurokinins and also to the NK-2 selective agonist. Phosphoramidon, an enkephalinase inhibitor, was more potent than epithelium removal in enhancing the contractile responses to these agonists. However, epithelium removal and phosphoramidon did not increase the weak responses to the NK-1 and NK-3 selective compounds. In the presence of phosphoramidon, removal of the epithelium slightly enhanced the contractile responses to NKA and [Nle]NKA(4-10) but not to SP and NKB.(ABSTRACT TRUNCATED AT 250 WORDS)

Indacaterol is a novel b 2 -adrenoceptor agonist in development for the once-daily treatment of asthma and chronic obstructive pulmonary disease. The present study evaluated the relaxant effect of indacaterol on isolated human bronchi obtained from lungs of patients undergoing surgery for lung carcinoma.Potency (-logEC50), maximal relaxant effect (Emax) and onset of action were determined at resting tone. Duration of action was determined against cholinergic neural contraction induced by electrical field stimulation (EFS).At resting tone, -logEC50 and Emax values were 8.82¡0.41 and 77¡5% for indacaterol, 9.84¡0.22 and 94¡1% for formoterol, 8.36¡0.16 and 74¡4% for salmeterol, and 8.43¡0.22 and 84¡4% for salbutamol, respectively.In contrast to salmeterol, indacaterol did not antagonise the isoprenaline response. Indacaterol's onset of action (7.8¡0.7 min) was not significantly different from that of formoterol (5.8¡0.7 min) or salbutamol (11.0¡4.0 min), but it was significantly faster than that of salmeterol (19.4¡4.3 min). EFS-induced contractions were inhibited with -logIC50 values of 6.96¡0.13 (indacaterol), 8.96¡0.18 (formoterol), 7.18¡0.34 (salmeterol) and 6.39¡0.26 (salbutamol). Duration of action was .12 h for indacaterol and salmeterol, and 35.3¡8.8 and 14.6¡3.7 min for formoterol and salbutamol, respectively.In isolated human bronchi, indacaterol behaved as a long-acting b 2 -adrenoceptor agonist with high intrinsic efficacy and fast onset of action.