Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea‐pig isolated bronchus

1 We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. 2 Cyclosporin A (10 μm) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-l-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. 3 Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 μm) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. 4 The N-type calcium channel blocker, ω-Conotoxin (ωCTX: 10 nm), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, ω-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. 5 In bronchial preparations desensitized by repeated application of capsaicin (1 μm), the contractile responses to both cyclosporin A (100 μm) and FK506 (100 μm), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 μm) were not altered. Furthermore, repeated application of cyclosporin A (100 μm) significantly inhibited the contractile response to capsaicin (1 μm). 6 The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels. British Journal of Pharmacology (1998) 125, 1405–1412; doi:10.1038/sj.bjp.0702198