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

Abstract

1 We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. 2 Cyclosporin A (10 mM) failed to signi®cantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine E max ) induced by electrical ®eld stimulation (EFS). In contrast, eNANC responses were signi®cantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (tri¯uoromethyl)-benzyl and SR48968, respectively. 3 Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was signi®cantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 mM) signi®cantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. 4 The N-type calcium channel blocker, o-Conotoxin (oCTX: 10 nM), signi®cantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, o-CTX failed to signi®cantly reduce the contractile potency to capsaicin or cyclosporin A. 5 In bronchial preparations desensitized by repeated application of capsaicin (1 mM), the contractile responses to both cyclosporin A (100 mM) and FK506 (100 mM), were signi®cantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 mM) were not altered. Furthermore, repeated application of cyclosporin A (100 mM) signi®cantly inhibited the contractile response to capsaicin (1 mM). 6 The ®ndings 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 dierent mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.

Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats

“…However, disparate effects of CsA and tacrolimus on many mechanisms, such as in vitro constriction ( Epstein et al , 1998 ), and prostanoid ( Benigni et al , 1992 ) and NO production ( Dusting et al , 1999 ), have been described, so there is a clear precedent for differences in their pharmacodynamic actions. A recent example that may be relevant to their differential regional haemodynamic effects is the observation of Harrison et al (1998) that CsA and tacrolimus can both release neuropeptides from sensory nerves, but by different mechanisms. Furthermore, our finding that prolonged infusion of tacrolimus caused some mesenteric and hindquarters vasoconstriction in association with a slowly developing pressor effect might be explained by pharmacokinetic differences between tacrolimus and CsA, as might the differences in the rates of onset of the pressor effects of the two drugs when given by rapid bolus injection.…”

Sensory Nerves and Airway Irritability

“…By contrast, bradykinin, which acts only partially through TRPV1 gating on bronchopulmonary C-fibers, evokes little if any axon reflex (Mizrahi et al 1982;Bramley et al 1990;Schlemper and Calixto 2002). Other stimuli evoking an axon reflex include hypertonic saline, cold, dry air, PAR2 agonists, nicotine, immunosuppressants (cyclosporin A, FK 506), and TRPA1 receptor activation (Lundberg et al 1983;Umeno et al 1990;Mapp et al 1991;Harrison et al 1998;Pedersen et al 1998;Yoshihara et al 1998;Carr et al 2000;Ricciardolo et al 2000;Andresen and Saugstad 2008;Taylor-Clark et al 2008).…”