Microinjection of kynurenic acid induces airway smooth muscle relaxation in ferrets

Abstract

Beside extensive study central mechanisms and neuronal networks that control airway constriction and relaxation remain unclear and poorly understood. In the present study realized in anesthetized, paralyzed and artificially ventilated ferrets we sought to determine whether nicotinic acetylcholine receptors (nAChRs) dominate respiratory drive under control conditions due to suppression of N‐methyl‐D‐aspartate (NMDA) receptors. We observed that blockade of cholinesterase activity by administration of eserine is followed by increased cholinergic outflow and airway smooth muscle tone (ASMT). Microinjection of kynurenic acid (KYNA) as NMDA receptor blockers, into the region of the ventrolateral medulla where airway related vagal preganglionic neurons (AVPNs) are located, significantly decreased the reflex changes in tracheal tone. KYNA, a product of tryptophan metabolism has neuroprotective and neuroinhibitory properties that have been attributed to its action as competitive antagonist at the glycine site on NMDA receptors. Furthermore, KYNA non‐competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. In our physiological experiments performed under in vivo conditions we conclude that stimulation or inhibition of AVPNs by eserine or KYNA was manifested with increase or decrease, respectively, of pressure in tracheal segment (Ptseg), lung resistance (RL), or dynamic compliance (Cdyn). Our results indicate that nAChRs might be targets for KYNA and suggest a functionally significant cross reaction between the nicotinic cholinergic system and kynurenine pathway in AVPNs and respiratory drive.