NMDA receptors and Nitric Oxide Synthase Regulate Encoding of Cough in the nTS

Abstract

We sought to locate and characterize the central terminations of cough receptor airway afferents in the nucleus tractus solitarii (nTS) of guinea pigs. Neuronal tracing indicated that cough receptors terminate in locations bordering the medial and intermediate nTS. Microinjection of NMDA receptor antagonists into these locations nearly abolished cough evoked by citric acid (0.001‐2M; 100μl aliquots) applied to the trachea of anaesthetised animals (vehicle: 10±3; AP‐5: 3±2; SDZ 220‐581: 0±0 coughs; n=3‐6).Microinjection of NMDA produced respiratory perturbations including tachypnoea (0.01nmol NMDA) and bradypnoea/apnoea (0.1nmol NMDA) that were eliminated by NMDA receptor antagonists or inhibitors of nitric oxide synthase (NOS): L‐NNA (non‐specific) or N‐propyl‐L‐arginine (NPLA) (neuronal NOS‐specific). NOS inhibitors also reduced citric acid‐evoked coughing (Vehicle: 11±2; L‐NNA: 4±1; NPLA 4±2 coughs; n=6‐8). Citric acid‐induced cough was not attenuated after inhibition of soluble guanylate cyclase (sGC) with ODQ (vehicle: 11±3 coughs; ODQ: 14±2 coughs; n=8) or potentiated after inhibition of phosphodiesterase‐5 (PDE5) with zaprinast (vehicle: 9±3 coughs; zaprinast 10±1 coughs; n=3). Our data indicates that reflex cough is dependent on NMDA receptor activation and/or NO in the nTS. NO signalling occurs independent of either sGC or PDE5, suggesting that alternative signalling mechanisms are at play.Work supported by NIH.