AUTHOR=Domnik Nicolle J. , Vincent Sandra G. , Fisher John T. 

TITLE=Mechanosensitivity of Murine Lung Slowly Adapting Receptors: Minimal Impact of Chemosensory, Serotonergic, and Purinergic Signaling

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.833665

DOI=10.3389/fphys.2022.833665

ISSN=1664-042X

ABSTRACT=<p>Murine slowly adapting receptors (SARs) within airway smooth muscle provide volume-related feedback; however, their mechanosensitivity and morphology are incompletely characterized. We explored two aspects of SAR physiology: their inherent static mechanosensitivity and a potential link to pulmonary neuroepithelial bodies (NEBs). SAR mechanosensitivity displays a rate sensitivity linked to speed of inflation; however, to what extent static SAR mechanosensitivity is tuned for the very rapid breathing frequency (B<italic><sub>f</sub></italic>) of small mammals (e.g., mouse) is unclear. NEB-associated, morphologically described smooth muscle-associated receptors (SMARs) may be a structural analog for functionally characterized SARs, suggesting functional linkages between SARs and NEBs. We addressed the hypotheses that: (1) rapid murine B<italic><sub>f</sub></italic> is associated with enhanced <italic>in vivo</italic> SAR static sensitivity; (2) if SARs and NEBs are functionally linked, stimuli reported to impact NEB function would alter SAR mechanosensitivity. We measured SAR action potential discharge frequency (AP <italic>f</italic>, action potentials/s) during quasi-static inflation [0–20 cmH<sub>2</sub>O trans-respiratory pressure (P<sub>TR</sub>)] in NEB-relevant conditions of hypoxia (F<sub>I</sub>O<sub>2</sub> = 0.1), hypercarbia (F<sub>I</sub>CO<sub>2</sub> = 0.1), and pharmacologic intervention (serotonergic 5-HT<sub>3</sub> receptor antagonist, Tropisetron, 4.5 mg/kg; P2 purinergic receptor antagonist, Suramin, 50 mg/kg). In all protocols, we obtained: (1) AP <italic>f</italic> vs. P<sub>TR</sub>; (2) P<sub>TR</sub> threshold; and (3) AP <italic>f</italic> onset at P<sub>TR</sub> threshold. The murine AP <italic>f</italic> vs. P<sub>TR</sub> response comprises high AP <italic>f</italic> (average maximum AP <italic>f</italic>: 236.1 ± 11.1 AP/s at 20 cmH<sub>2</sub>O), a low P<sub>TR</sub> threshold (mean 2.0 ± 0.1 cmH<sub>2</sub>O), and a plateau in AP <italic>f</italic> between 15 and 20 cmH<sub>2</sub>O. Murine SAR mechanosensitivity (AP <italic>f</italic> vs. P<sub>TR</sub>) is up to 60% greater than that reported for larger mammals. Even the maximum difference between intervention and control conditions was minimally impacted by NEB-related alterations: Tropisetron −7.6 ± 1.8% (<italic>p</italic> = 0.005); Suramin −10.6 ± 1.5% (<italic>p</italic> = 0.01); hypoxia +9.3 ± 1.9% (<italic>p</italic> &lt; 0.001); and hypercarbia −6.2 ± 0.9% (<italic>p</italic> &lt; 0.001). We conclude that the high sensitivity of murine SARs to inflation provides enhanced resolution of operating lung volume, which is aligned with the rapid B<italic><sub>f</sub></italic> of the mouse. We found minimal evidence supporting a functional link between SARs and NEBs and speculate that the &lt;10% change in SAR mechanosensitivity during altered NEB-related stimuli is not consistent with a meaningful physiologic role.</p>