Abstract
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 (Bf) 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 Bf is associated with enhanced in vivo 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 f, action potentials/s) during quasi-static inflation [0–20 cmH2O trans-respiratory pressure (PTR)] in NEB-relevant conditions of hypoxia (FIO2 = 0.1), hypercarbia (FICO2 = 0.1), and pharmacologic intervention (serotonergic 5-HT3 receptor antagonist, Tropisetron, 4.5 mg/kg; P2 purinergic receptor antagonist, Suramin, 50 mg/kg). In all protocols, we obtained: (1) AP f vs. PTR; (2) PTR threshold; and (3) AP f onset at PTR threshold. The murine AP f vs. PTR response comprises high AP f (average maximum AP f: 236.1 ± 11.1 AP/s at 20 cmH2O), a low PTR threshold (mean 2.0 ± 0.1 cmH2O), and a plateau in AP f between 15 and 20 cmH2O. Murine SAR mechanosensitivity (AP f vs. PTR) 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% (p = 0.005); Suramin −10.6 ± 1.5% (p = 0.01); hypoxia +9.3 ± 1.9% (p < 0.001); and hypercarbia −6.2 ± 0.9% (p < 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 Bf of the mouse. We found minimal evidence supporting a functional link between SARs and NEBs and speculate that the <10% change in SAR mechanosensitivity during altered NEB-related stimuli is not consistent with a meaningful physiologic role.
Highlights
Several laboratories are known for seminal studies of the electrophysiologic characteristics of three primary populations of mammalian pulmonary vagal afferent fibers: myelinated, mechanosensitive slowly adapting (SARs) and rapidly adapting receptors (RARs; Adrian, 1933; Widdicombe and Nadel, 1963; Miserocchi and Sant’Ambrogio, 1974; Bartlett and Sant’Ambrogio, 1976; Sant’Ambrogio and Mortola, 1977), and non-myelinated, nociceptive C-fibers (Paintal, 1969; Coleridge and Coleridge, 1984; Lee and Pisarri, 2001; Carr and Undem, 2003; Canning et al, 2006)
We addressed the fundamental mechanosensitive properties of murine Slowly adapting receptors (SARs) referenced to AW pressure with a range of indices including static sensitivity (AP f) of the receptor to transmural pressure, Trans-respiratory pressure (PTR) threshold for activation, and the threshold Action potential (AP) f
We report : (1) the first in-depth characterization of murine SAR mechanosensitivity relative to trans-respiratory pressure in the C57BL/6 strain of mice commonly employed in biomedical research and (2) characterization of murine SAR chemosensitivity and pharmacology
Summary
Several laboratories are known for seminal studies of the electrophysiologic characteristics of three primary populations of mammalian pulmonary vagal afferent fibers: myelinated, mechanosensitive slowly adapting (SARs) and rapidly adapting receptors (RARs; Adrian, 1933; Widdicombe and Nadel, 1963; Miserocchi and Sant’Ambrogio, 1974; Bartlett and Sant’Ambrogio, 1976; Sant’Ambrogio and Mortola, 1977), and non-myelinated, nociceptive C-fibers (Paintal, 1969; Coleridge and Coleridge, 1984; Lee and Pisarri, 2001; Carr and Undem, 2003; Canning et al, 2006). SARs are identified on the basis of an augmenting action potential (AP) discharge frequency (AP f, i.e., AP/s relative to airway pressure or trans-respiratory pressure, PTR) during inflation and a sustained discharge with minimal adaptation during maintained inflation [i.e., the adaptation index We addressed the fundamental mechanosensitive properties of murine SARs referenced to AW pressure with a range of indices including static sensitivity (AP f) of the receptor to transmural pressure, PTR threshold for activation, and the threshold AP f. We speculate that the rapid breathing frequency (Bf) of the mouse, which ranges from approximately 150 to 200 breaths per minute at rest (Mortola and Noworaj, 1985; Vincent et al, 2007), would benefit from an enhanced static SAR mechanosensitivity in order to achieve sensory feedback on operating lung volumes (Vinegar et al, 1979). Feedback on operating lung volumes is important in health and disease (O’Donnell et al, 2016, 2017), as well as in breath-by-breath regulation of Bf and tidal volume
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