Inhalation of irritants activates airway vagal afferent nerves, evoking cardiopulmonary reflexes. Evidence suggests that cardiopulmonary reflexes evoked by irritant/pollution inhalation are remodeled from bradycardia in normal subjects to tachycardia and ventricular arrhythmia in patients with pre-existing cardiovascular disease. We have shown similar remodeling in the spontaneously hypertensive (SH) rat: selective activation of airway vagal afferent nerves via inhalation of the TRPA1-specific agonist allyl isothiocyanate (AITC) evoked parasympathetic-mediated reflex bradycardia in normotensive wistar-kyoto rats but evoked sympathetically-mediated tachycardia and premature ventricular contractions (PVCs) in spontaneously hypertensive (SH) rats.
Activation of TRPA1-expressing airway vagal afferents also evokes cough in some conscious animal models. Cough reflexes have been shown to be inhibited by nasal stimulation with L-menthol via activation of TRPM8 ion channels expressed on cold-sensitive trigeminal afferents which regulate brainstem respiratory networks. Here, we investigated the cardiopulmonary reflexes evoked by inhalation of L-menthol (150mg/ml) alone and in combination with AITC (4.7mg/ml) in SH rats. L-menthol inhalation alone had no effect on respiration/heart rate, but, when inhaled during AITC inhalation, L-menthol selectively inhibited the AITC-evoked tachyarrhythmia and tachypnea. Importantly, the inactive isomer D-menthol (150mg/ml) failed to affect AITC-evoked sympathoexcitatory reflexes. In another set of studies, the selective TRPM8 agonist WS-12 (300mM) also inhibited the AITC-evoked tachyarrhythmia. Therefore, we conclude that aberrant cardiopulmonary reflexes evoked by irritant inhalation are reduced by activation of menthol-sensitive pathways within the airways. This data supports the therapeutic potential of menthol treatment against irritant-evoked cardiopulmonary reflexes.
