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Acrolein Causes TRPA1-Mediated Sensory Irritation and Indirect Potentiation of TRPV1-Mediated Pulmonary Chemoreflex Response
HAZARI, M. S., N. HAYKAL-COATES, D. W. WINSETT, A. FARRAJ, AND D. L. COSTA. Acrolein Causes TRPA1-Mediated Sensory Irritation and Indirect Potentiation of TRPV1-Mediated Pulmonary Chemoreflex Response. Presented at Annual American Thoracic Society, San Diego, CA, May 15 - 20, 2009.
This study describes the effects of a single exposure to acrolein, in particular the potentiation of chemoreflex responsiveness during and following exposure. This study examines the role of the TRPA1 and TRPV1 channels in mediating the exaggerated response.
We previously demonstrated that acute exposure to acrolein causes immediate sensory irritation, with rapid decrease in heart rate (HR) and increase in inspiratory time (Ti), and potentiation of pulmonary chemoreflex response 24hrs later; of these effects only the latter is mediated by TRPV1 (Hazari et al. 2008). These experiments were designed to determine whether sensory irritation to acrolein is mediated by TRPA1 and to examine if blockade of TRPA1 prevents potentiation of chemoreflex response 24hrs later. Sprague-Dawley rats were treated with the general TRP-antagonist, ruthenium red (RR), the TRPA1 antagonist, camphor (CAM), or the novel TRPA1 antagonist, HC030031, and then exposed in a whole-body plethysmograph to either air or 3ppm acrolein for 3 hours while continuously monitoring ventilatory function and HR. 1 day later capsaicin (cap)-induced ventilatory and HR responses were measured in anesthetized rats. Acrolein exposure caused an immediate increase in Ti and drop in HR. Acrolein-induced increase in Ti was blocked in rats pretreated with RR or HC030031, but not CAM; whereas the drop in HR was completely prevented by HC030031 and only partially reduced by RR and CAM. 24hrs post-exposure, cap (1-8 μg/kg, iv) caused apnea in control rats, which was potentiated in rats exposed to acrolein. Only pretreatment with RR prevented potentiation of this apneic response to cap. Drugs had no effect on controls nor were there any differences in cap-induced HR response. These data suggest that sensory irritation during acrolein exposure is mediated by TRPA1; known partial activation of TRPV1 by CAM may explain why it had no effect. Prevention of chemoreflex potentiation 24hrs post-exposure by only RR and the lack of effect of CAM and HC030031 suggest that although TRPA1 is blocked, TRPV1 may still be sensitized by other mechanisms. In conclusion, although acrolein causes acute effects which are mediated by TRPA1, it may also indirectly result in the activation or sensitization of TRPV1, possibly through inflammation and release of mediators from damaged tissue. (This abstract does not reflect EPA policy.)