Characterization of the acute nasal response to inspired acetaldehyde in the F-344 rat

Date of Completion

January 1999

Keywords

Health Sciences, Toxicology|Environmental Sciences

Degree

Ph.D.

Abstract

Acetaldehyde is the aldehyde of greatest concentration in environmental tobacco smoke. Acetaldehyde is metabolized via aldehyde dehydrogenase to acetic acid. Both are sensory irritants. Acute exposure to acetaldehyde produced a prolonged, concentration dependent nasal vasodilatory response. The studies of the current project were designed to examine the hypothesis that inspired acetaldehyde and/or its metabolite, acetic acid stimulates nasal sensory nerves resulting in altered nasal vascular function mediated by the release of substance P and/or the production of nitric oxide. To examine the role of sensory nerves in the response to acetaldehyde, animals were pretreated with a dose of capsaicin known to defunctionalize sensory c-fibers. Capsaicin pretreatment significantly diminished the vasodilatory response suggesting that this response is mediated, in part, by sensory nerve stimulation. To examine the involvement of substance P, animals were pretreated with the NK-1 receptor antagonist ATFB. Pretreatment with ATFB was without effect on the response to acetaldehyde. Animals were pretreated with the nitric oxide synthase (NOS) inhibitor L-NAME to examine the role of nitric oxide. Pretreatment with L-NAME significantly attenuated the response to acetaldehyde. To provide information on the cellular source of nitric oxide, animals were pretreated with the neuronal NOS inhibitor, 7-Nitroindazole. 7-Nitroindazole was without effect suggesting that nerves are not the source of nitric oxide in the response to acetaldehyde. Exposure to acetic acid vapor produced a response identical to that of acetaldehyde, suggesting that this metabolite may play a role in acetaldehyde-induced vasodilation. To confirm that acetaldehyde is metabolized in nasal tissues, animals were pretreated with the ALDH inhibitor cyanamide. Cyanamide pretreatment inhibited ALDH specific activity in nasal tissues by 60% and diminished inspired acetaldehyde uptake. This suggests that a significant fraction of inspired acetaldehyde was metabolized by nasal ALDH. Pretreatment with cyanamide diminished the response to acetaldehyde at the highest exposure concentration tested. Together, these results suggest that this response may be dependent upon both acetaldehyde, and its metabolite, acetic acid. In summary, inspired acetaldehyde produces a nasal vasodilatory response which is mediated, in part, by sensory nerve stimulation and the production of nitric oxide and is dependent upon both parent and metabolite. ^

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