The hypoxic ventilatory response and TRPA1 antagonism in conscious mice.
OBJECTIVE
Recently, TRPA1 channels, richly expressed in both peripheral and central neural systems, have been proposed as novel sensors of changes in oxygen concentration along the hypoxic-hyperoxic continuum. In this study, we investigated the hypothesis that TRPA1 channels blockade should profoundly affect the hypoxic ventilatory response (HVR).


METHODS
We examined the chemosensory ventilatory responses in conscious mice before and after intraperitoneal administration of the specific TRPA1 antagonist HC-030031 in two doses of 50 and 200 (cumulative dose 250) mg kg(-1) . Ventilation and its responses to mild 13% and severe 7% hypoxia, pure O2 , and 5% CO2 in O2 were recorded in a whole-body plethysmograph.


RESULTS
TRPA1 antagonism caused a dose-dependent attenuation of the HVR. Ventilatory stimulation was virtually abrogated in response to the mild, but it remained viable, albeit slashed, at severe hypoxia after the bigger dose of HC-030031. The TRPA1 function seemed specific for the hypoxic chemoreflex as neither the response to pure O2 nor hypercapnia was appreciably influenced by the TRPA1 antagonist.


CONCLUSIONS
The study unravelled the role of TRPA1 in shaping the ventilatory response to low-intensity hypoxia, liable to be mediated by vagally innervated respiratory chemosensors of lower functional rank, but contradicted the TRPA1 being indispensable for the powerful carotid body chemoreflex in face of a severe hypoxic threat.
Clinical Research Centre, National Hospital Organization Murayama Medical Center, Musashimurayama City, Japan; Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
M
M
Pokorski
K
K
Takeda
Y
Y
Sato
Y
Y
Okada
D000083:Acetanilides / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002344:Carotid Body / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010101:Oxygen Consumption; D012123:Pulmonary Ventilation; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D011687:Purines; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse
carotid chemoreceptors; chemosensing; hypercapnia; hyperventilation; hypoxia; oxygen sensor