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Abstract
Previous studies have suggested that carbon monoxide (CO) poisoning stimulates cAMP production via purine P2Y11-like receptors in the rat striatum, activating cAMP signaling pathways, resulting in hydroxyl radical (•OH) production. Extracellular ATP was thought likely to trigger the cascade, but the present study has failed to demonstrate a clear increase in the extracellular ATP due to CO poisoning. The CO-induced •OH production was attenuated by the P2Y11 receptor antagonist NF157, in parallel with its abilities to suppress the CO-induced cAMP production. The •OH production was more strongly suppressed by a non-selective P2 receptor antagonist, PPADS, which had no effect on cAMP production. More selective antagonists toward the respective P2 receptors susceptible to PPADS, including NF279, had little or no effect on the CO-induced •OH production. The intrastriatal administration of exogenous ATP dose-dependently stimulated •OH production, which was dose-dependently antagonized by PPADS and NF279 but not by NF157. Exogenous GTP and CTP dose-dependently stimulated •OH production, though less potently. The GTP-induced •OH production was susceptible to both of NF279 and PPADS, but the CTP-induced •OH production was resistant to PPADS. The mechanism of •OH production may differ between CO poisoning and exogenous ATP, while multiple P2 receptors could participate in •OH production. The CO-induced •OH production was susceptible to the inhibition of NADPH oxidase, but not xanthine oxidase. Also, the NADPH oxidase inhibition suppressed •OH production induced by forskolin, a stimulator of intracellular cAMP formation. It is likely that •OH is produced by NADPH oxidase activation via cAMP signaling pathways during CO poisoning.