Nitric oxide production is enhanced in rat brain before oxygen-induced convulsions

Abstract

Central nervous system oxygen toxicity (CNS O 2 toxicity) is preceded by release of hyperoxic vasoconstriction, which increases regional cerebral blood flow (rCBF). These increases in rCBF precede the onset of O 2-induced convulsions. We have tested the hypothesis that hyperbaric oxygen (HBO 2) stimulates NO production in the brain that leads to hyperemia and anticipates electrical signs of neurotoxicity. We measured rCBF and EEG responses in rats exposed at 4 to 6 atmospheres (ATA) of HBO 2 and correlated them with brain interstitial NO metabolites (NO x ) as an index of NO production. During exposures to hyperbaric oxygen rCBF decreased at 4 ATA, decreased for the initial 30 min at 5 ATA then gradually increased, and increased within 30 min at 6 ATA. Changes in rCBF correlated positively with NO x production; increases in rCBF during HBO 2 exposure were associated with large increases in NO x at 5 and 6 ATA and always preceded EEG discharges as a sign of CNS O 2 toxicity. In rats pretreated with l-NAME, rCBF remained maximally decreased throughout 75 min of HBO 2 at 4, 5 and 6 ATA. These data provide the first direct evidence that increased NO production during prolonged HBO 2 exposure is responsible for escape from hyperoxic vasoconstriction. The finding suggests that NO overproduction initiates CNS O 2 toxicity by increasing rCBF, which allows excessive O 2 to be delivered to the brain.