Oxygen is a potent cerebral vasoconstrictor, but excessive exposure to hyperbaric oxygen (HBO2) can reverse this vasoconstriction by stimulating brain nitric oxide (NO) production, which increases cerebral blood flow (CBF)—a predictor of O2 convulsions. We tested the hypothesis that phosphodiesterase (PDE)-5 blockers, specifically sildenafil and tadalafil, increase CBF in HBO2 and accelerate seizure development. To estimate changes in cerebrovascular responses to hyperoxia, CBF was measured by hydrogen clearance in anesthetized rats, either control animals or those pretreated with one of these blockers, with the NO inhibitor Nω-nitro-l-arginine methyl ester (l-NAME), with the NO donor S-nitroso- N-acetylpenicillamine (SNAP), or with a blocker combined with l-NAME. Animals were exposed to 30% O2 at 1 atm absolute (ATA) (“air”) or to 100% O2 at 4 or 6 ATA. EEG spikes indicated central nervous system CNS O2 toxicity. The effects of PDE-5 blockade varied as a positive function of ambient Po2. In air, CBF did not increase significantly, except after pretreatment with SNAP. However, at 6 ATA O2, mean values for CBF increased and values for seizure latency decreased, both significantly; pretreatment with l-NAME abolished these effects. Conscious rats treated with sildenafil before HBO2 were also more susceptible to CNS O2 toxicity, as demonstrated by significantly shortened convulsive latency. Decreases in regional CBF reflect net vasoconstriction in the brain regions studied, since mean arterial pressures remained constant or increased throughout. Thus PDE-5 blockers oppose the protective vasoconstriction that is the initial response to hyperbaric hyperoxia, decreasing the safety of HBO2 by hastening onset of CNS O2 toxicity.
HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies
