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Phosphodiesterase-5 inhibitors oppose hyperoxic vasoconstriction and accelerate seizure development in rats exposed to hyperbaric oxygen

¹Center for Hyperbaric Medicine and Environmental Physiology, ²Department of Anesthesiology, and ³Division of Pulmonary Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina; and ⁴Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

Submitted 23 October 2008 ; accepted in final form 22 January 2009

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 N-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.

nitric oxide; oxygen seizures; phosphodiesterase-5 blockers; cerebral blood flow