title: Phosphodiesterase-5 inhibitors oppose hyperoxic vasoconstriction and accelerate seizure development in rats exposed to hyperbaric oxygen.
abstract: Oxygen is a potent cerebral vasoconstrictor, but excessive exposure to hyperbaric oxygen (HBO(2)) can reverse this vasoconstriction by stimulating brain nitric oxide (NO) production, which increases cerebral blood flow (CBF)-a predictor of O(2) convulsions. We tested the hypothesis that phosphodiesterase (PDE)-5 blockers, specifically sildenafil and tadalafil, increase CBF in HBO(2) 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(omega)-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% O(2) at 1 atm absolute (ATA) ("air") or to 100% O(2) at 4 or 6 ATA. EEG spikes indicated central nervous system CNS O(2) toxicity. The effects of PDE-5 blockade varied as a positive function of ambient Po(2). In air, CBF did not increase significantly, except after pretreatment with SNAP. However, at 6 ATA O(2), 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 HBO(2) were also more susceptible to CNS O(2) 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 HBO(2) by hastening onset of CNS O(2) toxicity.
authors.affiliation: Center for Hyperbaric Medicine and Environmental Physiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ivan T
authors.initials: IT
authors.lastname: Demchenko
authors.forename: Alex
authors.initials: A
authors.lastname: Ruehle
authors.forename: Barry W
authors.initials: BW
authors.lastname: Allen
authors.forename: Richard D
authors.initials: RD
authors.lastname: Vann
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000758:Anesthesia; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D006931:Hyperbaric Oxygenation; D018496:Hyperoxia / Q000188:drug therapy / Q000503:physiopathology*; D007262:Infusions, Intravenous; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D052248:Nitric Oxide Synthase Type I; D006162:Guanylate Cyclase; D006152:Cyclic GMP