Halothane attenuates the cerebroprotective action of several Na+ and Ca2+ channel blockers via reversal of their ion channel blockade.
We have previously shown the involvement of Na(+) channel as well as N-type and P/Q-type Ca(2+) channels in the oxygen and glucose deprivation-induced injury in rat cerebrocortical slices. In the present study, we investigated the influence of halothane on the cerebroprotective effects of a variety of Na(+) and Ca(2+) channel blockers in rat cerebrocortical slices. The hypoxic injury was attenuated by Na(+) channel blockers including tetrodotoxin, lidocaine and dibucaine, and Ca(2+) channel blockers, such as verapamil, omega-agatoxin IVA and omega-conotoxin GVIA. Halothane abolished the protective effects of lidocaine, dibucaine and verapamil, all of which block the respective cation channels in a voltage-dependent manner, without affecting the actions of tetrodotoxin, omega-agatoxin IVA and omega-conotoxin GVIA, which reveal voltage-independent blockade. On the other hand, the nitric oxide synthesis estimated from the extracellular cyclic GMP formation was elevated during exposure to hypoxia. All channel blockers tested here attenuated hypoxia-evoked nitric oxide synthesis. Halothane blocked almost completely these actions of lidocaine and verapamil. Moreover, the Na(+) and Ca(2+) channel blockade by these compounds, as determined by veratridine- and KCl-stimulated nitric oxide synthesis, respectively, was also reversed by halothane. These findings suggest that an anesthetic agent halothane reversed the Na(+) and Ca(2+) channel blockade of several voltage-dependent ion channel blockers, leading to the attenuation of their cerebroprotective actions. Therefore, the influence of halothane anesthesia should be taken into consideration for the evaluation of neuroprotective action of Na(+) and Ca(2+) channel blockers.
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D006221:Halothane / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D009569:Nitric Oxide; D005947:Glucose; D006221:Halothane