title: Peroxynitrite donor impairs excitability of hippocampal CA1 neurons by inhibiting voltage-gated potassium currents.
abstract: Nitric oxide (NO) reacts rapidly with superoxide anion and produces peroxynitrite (ONOO(-)), which is a highly reactive free radical that has been shown to mediate much of the toxicity of NO. ONOO(-) has also been implicated as playing a role in the pathology of various brain disorders. The aim of this study was to investigate the actions of ONOO(-) on voltage-activated potassium currents and its effect on membrane excitability in hippocampal CA1 neurons. SIN-1(3-morpholino-sydnonimine), which leads to the simultaneous generation of superoxide anion and NO, and then forms the highly reactive species ONOO(-), induced a dose-dependent inhibition in amplitudes of transient potassium currents (I(A)) and delayed rectifier potassium currents (I(K)). SIN-1 (500 microM) produced a hyperpolarizing shift in the activation-voltage curve of both I(A) and I(K) and delayed the recovery of I(A) from inactivity, but did not have a marked effect on the inactivation parameters of I(A). However, co-treatment with SIN-1 and Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP, 100 microM), an ONOO(-) scavenger, had no effects on I(A) and I(K) currents. SIN-1 (500 microM) led to increase in action potential duration and decrease in action potential firing rate. The results suggest that changes of I(A) and I(K) currents induced by ONOO(-) in hippocampal neurons have influence on excitability of hippocampal CA1 neurons, which are related to its neurotoxicity.
authors.affiliation: Key Lab of Bioactive Materials, Ministry of Education, College of Life Science, Tianjin 300071, China.
authors.forename: Zhao Wei
authors.initials: ZW
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D030421:Peroxynitrous Acid; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D020030:Nitric Oxide Donors; D024642:Potassium Channels, Voltage-Gated; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid; C002385:linsidomine; D008981:Molsidomine