Peroxynitrite donor impairs excitability of hippocampal CA1 neurons by inhibiting voltage-gated potassium currents.

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.