"Janus face" of nitric oxide action on plasma membrane and intracellular ionic channels

This paper focused on the role played by nitric oxide free radical (NO^·) on different ion channels involved in the progression of brain ischemia and several neurodegenerative diseases. We reviewed the available evidence suggesting that NO^· modulates glutamate-operated channels, Na⁺-, Ca²⁺- and K⁺-channels. A special emphasis has been directed to the voltage dependent K⁺-channel (product of the human ether-a-gogo related gene: hERG) which had extensively been studied in our laboratory. We have shown that the inhibition of nitric oxide synthase (NOS) by L-N^G-Nitroarginine methyl ester (L-NAME) (0.03-3.0 mM) dose-dependently suppresses the outward currents carried by the hERG K⁺-channels expressed in Xenopus oocytes, whereas the increase in NO^· levels achieved by exposure to L-arginine (0.03-10.0 mM) inhibits these currents. Similar results were obtained using four NO^· donors belonging to different chemical classes, such as sodium-nitroprussiate (SNP) (1-1000 μM), 3-morpholino-sydnonimine (SIN-1) (100-1000 μM), DiethylenetetramineNONOate (NOC-18) (1-300 μM), and S-nitroso-N-acetylpenicillamine (SNAP) (1-300 μM). The inhibitory effect of NO^·-donors on hERG K⁺-channels was prevented by the NO^·-scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) and hemoglobin. One mM 8-Br-cGMP, a membrane permeable analogue of cGMP, failed to reproduce the inhibitory action of NO^·-donors on hERG K⁺-dependent outward currents, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (50 μM), a specific inhibitor of the NO^·-dependent guanylyl cyclase, did not interfere with outward hERG K⁺ currents and did not prevent their inhibition by 0.3 mM NOC-18. Evidence suggesting that NO^·-action on hERG-K⁺-channels is dependent on the reactive oxygen species (ROS) scavenging effect of this gas has been presented.