Functional significance of NO in the inner ear

Significant advances have been made in our understanding of the functional significance of nitric oxide (NO) in the inner ear. The localization of NO synthase and the nitric oxide production site has now been established by immunohistochemistry and the fluorescent indicator of NO. The functional significance of NO in the inner ear, especially as a neurotransmitter, is becoming increasingly clear. Mounting evidence suggests that excessive NO production may play an essential role in inner ear disorders as well. The production of an inducible type of NO synthase may be closely related to this phenomenon. Based on the mechanisms of inner ear disorders, new pharmacological strategies for preventing and/or treating inner ear disorders have also been suggested. Controlled production of nitric oxide (NO) plays an important role in mediating neurotransmission, regulating vascular tone and in pathophysiology. NO is synthesized by NO synthase (NOS) in an unusual reaction that converts arginine (Arg) and oxygen into citrulline and NO. Although several NOS isoforms have been isolated, all are homologous and fall into two categories with different activities and regulatory mechanisms. The constitutive neuronal (NOS I, nNOS, ncNOS) and endothelial (NOS III, eNOS, ecNOS) NOS are always present. These NOS isoforms are inactive until intracellular calcium levels increase, the calcium-binding protein calmodulin binds to calcium and the calcium calmodulin complex binds to and activates NOS. The constitutive types of NOS (cNOS) synthesize small amounts of NO until calcium levels decrease. This intermittent production of small amounts of NO transmits signals. In contrast, the inducible NOS isoform, NOS II (iNOS), is usually absent, but can be synthesized by virtually any cell type when adequately stimulated with cytokines or some other agent. Once produced, it invariably synthesizes large amounts of NO. The continuous production of a large quantity of NO kills or inhibits pathogens. Recent evidence suggests that NO may play a significant role in the inner ear. Recent years has seen important advances in our understanding of the action of NO in the inner ear, not only in normal but also under pathological conditions, which this review summarizes and evaluates. Functional significance of NO in the inner ear Constitutive isoforms of NOS (NOS I and III). In the inner ear, constitutive isoforms of NOS (NOS I and III) have recently been identified both in the cochlea and in the vestibular end organs, mainly by using NADPH-diaphorase histochemistry and immunohistochemistry (1-5). In the organ of Corti, NOS I was localized in the nerve fibres of the spiral ganglion itself, spiral ganglion cells, the nerve fibres, nerve endings below the inner and outer hair cells, the inner and outer hair cells, Deiters’ cells, pillar cells, stria vascularis and spiral ligament (1,2,4,5). In the vestibular end organs, i.e. crista ampullares, utricular and saccular maculae, NOS I was localized in the vestibular ganglion cells, nerve fibres, the cytoplasm of both type I and type II sensory cells, the nerve fibres contacting the type II cells, dark cells and transitional cells (2, 3). In the cochlea, NOS III was localized in the nerve fibres of the spiral ganglion, the spiral ganglion cells, the nerve fibres, nerve endings below the inner and outer hair cells, the inner and outer hair cells, Deiters’ cells, pillar cells, stria vascularis, spiral ligament, the endothelium of blood vessels 345 Correspondence to: Masaya Takumida, Department of Otolaryngology, Hiroshima University School of Medicine, 1-2-3 Kasumicho, Minamiku, Hiroshima 734-8551, Japan. e-mail: [email protected]