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Nitric oxide (NO) has been shown to be an important mediator of febrile response to lipopolisaccharide (LPS). To clarify the role of different isoforms of NO synthase (NOS) in febrile response to immune challenge, effects of selective iNOS and nNOS inhibitors on fever to LPS were examined in freely moving biotelemetered rats. Vinyl-L-NIO (N5 - (1-Imino-3-butenyl) - ornithine (vL-NIO), a neuronal nitric oxide synthase (nNOS) inhibitor, and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor, were injected intracerebroventricularly at a dose of 10 µg/rat just before intraperitoneal injection of LPS at a dose of 50 µg/kg. Both inhibitors injected at a selected doses had no effect on normal day-time body temperature (Tb) and normal night-time Tb. vinyl-L-NIO and aminoguanidine injected intracerebroventricularly at a dose of 10 µg/animal suppressed the LPS-induced fever in rats. The fever index calculated for rats pretreated with v-LNIO or with aminoguanidine and injected with LPS was reduced by 43% and 72%, respectively, compared to that calculated for water-pretreated and LPS-injected rats. Whereas vL-NIO partly attenuated both phases of febrile rise in Tb, administration of aminoguanidine into the brain completely prevented fever induced by LPS. These data indicate that activation of iNOS inside the brain is not only responsible for triggering but also for maintaining of LPS-induced fever in rats. It is, therefore, reasonable to hypothesize that, activation of iNOS inside the brain is more important in fever development than activation of nNOS.
The purpose of this study was to investigate the role of neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) in the brain during development of fever in response to localized tissue inflammation caused by injection of turpentine in freely moving biotelemetered rats. To determine the role of both NOSs in turpentine-induced fever, we injected vinyl-L-NIO (N5 – (1-Imino-3-butenyl) – ornithine (vL-NIO), a selective nNOS inhibitor, and aminoguanidine hydrochloride, a selective iNOS inhibitor, intracerebroventricularly (i.c.v.) 5 h after turpentine injection. Rats responded with fever to intramuscular injection of 20 µl of turpentine that commenced about 5 - 6 h after injection and reached peak value between 9 - 11 h post-turpentine. The inhibition of nNOS as well as iNOS in the brain did not affect fever induced by turpentine. Fevers in control rats (treated i.c.v. with pyrogen-free water) and iNOS or nNOS inhibitor-i.c.v. treated rats injected with turpentine were essentially the same. Furthermore, on the basis of these data, we concluded that iNOS and nNOS inside the brain do not participate in generation of fever to turpentine in rats.
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