Inhibition of nitric oxide synthesis suppresses sleep in rabbits

Kapás, Levente; Shibata, Masaaki; Kimura, Masaichi; Krueger, James M.

doi:10.1152/ajpregu.1994.266.1.r151

Cited by 63 publications

(51 citation statements)

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“…It is possible that ghrelin's wake-and feeding-promoting effects are mediated through MPA nitric oxide (NO). NO-producing mechanisms are implicated in the regulation of sleep (20) and feeding (33). Microinjection of a NO-donor into the MPA increased arousal (45).…”

Section: Discussionmentioning

confidence: 99%

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Szentirmai¹,

Kapás²,

Krueger³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

110

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Szentirmai É , Kapás L, Krueger JM. Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats. Am J Physiol Regul Integr Comp Physiol 292: R575-R585, 2007. First published August 17, 2006; doi:10.1152/ajpregu.00448.2006.-Ghrelin, a gutbrain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 g (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleepsuppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake-and arousalpromoting network formed by orexin and NPY. lateral hypothalamus; medial preoptic area; paraventricular nucleus; electroencephalogram; slow-wave activity; sleep GHRELIN IS A 28-AMINO ACID peptide produced by endocrine cells in the gastrointestinal system and by neurons in the central nervous system (21). Circulating ghrelin is derived mainly from the stomach (1). Plasma ghrelin levels inversely correlate with feeding; fasting increases, while food intake reduces, plasma ghrelin concentrations (7, 61). In the brain, ghrelin is produced by arcuate nucleus (ARC) neurons and by a distinct hypothalamic neuronal population in the internuclear region (6). Ghrelin's actions are mediated by the growth hormone secretagogue receptor (GHS-R) (21). GHS-R mRNA is widely distributed in the gastrointestinal tract, sensory vagus fibers, and the brain. Those hypothalamic nuclei that are implicated in the regulation of feeding and/or sleep-wake activity, such as the lateral hypothalamus (LH), paraventricular nucleus (PVN), ARC, dorsomedial hypothalamic nucleus, anteroventral preoptic nucleus, anterior hypothalamic area, suprachiasmatic nucleus, anterolateral hypothalamic nucleus, and the...

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Section: Discussionmentioning

confidence: 99%

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Szentirmai¹,

Kapás²,

Krueger³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

110

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“…The site of sleep-suppressing action of L-NAME is not known, although various brain stem structures may possibly play a role. Evidence for the brain stem site of action of NO arose from microinjection experiments where pontine administration of NOS inhibitors decreased NREMS and REMS amounts in rats (21,25) and in cats (10), and injection of N G -nitro-L-arginine into the medial pontine reticular formation decreased REMS in cats (30). Furthermore, injection of NO donors (10,21) or the NO precursor L-arginine (21) into the pedunculopontine tegmental nucleus elicited increases in NREMS and REMS.…”

Section: Discussionmentioning

confidence: 99%

“…There has been some controversy in the literature regarding the effects of L-NAME on sleep. Although the majority of the experiments reported thus far have shown that systemic administration of NOS inhibitors such as L-NAME (24,27,35,36,40), 7-NI (7,17), or 3 bromo-7-NI (15) suppress sleep, in contrasting reports, increased NREMS and/or REMS amounts were found in response to systemic injection of the NOS inhibitors L-NAME (7) and L-NMMA (16). In the latter studies, the NOS inhibitors were administered at dark onset or during the dark period.…”

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confidence: 99%

Day- and nighttime injection of a nitric oxide synthase inhibitor elicits opposite sleep responses in rats

Ribeiro¹,

Kapás²

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Ribeiro, Ana C., and Levente Kapás. Day-and nighttime injection of a nitric oxide synthase inhibitor elicits opposite sleep responses in rats. Am J Physiol Regul Integr Comp Physiol 289: R521-R531, 2005. First published April 28, 2005; doi:10.1152/ajpregu.00605.2004.-Previous studies suggest that nitric oxide (NO) may play a role in sleep regulation, particularly in the homeostatic process. The present studies were undertaken to compare the sleep effects of injecting a NO synthase (NOS) inhibitor when homeostatic sleep pressure is naturally highest (light onset) or when it is at its nadir (dark onset) in rats. Sleep, electroencephalogram delta-wave activity during nonrapid eye movement sleep (NREMS), also known as slow-wave activity (SWA), and brain temperature responses to three doses of the NOS inhibitor N -nitro-L-arginine methyl ester (L-NAME; 5, 50, and 100 mg/kg) injected intraperitoneally at light or dark onset were examined in rats (n ϭ 6 to 8). The effects of 5 mg/kg L-NAME were determined in both normal and vagotomized (VX) rats. Light onset administration of 50 mg/kg L-NAME decreased NREMS amounts and suppressed SWA and increased rapid eye movement sleep (REMS) amounts. At dark onset, L-NAME injection also dose dependently suppressed SWA; however, unlike light onset injections, both NREMS and REMS amounts were increased after all three doses. Sleep responses to 5 mg/kg L-NAME were not different in control and VX rats, suggesting that the sleep effects of L-NAME are not mediated through the activation of sensory vagal mechanisms. The present findings suggest that timing of the injection is a major determinant of the sleep responses observed after systemic L-NAME injection in rats. N-nitro-L-arginine methyl ester; slow-wave activity; homeostatic regulation; vagotomy; suprachiasmatic nucleus; thermoregulation; electroencephalogram power spectrum SLEEP REGULATION RELIES ON the interplay between the homeostatic and circadian processes (5). The homeostatic component manifests itself as an increasing sleep pressure due to prior waking periods, whereas the circadian component is an oscillating process that permits sleep to occur only during low sleep threshold periods. Normally, increased homeostatic pressure coincides with periods of decreased sleep threshold, thus allowing sleep to occur. In nocturnal animals, such as rats, this occurs at the beginning of the light period. A growing number of studies suggest that nitric oxide (NO)-ergic mechanisms play a role in sleep regulation, particularly in the homeostatic component.The two-process model of sleep regulation postulates that the homeostatic process relies on a neuronal mechanism, the activity of which increases during wakefulness and is dissipated during sleep (5). There is evidence that the activity of NO-generating mechanisms in the brain stem, thalamus, and cortex fits this pattern. For example, NO is released in an activity-dependent manner from neurons in brain stem areas involved in sleep regulation (29). In rats, cortical (6) and thalamic (49) NO ...

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“…The LPS-induced fever was attenuated by Dex, a potent inhibitor of the transcription of iNOS (Rees et al, 1990;Szabo et al, 1994;Wu et al, 1995) high dose (5000 gg) of L-NAME in rabbits (Kapas et al, 1994). L-NAME and L-NMMA are equally potent inhibitors of eNOS from porcine endothelial cells (Rees et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide synthase‐cyclo‐oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits

Lin

1996

British J Pharmacology

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. Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001–10 μ) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h. . The LPS‐induced febrile response was mimicked by intra‐OVLT injection of the nitric oxide (NO) donors, S‐nitroso‐acetylpenicillamine (SNAP, 1–10 μ), sodium nitroprusside (SNP, 50 μ), or hydroxylamine (10 μ), the cyclic GMP analogue 8‐bromo‐cyclic GMP (8‐Br‐cyclic GMP, 10–100 μ), or prostaglandin E2 (PGE2, 0.2 μ). . Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 μ), anisomycin (a protein synthesis inhibitor, 100 μ), L‐N5‐(1‐iminoethyl)ornithine (L‐NIO; an irreversible NOS inhibitor, 10–200 μ), aminoguanidine (a specific iNOS inhibitor, 1000 μ), or NG‐methyl‐L‐arginine acetate (L‐NMMA, a NOS inhibitor, 100 μ) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra‐OVLT dose of 1000 μ of NG‐nitro‐L‐arginine methyl ester (L‐NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects. . Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1–10 μ), 6‐(phenylamino)‐5,8‐quinolinedione (LY‐83583; an inhibitor of soluble guanylate cyclase and NO release, 20 μ), or indomethacin (an inhibitor of cyclo‐oxygenase, COX, 400 μ) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 μ) attenuated the fever induced by intra‐OVLT injection of SNAP. . The PGE2‐induced fever was potentiated, rather then attenuated, by pretreatment with an intra‐OVLT dose of animoguanidine (1000 μ), L‐NMMA (100 μ), or L‐NIO (200 μ). . These results suggest that iNOS‐COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.

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Inhibition of nitric oxide synthesis suppresses sleep in rabbits

Cited by 63 publications

References 0 publications

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

Day- and nighttime injection of a nitric oxide synthase inhibitor elicits opposite sleep responses in rats

Nitric oxide synthase‐cyclo‐oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits

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