We have reported that that bacterial endotoxin (lipopolysaccharide, LPS) interacts with opioid and excitatory amino acid inputs to gonadotropin-releasing hormone (GnRH) neurons to inhibit luteinzing hormone (LH) release in ovariectomized rats. The aim of this study was to examine possible roles of GABA and CRF in LPS-induced inhibition of LH release. Pretreatment with LPS (10ug/rat, iv), which did not affect the basal LH release by itself, significantly inhibited the steroid-induced LH surge. LPS also reduced Fos expression in GnRH neurons, and significantly increased the number of GABA immunoreactive cells in the mPOA. But no significant difference was detected in the number of CRF neurons in the PVN between the LPS-treated and control rats. Local, injection of muscimol (a GABA-A receptor agonist, 0.1ug/rat) into the mPOA significantly inhibited the steroid-induced LH surge. These results suggest that LPS might stimulate preoptic GABA neurons, either directly or indirectly, which, in turn, suppresse the activity of GnRH neurons, resulting in the inhibition of LH surge. As far as the number of CRF neurons is concerned, we could not obtain evidence for an involvement of CRF in LPS-induced suppression of gonadotropin release. Father studies on the influence of LPS on Fos expression in CRF neurons are necessary. [Jpn J Physiol 54 Suppl:S222 (2004)]

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The influence of exercise on endogenous levels of both beta-endorphin (BE) and histamine (HT) in hypothalamus were examined in F344 male rats. Rats, six weeks of age, were divided into two groups, involuntary exercised (IE) and control (C). Rats in IE group were exercise on a treadmill running instruments every day for 1 hour at the speed of 20m/min for 7 days. Immediately after training, hypothalamus was obtained from rats killed by decapitation. BE and HT levels in water soluble extracts of the organ was examined by ELISA. We also examined levels of BE and HT in plasma. The amount of BE in hypothalamus obtained from IE-rats was increased by exercise. On the other hand, exercise caused decrease in HT levels in hypothalamus. Although BE levels in plasma was increased by exercise, HT levels in plasma were not affected by exercise. It is reported that histamine in central nerves system exerts the suppressive effects on stress responses. Therefore, the present results may suggest that exercise for 7 days causes increase in BE levels in hypothalamus without stress. [Jpn J Physiol 54 Suppl:S222 (2004)]

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Galectin-1 belongs to a family of lectins and is expressed in many tissues such as placenta, liver, skeletal and smooth muscle. Galectin-1 is thought to be a versatile modulator, however, biological significance in its expression of human placenta remains unclear in detail. Galectin family is so far known to consist of 14 members of proteins on the basis of amino acids sequence. We made a monoclonal antibody, Gal3D11, against human galectin-1 and characterized the epitope using immunoblotting, high performance liquid chromatography and mass spectrometry. The epitope of this monoclonal antibody localized 29-44 amino acid residues in the N-terminal region of galectin-1. In this study, we used the antibody to clarify the expression of galectin-1 in various stages of placental development. We found that galectin-1 was expressed specifically in trophoblastic cells especially in syncytiotrophoblast cells through first, second to third trimester of placenta. It suggests galectin-1 plays an important role during development of placenta. This monoclonal antibody, Gal3D11 would be indispensable for further study to clarify the function of galectin-1 in various tissues. [Jpn J Physiol 54 Suppl:S222 (2004)]

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We have generated transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of the estrogen receptor α (ERα) promoter 0/B (Hamada et al., 2003). Here we report the pattern of the EGFP expression in the rat brain and other tissues in detail. Fluorescence of EGFP was observed extensively in the brain, particularly in the cortex, hippocampus, preoptic area, dorsal hypothalamic area, amygdala and midbrain central gray. A few, weakly fluorescent cells appeared in the ventromedial hypothalamic nucleus. Many EGFP-labeled cells were ERα immunoreactive in the medial preoptic nucleus, the bed nucleus of the stria terminalis and the medial amygdala. Unexpectedly, a few EGFP-labeled cells were immunoreactive to ERα antibody in the other areas of the brain. In the hippocampus, a subpopulation of fluorescent interneurons expressed GAD65/67. In the rostral midbrain central gray, fluorescent cells were found in the dorsal part whereas they were in the ventral part in the caudal portion of this structure. EGFP expressions were prominent on embryonic day 15; the expression gradually decreased as they developed. In the pituitary, EGFP fluorescent cells were also observed. These results suggest that the action of rat ERα promoter 0/B is regulated specifically in subregions of the brain, in different tissues or during the ontogeny. The transgenic rats would be useful for physiological studies on the role of estrogen signaling in the brain and other tissues. [Jpn J Physiol 54 Suppl:S223 (2004)]

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Sexually mature Long-Evans male rats show rigid preference for odors of receptive females over those of males or ovariectomized females. Our previous study demonstrated that orchidectomy induces feminized preference (preferring males to females), which is diminished during the course of observation over a 3 week period (Xiao et al., 2003). In the present experiment, we investigated the effects of cholesterol (C), testosterone (T) or dihydrotestosterone (DHT) on odor preference in orchidectomized males. Chronic exposure was accomplished by subcutaneous implantation of Silastic capsule containing these chemicals. The preference was also determined after the removal of the capsule. Both T and DHT, but not C, produced obvious masculine preference for receptive females. Males with T also preferred castrated males to sexually active males, whereas males with DHT had no preference for castrated males. After the removal of the capsules, both T and DHT males showed transient feminized preference for 2~3 weeks. When presented with receptive females, they were capable of displaying masculine sexual behavior. The results indicate that both T and DHT can induce masculine sexual preference. The diminished androgen after the removal of the capsule is sufficient for feminine, but insufficient for masculine, preference, presumably through androgen receptor because of effectiveness in nonaromatizable androgen, DHT. We suggest that neuroendocrine system regulating sexual preference is different from that of sexual behavior. [Jpn J Physiol 54 Suppl:S223 (2004)]

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In the preoptic area and the hypothalamus of rat brain, estrogen receptor (ER) α mRNA and protein are expressed and regulated by estrogen. Here we report sex difference and estrogen-dependent, region-specific regulation of ERβ, another major molecule which mediates estrogen action. ERβ mRNA and protein were visualized in the rat brain, in particular, the ventromedial nucleus of the hypothalamus, preoptic area and medial amygdala of both sexes, by either non-isotopic in situ hybridization or immunohistochemistry. In the ventromedial nucleus and the preoptic area of gonadectomized adult animals, a significantly larger number of neurons with ERβ message or protein were detected in females than in males. Such sex difference was not detected in the amygdala. In the ventromedial nucleus of either sex, estrogen administration to the gonadectomized adults caused a reduction of ERβ message or protein; no such effects were detected in the preoptic area or the amygdala. The results suggest that region-specific, ligand-dependent regulation of ERβ in the rat brain. [Jpn J Physiol 54 Suppl:S223 (2004)]

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Ca²⁺ oscillations due to IP₃ receptor-mediated repetitive Ca²⁺ release occur at fertilization of mammalian eggs and trigger egg activation. They are caused by a sperm factor driven into the egg upon sperm-egg fusion. It has recently shown that a novel sperm-specific phospholipase C isoform, PLCζ, generates Ca²⁺ oscillations when expressed in mouse eggs, probably via continuously produced IP₃. We injected RNA encoding PLCζ fused with a fluorescent protein Venus into mouse eggs to monitor expressed PLCζ by fluorescence. Ca²⁺ oscillations similar to those at fertilization appeared at 40-50 min after RNA injection when expressed PLCζ reached 10-40x10⁻¹⁵ g in the egg, comparable to estimated content of PLCζ in a single mouse sperm. PLCζ-Venus increased up to 3 h and attained a steady level at 4-5 h. Interestingly, PLCζ-Venus translocated into the pronucleus that was formed at 5-6 h, and continuously increased there. A splicing variant of PLCζ that lacks three of four EF hand domains was much less effective in induction of Ca²⁺ oscillations and little accumulated in the pronucleus, indicating a critical role of those domains. The ability of nuclear translocation qualifies PLCζ for a strong candidate of the Ca²⁺ oscillation-inducing sperm factor which is known to be concentrated to the pronucleus after fertilization and egg activation. [Jpn J Physiol 54 Suppl:S223 (2004)]

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Oxytocin (OT) serves as a neurotransmitter in the hypothalamic paraventricular nucleus (PVN). OT neuronal networks are thought to be involved in the regulation of male sexual behavior since administration of OT to males caused sexual behavior and this was reduced by an OT receptor antagonist. Recently, sexual behavior is mainly provoked by olfactory stimuli, possibly volatile pheromones released by the estrus female. We examined whether OT neurons in the PVN were activated by estrus female odor and sexual contact in sexually naïve and experienced Long-Evans rats. Male rats were not presented to anesthetized estrus females (control) or presented to the females without (exposure to the female odor without sexual contact) or with direct contact (exposure to the female odor with sexual contact). Exposure to the female odor with sexual contact significantly increased OT neurons with Fos expression in both males. Exposure to the female odor without contact increased OT neurons with Fos in sexually experienced males but not in naïve males, suggesting that the female odor without sexual contact activated the OT neuron in the PVN in the experienced males. Therefore, exposure to the estrus female odor itself may exert different effects on sexually naïve and experienced males. It is possible that female odors induce sexual arousal in males and the arousal is mediated by OT neurons in the PVN. [Jpn J Physiol 54 Suppl:S224 (2004)]

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OBJECTIVE: Endocrine disrupters (EDs) showing estrogen-like actions are believed to interfere with the function of reproductive systems. Although their effects on spermatozoa are extensively studied, few reports are available for oocytes. The present work therefore aims to elucidate the effects of estrogen itself and bisphenol-A (BPA) on mouse oocytes. METHODS: Immature germinal vesicle (GV) oocytes, obtained from the ovaries of adult mice (ICR strain), were loaded with Fura-2, and their dynamic changes in [Ca²⁺]_i were monitored using Argus 50 and Argus HiSCA image analyzers (Hamamatsu Photonics). RESULTS: The majority of oocytes exhibited spontaneous Ca²⁺ oscillations at regular intervals. Also, oocytes in ovarian slices with a thickness of approximately 100 mm showed similar Ca²⁺ oscillations. Application of 17β-estradiol (E2), the most potent natural estrogen, to oocytes by perfusion suppressed the Ca²⁺ oscillations in a dose-dependent manner (1 nM - 1 μM), i.e., 1) the regular pattern of Ca²⁺ oscillations was perturbed, 2) the interval between Ca²⁺ rises was prolonged with time, and 3) the amplitude of the Ca²⁺ elevation gradually decreased and was finally suppressed. Application of 10 mM BPA significantly disrupted the pattern of Ca²⁺ oscillations. DISCUSSION: The results suggest that 1) spontaneous Ca²⁺ oscillations in ovarian oocytes are controlled by estrogen, in preparation for fertilization, and 2) BPA affects oocytes by interfering with this control mechanism. [Jpn J Physiol 54 Suppl:S224 (2004)]

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Recent studies demonstrated that cerebral ischemia activated the proliferation and the differentiation of the endogenous neural stem cells (NSCs) in vivo. Since the lowered energy metabolism is known to mediate the ischemic effect, we examined the effect of hypoxia on the proliferation and the differentiation of NSCs in vitro. NSCs derived from the ganglionic eminence of E15.5 mice were cultured by a neurosphere method using EGF-containing medium, and exposed to various oxygen levels (20, 4, 0%O2) after mechanical dissociation. The proliferative activity of NCSs was examined by the WST-8 assay and BrdU incorporation assay, and by counting of the number of neurosphere in the presence of EGF (20ng/ml). The differentiation was induced by incubation in the 1% FBS-containing medium lacking EGF and was evaluated by the fluorescence-based immunocytochemistry and the ELISA using anti-Tuj 1 or anti-GFAP antibody. We found that in 0% O2 conditions, EGF-induced proliferation of NSCs was significantly diminished. However the treatment with 4% O2 significantly activated the proliferation when compared with 20% O2 condition. In the presence of 1% FBS, 4% O2 promoted astroglial differentiation. These results suggest that moderate hypoxia, but not severe hypoxia, activates proliferative activity and astroglial differentiation of the NSCs. [Jpn J Physiol 54 Suppl:S224 (2004)]

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Benzodiazepine compounds are widely used in clinical situations as somnifacient, antianxiety and antiepileptic drugs by acting at GABAa receptors in the central nervous system. On the other hand, the neural stem cells (NSCs) with self-renewal and multipoietic activities are recently found to exist in adult mammalian brain and seem to play some physiological roles. However, it is still unknown whether benzodiazepine affects NSCs functions. Therefore, we examined the effect of diazepam on the proliferative activity of cultured murine NSCs and the expression of GABAa receptor mRNA and GABA synthesizing enzymes (GAD) mRNA. The NSCs derived from the striatum of E15.5 mice were cultured by neurosphere method using EGF-containing medium. The proliferative activity of NSCs was examined by WST-8 assay and BrdU incorporation assay in the presence of EGF (20 ng/ml). The abundant expressions of GABAa receptor mRNA and GAD-65 and -67 mRNAs were measured by RT-PCR using specific primer sets. We found that diazepam suppressed EGF-induced proliferation in a concentration-dependent manner. GABAa receptor agonist, muscimol, also decreased NSCs proliferation. The expression of GABAa receptor alpha1 subunit mRNA as well as GAD-65 or -67 mRNAs were observed in the cultured NSCs. These results suggest that NSCs proliferation is regulated by GABAa receptor systems, which are activated by GABA autocreinally secreted from NSCs themselves. [Jpn J Physiol 54 Suppl:S225 (2004)]

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The neural stem cells (NSCs) are known to possess a self-renewal and multipoietic activity and are expected to be useful for several neurodegenarative diseases. However, the molecular mechanisms underlying the NSCs proliferation are not fully understood. Recently, Per2 gene was shown to have an important role in cell cycle regulation in tumor cells (Fu et al., 2002). Therefore, we speculate that Per2 plays a role in the proliferation of the NSCs. To assess this, we examined the time course of Per2 gene expression and proliferative activity in murine cultured NSCs. The NSCs derived from the striatum of E15.5 mice were cultured by neurosphere method. The cells were stimulated by EGF (20 ng/ml), a well known mitogen for NSCs, and the relative amount of Per2 mRNA and protein were measured by RT-PCR and immunocytochemistry, respectively. Simultaneously, the proleferative activity of NSCs was examined by WST-8 assay and BrdU incorporation assay. After EGF stimulation, the levels of Per2 mRNA and protein were transiently increased and subsequently showed circadian expressions with a period of 24 hr for at least 3 cycles. Furthermore, the degree of proliferation also showed circadian rhythm with an anti-phase to Per2 expression rhythm. These results suggest that Per2 gene plays a role in NSCs proliferation. [Jpn J Physiol 54 Suppl:S225 (2004)]

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Long-term administration of fish oil is well known to suppress cancer cell growth and metastasis. However, the mechanisms of fish oil by which the oil could exert anti-cancer effects are unexplained. Vascular endothelial factor (VEGF), which is produced by tumor cells is an essential factor for cancer cell growth and metastasis. In the present study, therefore, we examined whether fish oil could suppress VEGF production from tumor cells using B16 melanoma cells and several types of fish oil components in vitro. B16 melanoma cells were stimulated with 1.0 μg LPS in the presence of various concentrations of either DHA, DPA or EPA, which are the major components of fish oil. After 24h, culture super natants were obtained and the contents of VEGF was analyzed by ELISA. Addition of DHA and DPA at 0.5μg/ml and higher into cell cultures could inhibit the ability of B16 cells to produce VEGF, which was increased by LPS stimulation. On the other hand, EPA at more than 1.0μg/ml could not suppress VEGF production from B16 cells in response to LPS stimulation. DHA and DPA failed to suppress B16 cell growth even when there compounds were added to cell culture at more than 1.0μg/ml. These results may suggest that anti-cancer activity of fish oil is due, in part, to the inhibitory action of DHA and DPA on VEGF production. [Jpn J Physiol 54 Suppl:S225 (2004)]

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Human scoliosis is a disease that is characterized by deformities of axial spine beyond the limits of normal curvature and classified into three types. Among them, congenital scoliosis has abnormal shape of vertebrae congenitally with malalignment of axial spine. The genetic background and key gene for congenital kyphoscoliosis has not yet been clarified. Ishibashi rats (IS) have congenital malformations of lumbar vertebrae leading to kyphoscoliosis similar to that seen in human. Analysis of IS may thus provide insights into the genetic causes of human congenital scoliosis. In the present study, we characterized malformations of lumbar vertebrae in IS and screened for the difference of gene expression involved in skeletal formation between IS and Wistar strain rats. Significant differences on skeletal structures between IS and Wistar were found by roentogenographic analysis: (1) transitional vertebra; (2) anterior wedged vertebra; (3) union of anterior limbs; (4) an additional vertebra (7_th lumbar vertebra).
Furthermore, we designed probes for gene analysis of congenital kyphoscoliosis in IS. Hox10 and 11 paralogues play critical roles in the determination of characteristics of lumbar and sacral vertebrae. Shh, Notch1, Pax1, Pax9, Bapx1, Sox9, Col2α1, and Scleraxis may be involved in formation of axial skelton from unsegmented mesoderm. Analyses of these genes in IS by in situ hybridization and quantitative RT-PCR are under investigation. [Jpn J Physiol 54 Suppl:S225 (2004)]

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Using an in vitro apoptosis system, we have previously identified a novel nuclear factor designated Acinus that is a substrate of caspase-3 and responsible for apoptotic chromatin condensation. In this research, we performed the conditional gene targeting using the Cre/loxP system in order to study the role of Acinus in apoptosis and the function of Acinus in mammalian development and adult tissues.Mutant mice were generated in which 8 exons encoding the region important for the chromatin condensation activity of Acinus were flanked by loxP sites. These mutant mice were mated with CAG-Cre transgenic mice to obtain Acinus +/- mice. No homozygous Acinus -/- mice were obtained from interbreeding heterozygous Acinus +/- mice. Analysis of embryos at different stages of gestation indicated that Acinus -/- mutant embryos were smaller than Acinus +/+ and Acinus +/- embryos and did not survive past E12.5. Additionally, targeted deletion of Acinus that was restricted to the T-cell lineage caused a defect in T-cell maturation. These results suggested that Acinus plays an important role in mammalian development and T-cell maturation. [Jpn J Physiol 54 Suppl:S226 (2004)]

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We previously reported that arachidonic acid (AA) diet preserved the degree of LTP thus the synaptic plasticity was maintained in the aged rats at the hippocampal synapse as same as young control. One of the plausible mechanism to preserve LTP is switching the contribution of calcium entry from N-methyl-D-aspartate (NMDA) receptor channel to voltage dependent calcium channel (VDCC). We examine whether the primary calcium entry channel altered during aging and AA diet complemented the degraded calcium entry channel. Rats of 24 months old administered AA ester (old arachidonic group: OA) or control diet (old control group: OC) for at least 3.5 months or of 2 months old supplemented with control diet (young control group: YC) were used to record LTP from hippocampal slice of 300 μm with 6 x 6 multi-electrode-array. LTP was induced by θ-burst stimulation. Ca2+ channel was discriminated by perfusion of ACSF containing APV in 50 μM and nifedipin of 10 μM. VDCC dependent LTP (VDCC-LTP) tended to be greater than NMDA dependent LTP (NMDA-LTP) in OC compared with YC, whereas NMDA-LTP seemed to be more prominent than VDCC-LTP in OA as YC. The primary source of calcium entry from outside of a cell was predominant through NMDA receptor channel rather than VDCC in OA. This raised the possibility that oxygenated unsaturated fatty acid in the membrane of hippocampal neuron was complemented with AA diet in aged animal. [Jpn J Physiol 54 Suppl:S226 (2004)]

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Taurine has been considered to function as a neurotrophic factor during development of the central nervous system. In this study, we evaluated the effect of neonatal oral administration of taurine on brain-derived neurotrophic factor (BDNF) level in the developing hippocampus. Pregnant C57BL/6 mice were administered with taurine diluted in drinking water (400 mg/kg/day) from gestation day 17 to weaning period so as to dose taurine to newborn pups via maternal milk. Mice of the taurine-administered and control groups were processed for ELISA analysis of brain BDNF protein levels at 3, 4 and 6 weeks of age. Animals were anesthetized with sodium pentobarbital and decapitated. Fresh hippocampal and cortical tissues were homogenized in lysis buffer. Homogenates were centrifuged at 2,000 g for 20 min, and supernatants were treated with a immunoassay kit (BDNF Emax, Promega). The BDNF protein levels in the hippocampus and cerebral cortex declined from 3 to 6 weeks of age. The administration of taurine significantly facilitated the expression of BDNF protein in the hippocampus at 3 and 4 weeks after birth. These deta suggest that BDNF may be a factor to mediate the effects of taurine on early postnatal development of the hippocampus. [Jpn J Physiol 54 Suppl:S226 (2004)]

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Orexins (A and B) expressed in specific neurons of the lateral hypothalamic area, have been implicated in feeding and sleep regulation. To determine the mechanism of age-associated decrease in appetite and food intake, the stimulatory effect of intracerebroventricular administration of orexin-A on food intake was compared between young and old male rats. Different doses (0 = vehicle, 0.25, 1, and 3 nmol) of orexin-A were injected into the left lateral ventricle and food consumption during 1, 2, and 4 h after injection was measured. Orexin-A stimulated food intake in a dose-dependent manner in young rats. However, no effects were observed at any dose in old rats. To examine the mechanism, young and old rats, the hypothalamus was removed and the protein levels of orexin receptors (OX1R = a specific receptor for orexin-A, OX2R = a receptor for both orexin-A and -B) were determined by Western blotting. The protein level of OX1R in the hypothalamus of old rats was significantly lower than that of young rats, although the protein level of OX2R was rather higher in old rats. The present result indicates that the decline in appetite and food intake in old rats was caused by decreased function of orexin system. The decrease in protein level of OX1R in the hypothalamus could be responsible for the lack of stimulatory effect of orexin-A on food intake in old rats. [Jpn J Physiol 54 Suppl:S226 (2004)]

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In the previous studies we showed that when the rat medullary pyramid was stimulated the negative potentials were recorded from everywhere in the spinal cord at postnatal day 7 (P7), however, after P14 the positive potentials instead of the negative potentials were recorded in the ventrolateral side of spinal cord. In this study we investigated the properties of the negative and positive potentials electrophysiologically and pharmacologically. The CS tract was stimulated at the level of medullary pyramid and field potentials were recorded from the cervical cord (C7). Pharmacological agents were applied to recording sites by micro pressure ejection through the multi-barrel pipettes along with recording. The negative field potentials were evoked with constant latency and showed paired-pulse depression and frequency depression. Those potentials were reversibly blocked by an AMPA receptor antagonist, CNQX. The positive potentials were not affected by glycine receptor blocker, strychnine, GABA-A receptor blocker, bicuculline and CNQX. These indicate that the negative potentials evoked by the medullary pyramid stimulation are active sinks generated by the monosynaptic action of CS synapses, whereas the positive potentials recorded in ventrolateral side represent the passive sources. Together with the change of the distribution of the potentials during the development we conclud that the CS synapses are distributed widely in the spinal cord at P7 and subsequently they are eliminated from the vetrolateral side and restricted to the dorsomedial side of spinal cord. [Jpn J Physiol 54 Suppl:S227 (2004)]

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[Background] It has been reported that pupillary membrane (PM), a transient vascular network surrounded by iris, regresses by apoptotic process. In our previous study, we found that the PM regression occurred following the initiation of iris movement in rats and the transient cessation of PM blood flow took place in miosis. Therefore, we hypothesized that iris movement works as a mechanical factor of PM regression by induction of apoptosis.
[Methods ] Rat littermates (n = 10) were divided into three groups and instilled each eyedrop from postnatal day 7 (P7) to P12: (1) Control: saline, (2) Stimulation of iris movement: 0.005% physostigmine, and (3) Inhibition of iris movement: 1% atropine sulphate. At P12, we quantified the degree of PM regression by counting the number of vascular junctions of PM. We evaluated apoptotic vascular endothelial cell (VEC) of PM in groups 1 and 3.
[Results] The inhibition of iris movement group (group 3) showed the significant persistence of PM when compared with group 1 and 2 and decreased in the number of apoptotic VECs comparing with group 1.
[Conclusions] The iris movement triggers PM regression by inducing apoptosis. [Jpn J Physiol 54 Suppl:S227 (2004)]

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Standing position is basic for human. We studied body vertical sway with aging. METHOD: Subjects were 1784 healthy volunteers, aged from 3 to 94 years (yrs). Sum of the 3 signals from the gravicorders (G5500, ANIMA Corp. Japan) were analyzed for 1 min with eyes open (EO) and feet closed (FC), for 1 min with eyes closed (EC) and FC, for 1 min with EO and feet open (FO), for 1 min with EC and FO. The signals were sampled at 20 Hz and analyzed with the fast Fourier transform. RESULTS: With FC, the oscillation with EO was more stable than that with EC for all age groups. The oscillation around 7 Hz increased with the age with FC. The oscillation around 3 Hz was noted for the age group between 3 and 10 yrs, with EC and FC. With FO, the oscillation around 3 Hz was noted for the age group between 3 and 10 yrs, with EC and FO was remarkable, the oscillation between with EO and EC showed almost the same spectra for another groups. DISCUSSION: The length and areas of the trajectories were, reportedly, minimum around 40 yrs for the horizontal oscillation (Imaoka etal, Equilibrium Res Suppl 12, 1997). The vertical oscillation around 7 Hz with EC and FC for over 60 yrs was speculated to be aging. The vertical oscillation around 3 Hz with EC and FO below 10 yrs was speculated to be immature control for posture. [Jpn J Physiol 54 Suppl:S227 (2004)]

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In Drosophila, age related memory impairment (AMI) of a Pavlovian olfactory association task results from a decrease in amnesiac dependent middle-term memory (MTM). As flies age, their memory retention curves become identical to retention curves of amn mutants. In addition, there is no further decrease in memory upon aging in amn mutants indicating that these mutants are already defective for the memory component lost upon aging. MTM and AMI can be rescued by expression of an amn transgene primarily in DPM neurons which project onto the mushroom bodies. Given that amn mutants resemble aged flies with respect to AMI, it is possible that these mutants age prematurely. However, amn flies actually show a s ignificant extension of lifespan compared to wild type. The extended lifespan of amn is reduced to a normal level when a single copy of an amn transgene is induced, while lifespan is shorter than wild-type when two copies of the transgen e are induced. These results suggest that the amn gene regulates aging in a dose dependent manner. In contrast to long-lived mutants that are defective for insulin-like growth factor signaling (IGF signaling), such as chico and InR, amn mutants have normal body size and weight, and maintain higher locomotor activity and reproductivity even at old age. We are characterizing other memory mutants for lifespan alterations to define a novel interaction between memory, AMI and lifespan.. [Jpn J Physiol 54 Suppl:S227 (2004)]

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It has been found that neurogenesis occurs in the dentate granule cell layer (GCL) of the mammalian hippocampus throughout life, but how a newly generated cell differentiates into a neuron and is integrated into hippocampal circuitry remains to be elucidated. We have previously reported that intrinsic neurogensis occurs spontaneously in the organotypic slice culture of a rat hippocampus using 5-bromodeoxyuridine labeling method. In the present study, the newly divided cells and their descendents were labeled in the living slices with the enhanced green fluorescent protein (EGFP) through retrovirus vector transduction. We found that (1) the EGFP-labeled cells increased in number in the first two weeks and (2) the EGFP-labeled cells consisted of variety of phenotypes of both early and late stages of differentiation in four weeks after inoculation: about 25% NeuN-positive cells with appearances of neurons in the GCL, 25% immature neurons immunoreactive with Tuj1, approximately 30% GFAP-positive cells and 30% nestin-positive cells. These results suggest that the slice cultures intrisically retain neurogenic abilities for their cultivation period. Our slice culture system would provide a good model of animal experiments to follow up the newly divided cells for a certain long period. [Jpn J Physiol 54 Suppl:S228 (2004)]

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The purpose of our study is to investigate the effect of CO2 (100 ppm) bathing on local sweat rate, core and skin temperatures, and local cutaneous blood flow. Ten healthy students participated in this study. Each subject underwent fresh water bathing and CO2 water bathing on different days. The subject was immersed in a bath at a water temperature of 40°C for 10 min up to the nipple level after a rest of 20 min at 30°C (40%RH), and had a rest again for 30 min. Tympanic and skin temperatures and sweat rate and cutaneous blood flow in the non-immersed area of upper chest were measured continuously. The results were: (1) chest blood flow was significantly greater during the CO2 bathing than during the fresh water bathing, (2) chest sweat rate was significantly greater during the CO2 bathing than during the fresh water bathing, (3) the increase of tympanic temperature was significantly greater during the CO2 bathing than during fresh water bathing, and (4) skin temperature in the chest was not different between the CO2 water bathing and the fresh water bathing. We concluded that CO2 bathing at 100ppm affects thermoregulatory responses through the mechanism of cutaneous vasodilatation. [Jpn J Physiol 54 Suppl:S228 (2004)]

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In most mammalians, the homeostasis of body temperature is maintained within a narrowly defined range by autonomic and behavioral thermoregulatory responses. The same is also true that most mammalians are able to maintain their body temperatures at slightly lower than usual levels when they are constantly exposed to higher or lower than usual thermoneutral environmental temperature. These altered body temperatures are results of adaptation to new thermal environments, and underlying mechanisms of such alterations are well documented. In the present study, we examined a question whether repeated changes of environmental temperature exert any influence on animals. For this purpose, levels of plasma corticosterone, activity of animals, and their deep core temperature were monitored in rats while environmental temperature was changed with differing magnitude that was maintained for differing period of time. The deep core temperature was monitored using telemetry system. It was found that when environmental temperature was repeatedly changed with 1h cycle between 4C and 27C, plasma levels of corticosterone in this animal group were significantly higher than those of animals constantly exposed to 4C for the same period of time. It was also found that the former group exhibited higher levels of locomotion and core temperature than the latter group. The results are discussed in terms of thermal stress. [Jpn J Physiol 54 Suppl:S228 (2004)]

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Activator protein-1 (AP-1) is a transcription factor that regulates gene expression of many cytokines such as interleukin-1 (IL-1). It has repeatedly been demonstrated that LPS activates AP-1 in macrophages, leading to expression of cytokine mRNA. On the other hand, we have recently found that angiotensin II (ANG II) enhances hepatic expression of IL-1β mRNA induced in rats by intravenous injection of LPS. Since ANG II, too, has been shown to activate AP-1, it is possible that activation of AP-1 by LPS is mediated or enhanced by ANG II, leading to an increase in cytokine production. We examined this possibility and have gotten interesting results, which we will report in the forthcoming "Meeting of the Physiological Society of Japan". [Jpn J Physiol 54 Suppl:S229 (2004)]

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Cholecystokinin (CCK) is an important gastointestinal hormone as well as a neurotransmitter. Two types of CCK receptors (types A and B) have been cloned. CCK-A receptors are present only in certain regions including the hypothalamus, whereas CCK-B receptors are widely distributed throughout the central nervous system. Otsuka Long-Evans Tokushima Fatty (OLETF) rats express CCK-B receptors and CCK genes normally in the brain but lack CCK-A receptors because of a genetic abnormality. These animals become stout, and develop diabetes mellitus after about 18 weeks of age. We have clarified that these animals experience deterioration of the circadian rhythmicity of body temperature and thermoregulatory ability under thermal stress from this age. In the present study, we examined thermoregulatory responsiveness, e.g., vasomotor responses and shivering, to thermal stimulation of the hypothalamus in these animals. A thermode was implanted into the preoptic area and anterior hypothalamus (PO/AH) under anesthesia. Rectal temperature and paw and tail skin temperatures were monitored by thermistors. EMG of the neck muscle was also measured. There were no differences between threshold temperatures of vasomotor and shivering. These results indicate that OLETF rats possess normal thermoregulatory responsiveness to thermal stimulation of the PO/AH. It is suggested that the abnormality of circadian rhythm and the deterioration of thermoregulatory ability of these animals might be due to dysesthesia caused by diabetes mellitus. [Jpn J Physiol 54 Suppl:S229 (2004)]

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Torii, M., and Hamada, S.Dept. Biol. & Func. & Eng., Graduate sch. Life Sci. & Systems Eng, Kyushu Instit. Tech., Kitakyushu JapanThermal balance and conductance in exercising pre-pubescent boysThe purpose of the present study was to compare thermal balance and conductance to cycle exercise of pre-pubescent boys (B) with those of adult men (AM). Subjects (5 elementary school boys, aged 11-12 yr and 5 university students, aged 19-22 yr) conducted cycle exercise for 40 min in an ambient temperature of 25°C (rh, 50%). Whole-body sweating, rectal (T_c) and skin temperatures (T_sk), oxygen uptake and heart rate were measured simultaneously.　Thermoequilibrium and tissue conductance (K) were calculated. Metabolic rate increased in proportion with work intensity in both groups.　Evaporative heat loss (E) and K during exercise at lower and moderate works were markedly lower in the B than in the AM. In contrast, heat storage of the body during exercise at the both lower and moderate works was significantly higher in the B than in the AM. Sensitivity of T_c-to-E relation was likely to same tendency in the AM and the B. In the B, threshold temperatures of T_c-to-E and T_c-to-K relation were significantly (P<0.01) sifted to hyperthermia side as compared with the AM. T_sk-to-K relation was positive correlations in the AM, but not significant relationship in the boys. The present results suggest that set-point temperature in the pre-pubescent children may be changed to hyperthermia. [Jpn J Physiol 54 Suppl:S229 (2004)]

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The purpose of this study was to investigate the effect of radiation on thermoregulatory response during exercise. Some healthy male subjects dressing shorts and shoes remained seated resting for at least more than 40 min, and performed 20 min or more of cycle ergometer at several intensities in climatic chamber. The dorsal aspect of trunk was irradiated by infrared heater with main emissivity intermediate-infrared (MIR; 3.5μm) regions . Esophageal (Tes) and skin (Tsk) temperatures, local sweat rate (SR), local skin blood flow (SkBF), heat flax (HF), heart rate (HR), oxygen consumption (VO₂) were measured continually throughout the experiment. Body weight loss was measured at the end of experiment. All experiments were conducted in winter season. Thus the subjects were not naturally heat acclimated. In the condition with radiation, vasodilation was promoted by irradiation. SR increased since start of exercise. Tsk of upper back achieved about 40°C. HF increased in a direction toward ambient from body. So Tsk of upper back decreased, and Tes reached a constant value. These data suggest that thermoregulation may be affected by radiation. [Jpn J Physiol 54 Suppl:S229 (2004)]

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We investigated how the sweating and shivering thresholds were affected by starvation in humans. Three male and 5 female volunteers were fasted for 24 hours (13:00-13:00h). Rectal temperature (Tre) and skin temperatures at 7 sites were measured with thermistors. Sweating rates at the forearm and chest were measured by a capsule ventilation method. The subjects were rested in a chair at an ambient temperature of 26°C and relative humidity of 45%. Then, both legs were immersed in warm water (42°C) and sweating was induced. After a 20 min-rest and blood sampling, the subjects had cold isotonic water with their both legs immersed in cold water (15°C), and shivering was induced. Tre and mean body temperature (Tmean) at the onsets of sweating and shivering were determined. In the fasting condition, the plasma levels of free fatty acid and leptin and plasma osmolality were significantly lower than those in the control condition. The 24-hour fast significantly decreased the threshold Tre and Tmean for shivering, but did not affect the threshold Tre and Tmean for sweating. The results suggest that in humans, fasting inhibits the activations of metabolic response to cold stimuli, which may be beneficial to conserve energy. However, short-term starvation has little effect on the heat loss system. [Jpn J Physiol 54 Suppl:S230 (2004)]

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We previously reported that s.c. hypertonic-saline increased operant heat-escape/warm-seeking behavior in rats. In this study, to assess the mechanism involved, the behavior was measured in rats of which the median preoptic nucleus (MnPO) was chemically ablated (ibotenic acid, 5 μg). The lesion was verified success by an attenuation of the drink after i.c.v. injection of angiotensin II. Thirty minutes after s.c. injection of either 2500- or 154-mM saline (1.0 ml/100 g), rats were successively placed at 26, 35 and 40°C for 1 h each. They could trigger 0°C-air for 45s when entered a specific area (i.e. operant behavior). In the sham-operated rats, counts of the operant behavior was greater (p<0.05) in 2500-mM than 154-mM saline during 35 and 40°C-heat. However, in the lesioned-rats, the counts did not differ between the two trials, and were at the same level as those in the sham-operated rats in 154-mM saline trial. These results suggest that the MnPO is involved in the mechanism which activates heat-escape/warm-seeking behavior after hypertonic-saline injection. Howeover, the MnPO is not associated with the behavior in euhydrated condition. [Jpn J Physiol 54 Suppl:S230 (2004)]

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It is well known that alcohol elicits decreases in body temperature (Wasielewski and Holloway. 2001). It is generally considered that alcohol directly acts on cutaneous blood vessels to induce vasodilation, that is, to increase heat dissipation. On the contrary, alcohol that freely crosses blood brain barrier, might act on thermoregulatory center itself so that body temperature was regulated at lower level than normal. In this study, to test this possibility we investigated that the effects of alcohol on thermoregulatory responses and thermal sensations in humans. Six healthy male subjects participated in this study. Experiments were conducted twice for each subject at a room temperature of 33°C. After 30 min resting period the subject drank either 15% alcohol (alcohol session) or water (water session) at a volume of 3 ml/kgwt. Skin blood flow and sweat rate of the chest were measured. Deep body temperature was measured with a telemetry. In response to alcohol drinking sweat rate increased and reached the peak at 20 min after drinking. Deep body temperature decreased after the onset of sweating. Subjects reported increased hot sensation which temporary paralleled with change in sweat rate. These results suggest that in addition to the direct peripheral effect alcohol would act on thermoregulatory center so as to lower body temperature. (This study was approved by the ethical committee of Waseda Univ.) [Jpn J Physiol 54 Suppl:S230 (2004)]

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Prostaglandin E₂ (PGE₂), the final mediator of fever, is thought to be produced in brain endothelial cells through the enzyme cascade of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), since various pyrogenic stimuli induce these enzymes in brain endothelial cells. The essential role of COX-2 in brain PGE₂ synthesis and fever has been shown by using COX-2-specific inhibitors or COX-2-gene deficient mice. We here examined the role of mPGES-1 in these reactions by using mPGES-1 gene deficient (mPGES-1(-/-)) mice. Abdominal temperature of mPGES-1(-/-) mice and wild type mice were monitored with a telemetry system. The mice were challenged with 4 pyrogenic stimuli, i.e., lipopolysachharide (LPS, intraperitoneal injection), turpentine (subcutaneous injection), interleukin-1 beta (intracerebroventricular injection), and PGE₂ (intracerebroventricular injection). Both types of mice responded to PGE₂ with a similar degree of fever, whereas pyrogenic stimuli other than PGE₂ evoked fever only in wild type mice. The LPS stimuli elevated PGE₂ level in the brain only in wild type mice whereas LPS-induced plasma interleukin-1 beta and brain endothelial COX-2 levels were similar in these two types of mice. These results clearly demonstrate that mPGES-1 plays an essential role in the brain PGE₂ synthesis and fever under various inflammatory/infectious states. [Jpn J Physiol 54 Suppl:S230 (2004)]

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Prostaglandin E₂ (PGE₂), the brain mediator of fever, is thought to be produced in brain endothelial cells, as these cells express PGE₂-synthesizing enzymes such as cyclooxygenase-2 (COX-2) and microsomal-type PGE synthase in response to pyrogen lipopolysaccharide (LPS). However, it is not directly demonstrated yet if these cells actually produce PGE₂ in response to LPS, and which type of phospholipase A₂ (PLA₂) is working in the upstream of COX-2. To solve these issues, we here established an ex vivo model of PGE₂ production in brain blood vessels. Subarachnoidal blood vessels together with arachnoidal membrane were isolated from the rat brain 4 hrs after intraperitoneal injection of either saline or LPS (400 mg/kg). The samples were incubated in HEPES-buffered Ringer solution for one hour at 37°C in the presence or the absence of various enzyme inhibitors, and concentrations of PGE₂ in the incubation medium were measured using EIA. PGE₂ production was significantly enhanced in blood vessels from LPS-treated rats compared to those from saline-treated ones. A COX-2 inhibitor added to the incubation medium significantly suppressed the PGE₂ production. Since endothelial cells are the major COX-2 expressing cells there, these results directly indicate that brain endothelial cells enhance PGE₂ production in response to peripheral LPS stimulus. This ex vivo model could be further useful to examine the type of PLA₂ involved in PGE₂ production during fever. [Jpn J Physiol 54 Suppl:S231 (2004)]

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GABAergic inhibition of neurons in the preoptic area (POA) is involved in thermogenesis elicited by cooling stimulation of the skin. In the present study, we investigated hypothalamic sites mediating thermogenesis induced by microinjection of GABA into the POA in urethane-chloralose-anesthetized rats. Unilateral microinjection of GABA (0.3 M, 100 nl) into the POA increased the rate of whole body oxygen consumption (VO₂), colonic temperature, and temperature of brown adipose tissue. By pretreatment of the dorsomedial hypothalamic nucleus (DMH) with a microinjection of the local anesthetic lidocaine (10%, 100 nl), the thermogenic responses were largely attenuated although the injection of lidocaine alone had no significant effect on VO₂. The magnitude of GABA-induced thermogenic responses recovered within 60 min after the lidocaine injection into the DMH. Microinjection of lidocaine into the ventromedial hypothalamic nucleus or lateral hypothalamic area, and microinjection of physiological saline into the DMH had no effect on the GABA-induced thermogenic responses. These results suggest that the DMH is, at least in part, involved in efferent pathways for the thermogenesis elicited by microinjection of GABA into the POA. [Jpn J Physiol 54 Suppl:S231 (2004)]

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The preoptic area (POA) of the hypothalamus is known to be the primary locus for body temperature regulation. Bilateral microinjections of GABA (300 mM, 100 nl) or the GABA_A receptor agonist muscimol (100 μM, 100 nl) into the POA increased the rate of whole body oxygen consumption (VO₂) and body core (colonic) temperature of urethane-chloralose-anesthetized, artificially ventilated rats. The GABA-induced thermogenesis reflected mainly nonshivering thermogenesis, because it was suppressed by pretreatment with intravenous administration of the β-blocker propranolol and was not affected significantly by that with the muscle relaxant. Then, the involvement of GABA in cold-induced thermogenesis was examined. Non-noxious cooling stimuli were delivered to the shaved back of rats by contact with a plastic bag containing 28°C water. Cooling of the skin increased the VO₂, which response was also suppressed by pretreatment with propranolol but not by that with the muscle relaxant. Bilateral microinjections of the GABA_A receptor antagonist bicuculline (500 μM, 100 nl), but not those of vehicle saline, into the POA blocked the thermogenic response elicited by cooling of the skin. These results suggest that GABA and GABA_A receptors in the POA mediate cold-induced nonshivering thermogenesis. [Jpn J Physiol 54 Suppl:S231 (2004)]

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Cold constitution is a condition in which the patient feels uncomfortably chilly especially the fingers, legs, waist and shoulders. Many oriental people have this condition, especially a number of women in Japan. Cold constitution might be related to dysfunction of autonomic nervous system as well as a lack of female hormone, estrogen. In the present study, we examined the electrocardiogram (ECG) and pulmonary function in the young females with cold constitution, and compared the findings with normal females. Young female students (19.1±0.8 years-old; n=207) were divided into two groups; normal students (normal group; n=107) and students with cold constitution (cold group; n=100). The cold group was further divided into three groups; weak, middle and severe cold groups. The body weight, body mass index (BMI), subcutaneous fat thickness, body fat rate, and body fat weight in the cold group were significantly low, compared with those in the normal group. Among three cold groups, these data were low in proportion to the severity of cold constitution. The R-R interval and QT interval of the ECG were significantly prolonged in the cold group, dependent on the severity of the disease. However, the QTc intervals in the cold group were similar to those in the normal group. On the other hand, no significant changes in the values of several factors related to the pulmonary function, measured by a spirometer, were observed in between the cold and normal groups. These findings show a significantly positive relation among the severity of the cold constitution, slender figure, and bradycardia. [Jpn J Physiol 54 Suppl:S231 (2004)]

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We investigated participation of salivary glands in formation of taste preference by analyzing preferences for (48hr-two bottle choice test) and concentrations of serum amino acids in rats with removal of the submandibular and sublingual glands, and L-lysine (lysine) deficient rats. Intact control animals preferred L-arginine solution to lysine solution and water whereas sialoadenectomized animals and lysine deficient animals preferred lysine solution to L-arginine solution and water. Amino-acid analysis showed that serum concentrations of lysine and L-isoleucine in sialoadenectomized animals, being approximately equal to those in lysine deficient animals, were significantly lower than those in controls. Even after oral administration of 25% skim milk, lysine levels were low in sialoadenectomized animals compared with in controls over at least two hours. These results suggest that even when animals are fed lysine sufficient diet, sialoadenectomy brings about lysine deficiency, where taste for amino acids changes. This study also showed the presence of at least three lysine-binding (60-67 kDa) proteins in submandibular-sublingual saliva. The lack of these proteins could be attributed to lysine deficiency caused by sialoadenectomy. [Jpn J Physiol 54 Suppl:S232 (2004)]

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Purpose : Alcohol dehydrogenase (ADH) is the principal enzyme responsible for ethanol oxidation. It is well established that ethanol preferences are important factors for evaluating the ethanol drinking capacity. However, their relationships are unknown. Therefore, the present study examined to clarify the relation between C57BL/6J and DBA/2J mice (7 wks old) in the ADH activity and the preference for ethanol. Methods and Materials : The mice were sacrificed by cervical dislocation and the livers were removed, weighed, and perfused with ice-cold 0.9% NaCl solution. 10% homogenates were prepared in ice-cold 0.1% Triton X-100 in 0.9% NaCl solution. The homogenate was centrifuged. The pellet was discarded, and the supernatant was spun. The resulting supernatant cytosolic fraction was used for the determination of ADH activity (38°C, pH9.0). The ADH activities were expressed as nM of NADH per min per mg protein. Results : The liver weight per body weight showed no significant difference. However, the ADH specific activities and total ADH activities of both strain mice were ca.1.33 times higher in female than in male. The ADH specific activities and total ADH activities of male and female C57BL/6J mice were ca.1.6 times higher than DBA/2J mice. These results suggest that the liver cytosolic ADH activities depend upon the level of the preference for ethanol and are influenced by sex-hormones. [Jpn J Physiol 54 Suppl:S232 (2004)]

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Purpose : Alcohol dehydrogenase (alcohol : NAD+ dehydrogenase, E.C.1.1.1.1 ; ADH) catalyzes a rate-determining reaction in the metabolism of ethanol in the liver. On the other hand, stress which stimulates the hypothalamo-hypophyseal-adrenocortical axis and the sympathetic nervous system increases liver ADH activity. However, few studies reported the effects of food-deprivation on the ethanol oxidation rate in rats. Therefore, the effects of food-deprivation on liver cytosolic ADH activities in the infant, adult and aged rats were studied. Methods : Infant (3 wks old), adult (7 wks old) and aged (50 wks old) male Sprague Dawley rats were divided into the control (CON) and the fasting (FAS) groups. Food-deprivation was maintained for 3, 6 and 8 days, respectively. 10% liver homogenates were prepared under ice-conditions. The supernatant cytosolic fraction was used for the determination of ADH specific activities. The ADH activities were assayed at 38°C and pH 9.0. Results : The body weights, the liver weights per body weights, the total liver cytosolic protein contents, the liver cytosolic ADH activities and the total ADH activities of FAS were markedly lower than those of CON. In conclusion, rat liver cytosolic ADH activities evidently decreased by food-deprivation, and the magnitude of decreased action of ADH activities was prominent in the infant rats. [Jpn J Physiol 54 Suppl:S232 (2004)]

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Purpose : Capsaicin (CAP) and dihydrocapsaicin are the major pungent principles of hot pepper. Capsaicinoids and their analogues are ingested as components of spices. Recent studies showed CAP enhanced the energy metabolism of rats through adrenergic actions. However, reports on its nutritional influences from a standpoint of different life-stages are few. Therefore, comparisons among three life-stages in CAP-induced changes of plasma glucose, triglyceride and total cholesterol concentrations were studied. Methods : The male SD (3 wks old : infant, 8 wks old : adult and 50 wks old : aged) rats were divided into the control (CON) and CAP-administered (dose=3mg/kg BW, ADM) groups. The administrations of CAP and CAP-free solutions to rats were carried out from the subcutaneous of cervical region of back. Plasma energy substrate concentrations were assayed by the routine method. Results : CAP markedly raised the plasma glucose levels in the three life-stage rats although plasma volume ratios showed no significant differences. The magnitude of the CAP-induced glucose responses, evaluated from the ratio of the ADM group to the CON group, was 1.43, 2.08 and 1.67, respectively, in 1 hour after administration, in infant, adult and aged rats. In conclusion, the results show that CAP-induced glucose responses are different from age to age. [Jpn J Physiol 54 Suppl:S232 (2004)]

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Purpose : It is generally accepted that glucocorticoids such as cortisol and hydrocortisone (HYD) promote gluconeogenesis and enhance the degradation of fat and protein. However, it is not clarified whether high levels of glucocorticoids released to blood from adrenal cortex under high stress conditions influence plasma energy substrate levels and extracellular fluid volumes. Therefore, we examined the in vivo effect of HYD on the plasma energy substrate (glucose, triglyceride and total cholesterol) concentrations and hematocrit (Ht) values in rats. Methods : Male SD (7 weeks old, n=16) rats were used. HYD (dose = 5mg/ kg BW) was administered to rats. In the control (CON) rats, a corn oil of an equivalent volume was administered. Results : Plasma glucose concentrations of HYD did not change up to 8 hrs after the administration and were 1.20 times significantly higher than those of CON in 34 hrs. Plasma total cholesterol concentrations of HYD were 1.19-1.29 times significantly higher in 2 to 8 hrs than those of the CON. Plasma triglyceride concentrations of HYD were 0.77-0.71 times significantly lower in 4 to 8 hrs than those of the CON and returned to the beginning level at 34 hrs. Hematocrit values of HYD were 1.06 times significantly higher in 8 to 34 hrs than those of the CON. Conclusion : HYD induces the decline of rat extracellular fluid volumes and mobilization patterns in plasma depend on kinds of the energy substrates. [Jpn J Physiol 54 Suppl:S233 (2004)]

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Purpose : It is generally accepted that glucocorticoids promote gluconeogenesis and enhance the degradation of fat and protein. Further, glucocorticoids are also known to play an essential role in the induction of many enzymes such as tyrosine aminotransferase and aspartate aminotransferase. However, the physiological changes by acute administration of glucocorticoids have not been elucidated systematically. Therefore, acute effects of dexamethasone (DEX) on the plasma energy substrate (glucose, total cholesterol and triglyceride) levels and hematocrit in rats were studied. Methods : 7 weeks old male SD rats (n=16) were used. DEX (dose=2 mg/kg BW) was administered to rats. An equivalent volume of 0.9% NaCl solution was administered to the rats of control (CON) group. Results : Plasma glucose concentrations were 1.2-1.5 times higher than those of the CON in 4 to 34 hrs after administration. Plasma total cholesterol concentrations were also 1.2-1.5 times higher than those of the CON in 6 to 34 hrs after administration. However, plasma triglyceride concentrations were 0.4-0.6 times lower than those of the CON in 4 to 8 hrs, and 1.4 times higher than those of the CON in 34 hours. Hematocrit values showed no significant changes. In conclusion, DEX induced the increase of plasma glucose and total cholesterol levels and the decrease of plasma triglyceride levels, without changing hematocrit values after administration. [Jpn J Physiol 54 Suppl:S233 (2004)]

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Purpose : Regulation of food intake might be simply based on the total food energy ingested or could involve separate regulatory signals specific to each of the component nutrients. However, there are few data in regard to whether there is a regulation of the intake of individual macronutrients. Further, it is unclear whether food-deprivation can alter the levels of blood energy substrates in the weaning period. Therefore, the age-related effects of food-deprivation on plasma energy substrate (glucose, triglyceride and total cholesterol) levels in rats were studied. Methods : Infant (3 wks old), adult (7 wks old) and aged (50 wks old) Sprague Dawley male rats were divided into the control (CON) and the fasting (FAS) groups. Food-deprivations in the infant, adult and aged rats were maintained for 3, 6 and 8 days, respectively. Results : The body weights of FAS groups in three different aged rats decreased markedly with the increase of fasting days. Plasma glucose concentrations in FAS groups of three different aged rats were significantly lower than those in CON groups. Plasma triglyceride concentrations in FAS groups of infant and adult rats were significantly lower than those in CON groups. These results show that food-deprivation decreases age-dependently plasma glucose and triglyceride levels, and the magnitude of the decreased actions is in the order of infant>adult>aged rats. [Jpn J Physiol 54 Suppl:S233 (2004)]

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Nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) are transcription factors that regulate gene expression of many cytokines such as interleukin-1 (IL-1). It has repeatedly been demonstrated that LPS activates NF-κB and AP-1 in monocytes, leading to cytokine production. On the other hand, we have recently found that brain angiotensin II (ANG II) enhances an increase in brain levels of IL-1 induced in rats by intracerebroventricular injection of LPS. Since ANG II, too, has been shown to activate NF-κB and AP-1, it is possible that activation of NF-κB and/or AP-1 by LPS is mediated or enhanced by ANG II, leading to an increase in cytokine production. We examined this possibility and have gotten interesting results, which we will report in the forthcoming "Meeting of the Physiological Society of Japan". [Jpn J Physiol 54 Suppl:S233 (2004)]

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Previous studies reported that cobalt chloride (CoCl₂) caused the reduction of serum glucose concentration in streptozotocin (STZ)-induced diabetic rats. The reduction should be resulted from the decreases in systemic glucose production and/or the increases in cellular glucose uptake. Furthermore, CoCl₂ has been known to stimulate expressions of glucose transporters. Here, we hypothesized that the increases in glucose uptake due to the enhancement of the expression would lead to increase glycogen contents, and determined glycogen contents in the rat muscle and liver where glycogen is mainly stored. The serum insulin concentrations at 3 weeks after the injection of STZ were depleted, accompanied with the increases in serum glucose from 65.9 ± 9.8 to 410 ± 45.7 mg/dl (P<0.01). The liver glycogen contents decreased from 46.5 ± 27.7 to 1.5 ± 0.9 mg/g tissue (P<0.01). However, STZ had no effects on muscle glycogen contents. When the rats were treated with 2 mM CoCl₂, the serum glucose concentrations decreased to 338 ± 24.1 mg/dl (P<0.05). The serum insulin concentrations remained the depletion. No changes in the muscle glycogen contents were observed. In contrast, the liver glycogen contents significantly increased to 29.1 ± 18.1 mg/g tissue (P<0.01). These data suggest that the serum glucose-lowering effect of CoCl₂ on the STZ-diabetic rats is mediated by increase of liver glycogen content. [Jpn J Physiol 54 Suppl:S234 (2004)]

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Purpose : Anabolic steroids and β₂-agonists are known to induce muscle hypertrophy. Few reports, however, exist concerning the physiological effects of over dosage. Therefore, acute effects of β₂-agonist, clenbuterol (CLE) on plasma volume ratio (PVR : index of extracellular fluid volume), and plasma glucose, triglyceride and total cholesterol, insulin and cyclic AMP levels in rats were studied. Methods : Male SD rats (n = 48) were used. Two experiments were carried out : 1) the dose (0.01, 0.05 and 0.5 mg/kg BW)-response effects of CLE on plasma energy substrate and PVR levels, and 2) the acute effect of CLE (1.0 mg/kg BW) on plasma insulin and cyclic AMP levels. 0.9% NaCl solution was administered to the control rats. Plasma energy substrates were assayed by the routine methods. Plasma insulin and cyclic AMP were assayed by ELISA. Results : CLE increased significantly plasma glucose, triglyceride and total cholesterol according to the dose-dependent manner. PVR also increased with the increase of CLE dose, suggesting the increase of the dose-dependent extracellular fluid volume. CLE increased the plasma insulin concentration to 8.1 times, in 1 hours after administration, compared with the control. However, plasma cyclic AMP levels showed no significant changes. Conclusion : CLE increased dose-dependently rat plasma energy substrate level and PVR. Further, CLE increased plasma insulin levels without changing plasma cyclic AMP. [Jpn J Physiol 54 Suppl:S234 (2004)]

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Plasma hyperosmolality inhibits thermoregulatory responses during heat stress by elevating body core temperature (Tc) thresholds for cutaneous vasodilation (CVD) and sweating. To examine the role of vasoconstrictor system in the osmotic elevation of Tc threshold for CVD, we examined the effect of local bretylium treatment, which inhibits norepinephrine release from sympathetic nerve terminals, on cutaneous vascular response to passive body heating. Seven healthy male subjects were infused with either hypertonic (3% NaCl) or isotonic (0.9% NacCl) saline, and then passively heated by immersing their lower legs in 42 °C water for 60 min (room temperature, 28°C; RH, 40%). Bretylium tosylate was iontophoretically applied on forearm skin. We measured the skin blood flow by laser-Doppler flowmetery at the bretylium-treated and adjacent untreated sites, and deteremined the Tc (represented by esophageal temperature) threshold for CVD in each subject in each condition and treatment. Plasma osmolality was increased by 13 mOsm/kg H₂O following hypertonic saline infusion, and was unchanged following isonotic saline. The Tc threshold for CVD was elevated by ~1.0°C following hypertonic saline infusion. This elevation was not influenced by treatment with bretylium. These results suggest that osmotically-induced elevation of body core temperature threshold for CVD is primarily due to inhibition of active vasodilation, but not due to the enhancement of vasoconstrictor system. [Jpn J Physiol 54 Suppl:S234 (2004)]

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We estimated the regional temperature of the human brain in normal resting adult volunteers using ¹H magnetic resonance spectroscopy (¹H-MRS) at 3T, and compared our data with the results reported previously. Among 36 volunteers (19–65 years old), values of the temperature at deep white matter near the left cingulate gyrus and frontal lobe in 18 males were 37.4±0.4 (mean±SD) and 37.0±0.6°C (significantly different, paired t-test, P<0.05), and those in 18 females were 37.4±0.4 and 37.4±0.6°C (not significant). The temperature at the frontal lobe in the males was lower than that in the females (P<0.05). Moreover, the temperature at the deep white matter in the males, but not in the females, correlated with tympanic temperature (r=0.809, P<0.001). The measured values of the regional brain temperature were almost all consistent with the data reported previously, but some, such as the difference in regional brain temperature between males and females, or the correlation between the brain temperature and the tympanic temperature in males, are different from the results in previous reports. Our comparative study appears to indicate that factors affecting temperature should be taken into account to determine the regional brain temperature in detail. [Jpn J Physiol 54 Suppl:S234 (2004)]

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We have been selected rats by heat for many generations and developed an inbred FOK rat. The FOK rats resist heat using long-lasting saliva spreading despite severe dehydration. In addition, FOK rats congenitally resist to cold by increase in oxygen consumption. . In the present study, changes in levels of parameters related to lifestyle diseases were studied in the FOK rat. FOK rats were mildly fat than the other strains. Size of visceral fat was larger than those in other strains. Plasma triglyceride level was lower than those in the other strains. It was partially recovered by β-adrenergic blocker. Phospholipids level was higher than those in the other strains. Therefore, major component of plasma lipid in FOK rats was phospholipids. Polyunsaturated fatty acids, DHA and arachidonic acid, in plasma phospholipids were higher than those in the other strains. The FOK rat was one of strains which responded with large psychological stress-induced fever. Microarray analysis showed a possibility that gene expressions of AIM-1, aldosterone receptor and iron-responsive element -binding protein were increased in the hypothalamus in FOK rats. These increase in gene expression suggested a possible changes in osmoregulation, lipid metabolism, brain-Na induced hypertension, sympathetic outflow, and oxidative stress, especially genotoxic stress, in FOK rats. These findings suggested that heat selection for generations changes values of parameters related to lifestyle diseases. [Jpn J Physiol 54 Suppl:S235 (2004)]

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