[Study on the characteristics and clinical significance of relief of nystagmus during the restoration of benign paroxysmal positional vertigo with posterior semicircular canal].

Objective:The features and parameters of the relief of nystagmus during the restoration of benign paroxysmal positional vertigo(PC-BPPV) in the posterior semicircular canal were observed to explore its clinical significance and mechanism.Method: Sixty-eight patients with PC-BPPV were treated with the Epley method. According to the subject' nystagmus relief was present or not, they were divided into two groups: group A showed relief of nystagmus during the restoration process, and group B showed no relief of nystagmus during the restoration. The effect of restoration between group A and group B was compared, and the parameters of nystagmus between the detached nystagmus and the Hallpike position in group A patients with detachable nystagmus were compared. Result: Of the 68 patients with PC-BPPV, 33(48.5%) experienced detachment of nystagmus in the same direction as the initial nystagmus(Group A) during the restoration; 35(51.5%) patients had no nystagmus during the restoration(Group B). After the instrument was reset for 2 h, Dix-Hallpike test was performed again. The success rate of reset was 100% in group A,and that was 57% in group B(20 cases were successfully repositioned, and 15 cases showed typical nystagmus). The success rate of reset was statistically different between groups A and B(P<0.01). After one week of resetting, the telephone follow-up was carried out. The recovery rate of group A and group B were 93% and 74% separately.The recovery rates between group A and B were statistically different(P<0.05). In group A, the nystagmus latency at Hallpike was(2.63±2.17) s, and the duration was(17.27±5.94) s. The rate of nystagmus in the upper leaping eye was(16.19±9.54)°/s. The latency of liberation was(2.30±1.41) s and the duration was(11.84±5.98) s. In seconds, the slow phase phasic velocity of the nystagmus was(7.80±4.57)°/s; there was no statistical difference in latency between the detached nystagmus and the Hallpike nystagmus(P>0.05), while there was a statistically significant difference between the duration and the nystagmus intensity(P<0.01).Conclusion:For PC-BPPV restoration, the presence or absence of nystagmus can be used as a reference to judge whether the restoration succeed or not.The latency of nystagmus at the Hallpike position may be related to the stalactite precipitation rate. The duration and the slow phase angle velocity of the upper hop eye may be related to the otolith quantity.

[Observation on effect of retraining therapy in patients with chronic tinnitus].

Objective:To analyze the curative effect of tinnitus retraining therapy on patients with chronic decompensated tinnitus and to explore an effective method to treat patients with chronic decompensated tinnitus.Method:Thirty patients were treated for tinnitus retraining therapy for 12 months. The content of retraining therapy includes: tinnitus counseling,low intensity natural sound therapy, shift attention, and relaxation training.Result:The severity of tinnitus was compared in grading before treatment and after 12 months treatment: 56.7%(17/30) of grade Ⅲ before treatment, 36.7%(11/30) of grade Ⅳ and 6.7% (2/30) of grade Ⅴ;16.7%(5/30) of grade Ⅰ after treatment, 60.0% (18/30) of grade Ⅱ,16.7%(5/30) of grade Ⅲ,6.7% (2/30) of grade Ⅳ, where compensatory tinnitu was 76.7%(23/30), and decompensated tinnitus was 23.3%(7/30). The composition ratio of 30 subjects compensated tinnitus and decompensated tinnitus before and after treatment has significant changes, with statistical differences(P<0.01). The mean score of tinnitus severity before treatment was 14.40±2.60 in 30 subjects and 9.00±2.82 after treatment in assessment scale. There was a significant difference between the both groups(P<0.01).Conclusion:Tinnitus retraining therapy is an effective treatment of chronic decompensated tinnitus.

MicroRNA-338 inhibits proliferation, migration, and invasion of gastric cancer cells by the Wnt/ß-catenin signaling pathway.

OBJECTIVE: Emerging evidence suggests aberrant microRNAs (miRNAs) expression is involved in cancer development through multiple. Although miR338 has shown to have tumor suppression ability and anti-migration effects in some cancers, its regulatory role and molecular mechanism in the development of gastric cancer cells yet remains little known. This work aims to investigate miR-338 in regulating Wnt/ß-catenin pathway in epithelial-mesenchymal transition (EMT) in gastric cancers. MATERIALS AND METHODS: Human gastric cancer cells were transfected with either miR-338 mimic or erythropoietin-producing hepatocellular (Eph)A2-targeting siRNA. The biological function of miR-338 in gastric cancer cells was investigated using a MTT assay and invasion assay. Western blot assay was used to measure the levels of EphA2, GSK-3ß, phospho-GSK-3ßSer9, c-Myc, E-cadherin, Vimentin, and ß-catenin of at protein level. RESULTS: Our data showed that miR-338 inhibited proliferation, migration and invasion of human gastric cancer cells. miR-338 affected the Wnt/ß-catenin pathway by increasing p-GSK-3ßSer9 and decreasing GSK-3ßSer9 and c-Myc at protein levels. EphA2 protein level was downregulated and positively correlated with EMT markers. Both silencing of EphA2 and transfection with miR-338 mimic resulted in the up-regulation of the EMT molecular marker E-cadherin and down-regulation of Vimentin and ß-catenin at protein levels. CONCLUSIONS: This study indicated that miR-338 is a potential tumor suppressor in gastric cancer and miR-338 inhibited EMT of gastric cancer cells through deactivation of Wnt/ß-catenin signaling targeting at EphA2.

[Curative effect analysis of different degree of hearing lossin sudden deafness patients].

Objective:Through analysis of the clinical data for different degree of hearing loss in patients with sudden deafness,to learn the relationship between degree of hearing loss and therapeutic effect.Method:By selecting for nearly three years 264 cases of patients with sudden deafness hospitalized in our department,we classified them by the level of hearing loss,to comparatively analyze the therapeutic effect on different degree of hearing loss in patients with sudden deafness.Result:The more severe the degree of low-frequency hearing loss,the worse the therapeutic effect.In all frequency sudden deafness,there were no clinically significant in mild and moderate sudden deafness(P>0.05);The cure rate and effective rate among mild,moderate and total sudden deafness are statistically significant(P<0.05),and between severe and total sudden deafness recovery rate are statistically significant(P<0.05);and mild and severe as so(P<0.05),the rest are no statistical significance(P>0.05).Conclusion:The degree of hearing loss has important influence on the curative effect of sudden deafness.

Low-fasting triglyceride levels are associated with non-invasive markers of advanced liver fibrosis among adults in the United States.

BACKGROUND: Elevated fasting triglyceride is often associated with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease. On the other hand, as liver disease progresses, patients may develop hepatocellular dysfunction that impairs triglyceride production. AIM: To test the hypothesis that lower fasting triglyceride levels may paradoxically indicate more advanced liver disease. METHODS: A cross-sectional analysis of 11 947 adults aged 20 years or older without chronic viral hepatitis from the National Health and Nutrition Examination Survey 1999-2010 was performed to analyze the relationships between fasting triglyceride levels and five validated non-invasive indices of liver fibrosis, including Fibrosis 4 Score (FIB4), NAFLD Fibrosis Score (NFS), Ast-Platelet Ration Index, AST/ALT ratio and BARD. RESULTS: Low-fasting triglyceride levels were consistently associated with elevated liver fibrosis indices. Individuals in the lowest quintile of triglycerides (TG) had an adjusted odds ratio (OR) of 3.0 (95% CI, 1.7-5.2; P < 0.001) for advanced fibrosis estimated by FIB4 score and OR of 1.8 (95% Cl, 1.2-2.7; P = 0.009) estimated by NFS, compared to individuals in the highest quintile. This association remained highly significant when restricted to individuals with abnormal LFTs from suspected NAFLD. This inverse relationship was continuous, and more pronounced among men and whites (P interaction <0.001 and 0.008 respectively), but not modified by age or body mass index. In addition, fasting TG had a stronger, more direct association with liver fibrosis indices than did albumin or total bilirubin. CONCLUSIONS: Fasting triglyceride levels were inversely associated with liver fibrosis indicators in American adults, especially among white men. Our findings suggest that sequential lipid measurements may serve as a useful disease marker in the management of chronic liver disease patients.

Functional expression of P2X4 receptor in capillary endothelial cells of the cochlear spiral ligament and its role in regulating the capillary diameter.

The cochlear lateral wall generates the endocochlear potential (EP), which creates a driving force for the hair cell transduction current and is essential for normal hearing. Blood flow at the cochlear lateral wall is critically important for maintaining the EP. The vulnerability of the EP to hypoxia suggests that the blood flow in the cochlear lateral wall is dynamically and precisely regulated to meet the changing metabolic needs of the cochlear lateral wall. It has been reported that ATP, an important extracellular signaling molecule, plays an essential role in regulating cochlear blood flow. However, the cellular mechanism underlying ATP-induced regional blood flow changes has not been investigated. In the current study, we demonstrate that 1) the P2X4 receptor is expressed in endothelial cells (ECs) of spiral ligament (SL) capillaries. 2) ATP elicits a characteristic current through P2X4 on ECs in a dose-dependent manner (EC(50) = 0.16 mM). The ATP current has a reversal potential at ∼0 mV; is inhibited by 5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD), LaCl(3), pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt hydrate (PPADS), and extracellular acidosis; and is less sensitive to α,ß-methyleneadenosine 5'-triphosphate (α,ß-MeATP) and 2'- and 3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate (BzATP). 3) ATP elicits a transient increase of intracellular Ca(2+) in ECs. 4) In accordance with the above in vitro findings, perilymphatic ATP (1 mM) caused dilation in SL capillaries in vivo by 11.5%. N(ω)-nitro-l-arginine methyl ester hydrochloride (l-NAME), a nonselective inhibitor of nitric oxide synthase, or 5-BDBD, the specific P2X4 inhibitor, significantly blocked the dilation. These findings support our hypothesis that extracellular ATP regulates cochlear lateral blood flow through P2X4 activation in ECs.

Coherent terahertz emission of intrinsic Josephson junction stacks in the hot spot regime [corrected].

We report on THz emission measurements and low temperature scanning laser imaging of Bi2Sr2CaCu2O8 intrinsic Josephson junction stacks. Coherent emission is observed at large dc input power, where a hot spot and a standing wave, formed in the "cold" part of the stack, coexist. By changing bias current and bath temperature, the emission frequency can be varied by more than 40%; the variation matches the Josephson-frequency variation with voltage. The linewidth of radiation is much smaller than expected from a purely cavity-induced synchronization. Thus, an additional mechanism seems to play a role. Some scenarios, related to the presence of the hot spot, are discussed.

Effect of chromium nanocomposite supplementation on growth hormone pulsatile secretion and mRNA expression in finishing pigs.

The study was conducted to investigate the effect of chromium nanocomposite (CrNano) on growth hormone (GH) pulsatile secretion and pituitary GH mRNA expression in finishing pigs. Fifty-four crossbred pigs (65.57 ± 1.05 kg initial weight) were randomly allotted to one of the three treatments, with three replicate pens per treatment and six pigs per pen. Pigs were offered one of the four diets including a control diet or a control diet supplemented with 200 µg/kg chromium from either chromium chloride (CrCl3) or CrNano for 35 days. During the trial, all pigs were given free access to feed and water. After completion of the feeding trial, blood samples were taken via auriculares at 15 min intervals for 3 h and three pigs from each treatment were slaughtered to collect pituitary to determine GH mRNA level. The results of GH dynamic secretion showed that supplemental CrNano increased the mean level, the lowest value, peak value and peak duration of GH significantly, while there was no significant effect on peak amplitude. Pituitary mRNA expression of GH was improved significantly in pigs fed diet containing Cr from CrNano. These results indicated that CrNano increased GH mRNA expression and secretion in finishing pigs.

Population pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin in ill cows.

This study was performed in 105 ill cows to determine the best practical individualized dose of enrofloxacin after i.m. (2.5 mg/kg) single-dose administration. Samples were collected from each cow at random time to ensure the percentage of samples distributed equally in the absorption phase, distribution phase, and elimination phase of the drug. Drug concentrations were determined by high-performance liquid chromatography with fluorometric detector, analyzed by population pharmacokinetic (PPK) modeling with NONMEM. The concentration-time data for enrofloxacin in plasma and ciprofloxacin were fitted to the one-compartment model with first-order absorption and elimination. The final covariate model indicated that body weight and daily milk productions have significant influence on clearance (CL) of enrofloxacin and ciprofloxacin, and the volume (V) of distribution of enrofloxacin. The typical PPK parameters were K(a) = 3.33 h(-1), CL = 1.25 L/h/kg, and V = 2.98 L/kg of enrofloxacin, and the interindividual variability for CL and V were 20.2% and 24.3%, respectively, the population mean estimates of K(a), CL, and V for ciprofloxacin were 1.12 h(-1), 2.36 L/h/kg, 8.20 L/kg, respectively, and their interindividual variability was 36.9%, 15.8% and 14.1%, respectively.

Observation of hepatohilar peribiliary vascular plexus with complete absence of hepatic artery blood supply in rats.

OBJECTIVE: The purpose of this study was to examine the morphologic changes in the hepatohilar peribiliary vascular plexus (PVP) and the pathology of the bile duct walls after cessation of hepatic artery blood supply in mice. MATERIALS AND METHODS: Sprague-Dawley (SD) experimental mice were randomly divided into a control and a treatment group. The morphological structure of the hepatohilar PVP after cessation of blood supply was observed using ink perfusion transparency management with computerized 3 dimensional reconstruction. The inner layer of the PVP was analyzed quantitatively and pathological examination was performed on the bile duct wall. RESULTS: The treatment group showed disorder of the 3-dimensional hepatohilar PVP structure with a markedly reduced number of micrangium in the inner layer (P<.01). The number of arterioles in the inner layer of PVP also trended downward (P<.05) and there was chronic hyperplastic inflammation in each layer of the vascular wall. CONCLUSION: Without an arterial blood supply containing a high oxygen content, the morphologic structure of the PVP changes, producing consequent pathology in the bile duct wall.

Blockade of gap junction coupling by glycyrrhetinic acids in guinea pig cochlear artery: a whole-cell voltage- and current-clamp study.

BACKGROUND AND PURPOSE: Glycyrrhetinic acids (GAs) are widely used as gap junction blockers, but their efficacy and side effects have not been well determined. EXPERIMENTAL APPROACH: Whole-cell electrical recordings were made from vascular smooth muscle cells (VSMCs) embedded in or dissociated from, guinea pig cochlear artery segments. KEY RESULTS: 18beta- & 18alpha-GA concentration-dependently increased membrane input resistance (R(in)) of in situ VSMCs, with a maximal input conductance (G(in)=1/R(in)) reduction of 92% & 77% and IC(50) of 2.0 & 4.4 microm, respectively. 18betaGA (30 microM) resulted in a R(in) of 2.2 GOmega and C(in) of 12 pF, comparable to those of freshly dissociated VSMCs (3.1 GOmega & 6.1 pF). The GAs (> or =30 microM) caused a depolarization in VSMCs in situ. In dispersed VSMCs, they both inhibited delayed rectifiers; 18betaGA also activated a non-selective cation conductance while 18alphaGA inactivated a voltage-independent K+-conductance. ACh induced an outward current in VSMCs in situ at -40 mV, with a positive slope I/V relation and a reversal potential near E(K). The ACh-induced current was attenuated by 18beta- & 18alphaGA with an IC(50) of 4.3 & 7.8 microM, respectively. CONCLUSIONS AND IMPLICATIONS: 18betaGA blocked the vascular gap junctions, achieving a complete electrical isolation of the recorded VSMC at > or =30 microM while causing a mild depolarization by a complex conductance alteration. 18betaGA suppressed the ACh-induced current in VSMC by blocking the myoendothelial gap junction and by a non-junctional action. 18alphaGA at 30-100 microM failed to fully block the gap junctions while exerting side actions.

PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by up-regulating Bcl-2 expression.

Neurotoxicity in primary neurons was induced using hypoxia/hypoglycemia (H/H), veratridine (10microM), staurosporine (1microM) or glutamate (100microM), which resulted in 72%, 67%, 75% and 66% neuronal injury, respectively. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (PAN-811; 10microM; Panacea Pharmaceuticals, Gaithersburg, MD) pretreatment for 24 h provided maximal neuroprotection of 89%, 42%, 47% and 89% against these toxicities, respectively. Glutamate or H/H treatment of cells increased cytosolic cytochrome c levels, which was blocked by pretreatment of cells with PAN-811. Pretreatment of neurons with PAN-811 produced a time-dependent increase in the protein level of Bcl-2, which was evident even after glutamate or H/H treatments. An up-regulation in the expression of the p53 and Bax genes was also observed following exposure to these neurotoxic insults; however, this increase was not suppressed by PAN-811 pretreatment. Functional inhibition of Bcl-2 by HA14-1 reduced the neuroprotective efficacy of PAN-811. PAN-811 treatment also abolished glutamate or H/H-mediated internucleosomal DNA fragmentation.

Adenovirus expressing an NPC1-GFP fusion gene corrects neuronal and nonneuronal defects associated with Niemann pick type C disease.

Niemann Pick type C (NPC) disease is an autosomal recessive disorder characterized by abnormal cholesterol metabolism and accumulation in lysosomal and endosomal compartments. Although peripheral organs are affected, the progressive neurodegeneration in the brain is typically most deleterious, leading to dystonia, ataxia, seizures, and premature death. Although the two genes underlying this disorder in humans and mouse models of the disease have been identified (NPC1 in 95% and NPC2/HE1 in 5% of human cases), their cellular roles have not Been fully defined, and there is currently no effective treatment for this disorder. To help address these issues, we constructed a recombinant adenovirus, Ad(NPC1-GFP), which contains a cDNA encoding a mouse NPC1 protein with a green fluorescent protein (GFP) fused to its C-terminus. Fluorescence microscopy and cholesterol trafficking assays demonstrate that the GFP-tagged NPC1 protein is functional and detectable in cells from different species (hamster, mouse, human) and of different types (ovary-derived cells, fibroblasts, astrocytes, neurons from peripheral and central nervous systems) in vitro. Combined with results from time-lapse microscopy and in vivo brain injections, our findings suggest that this adenovirus offers advantages for expressing NPC1 and analyzing its cellular localization, movement, functional properties, and beneficial effects in vitro and in vivo.

Two resting potential levels regulated by the inward-rectifier potassium channel in the guinea-pig spiral modiolar artery.

1. Intracellular in vitro recordings were made from 771 cells from the spiral modiolar artery (SMA). The initial resting potentials (RPs) displayed a bimodal distribution that was well modelled as a mixture of two Gaussian distributions. About half of the cells had an average RP of -74 mV, and were termed high-RP cells, whereas the other half had an average RP around -41 mV, and were termed low-RP cells. Preparations that were incubated for longer than 24 h contained significantly more high-RP cells than those incubated for less than 8 h. 2. When labelled with the fluorescent dye propidium iodide, 68 and 36 cells were identified as smooth muscle cells (SMC) and endothelial cells (EC), respectively. The RP and input resistance were not significantly different between these two types of cell. Dye coupling was observed only in ECs. Dual cell recordings with 0.2-1.0 mm separation demonstrated the simultaneous existence of high- and low-RP cells and a heterogeneous low-strength electrical coupling. 3. The high-RP cells were depolarized by ACh and by high extracellular potassium concentration (high K(+)). The low-RP cells were usually hyperpolarized by moderately high K(+) (7.5-20 mM) and by ACh. The high K(+)-induced hyperpolarization was suppressed by barium (Ba(2+), 10-50 microM). The putative gap junction blocker 18 beta-glycyrrhetinic acid suppressed the ACh-induced responses in SMCs, but not in ECs. 4. Low-RP cells could rapidly shift the membrane potential to a permanent high-RP state spontaneously or, more often, after a brief application of hyperpolarizing agents including high K(+), ACh, nitric oxide and pinacidil. Once shifted to a high-RP state, the responses of these cells to high K(+) and ACh became similar to those of the original high-RP cells. 5. High-RP cells occasionally shifted their potentials to a low-RP state either spontaneously or after a brief application of 10-50 microM Ba(2+) or 100 microM ouabain. Once shifted to the low-RP state, the response of these cells to high K(+) and ACh became a hyperpolarization. The shift between high- and low-RP states was largely mimicked by wash-in and wash-out of low concentrations of Ba(2+). The shift often showed a regenerative process as a fast phase in its middle course. 6. It is concluded that the cochlear SMA in vitro is composed of poorly and heterogeneously coupled SMCs and ECs, simultaneously resting in one of two distinct states, one a high-RP state and the other a low-RP state. The two RP states are exchangeable mainly due to all-or-none-like conductance changes of the inward-rectifier K(+) channel.

Glutamate is a mediator of neurotoxicity in secretions of activated HIV-1-infected macrophages.

We sought to identify neurotoxin(s) secreted by HIV-1-infected mononuclear phagocytes that could contribute to the pathophysiology of HIV-1-associated dementia (HAD). Neurotoxic factors were characterized in batches of conditioned media (CM) from human monocyte-derived macrophages (MDM) infected with HIV-1(ADA) and/or activated with lipopolysaccharide (LPS). All of the neurotoxicity was: present in the <3000-Da fraction; blocked by 5 microM MK801; and not trypsin sensitive or extractable into polar organic solvents. Glutamate measured in CM accounted for all neurotoxic effects observed from HIV/LPS CM in astrocyte-poor neuronal cultures and may contribute to the pathophysiology of HIV-1-associated dementia.

Pre- and postsynaptic actions of serotonin on rat suprachiasmatic nucleus neurons.

Serotoninergic transmission is implicated in the photic and non-photic regulation of circadian rhythms. 5-HT (1-100 microM), carboxamidotryptamine (5-CT 0.1-10 microM) and (+)-8-hydroxy-dipropylaminotetraline (8-OH-DPAT, 1-30 microM) dose-dependently activated an outward current (5-100 pA) in 30% of neurons voltage-clamped at -60 mV in the suprachiasmatic nucleus (SCN) in vitro slice. EC(50) values were 7.0 microM for 5-HT and 0.2 microM for 5-CT. Serotonin-induced outward current was associated with an increase in input conductance, and the current was blocked by Ba(2+) (1 mM). The amplitude of the current was enhanced by depolarization, reduced by hyperpolarization, and reversed its polarity during a hyperpolarization beyond the potassium equilibrium potential. Mean amplitudes of the 5-HT outward current changed with time of the subjective circadian day. The value near CT2 (23.8 pA) was about 4 times greater than that around CT14 (6.7 pA). Cells that responded with an outward current showed four types of morphology: monopolar, simple bipolar, curly bipolar and radial shaped; they were localized in all parts of the SCN. The EPSC evoked by retino-hypothalamic-tract (RHT) stimulation was inhibited 26% but the inward current induced by exogenously applied glutamate or NMDA was not affected by serotonin agonists. Focal stimulation-induced and spontaneous IPSC but not the exogenous GABA-induced outward current were inhibited by 5-HT agonists in a subpopulation of cells. In conclusion, 5-HT regulates SCN neurons by both pre- and post-synaptic inhibitory mechanisms; the latter may play a key role in modulating SCN circadian rhythm by activation of 5-HT receptors and opening of a potassium channel.

Membrane properties and the excitatory junction potentials in smooth muscle cells of cochlear spiral modiolar artery in guinea pigs.

Blood circulation changes in the inner ear play an important role in many physiological and pathological conditions of hearing function. The spiral modiolar artery (SMA) is the terminal artery to the cochlea. It was surrounded with nerve fibers immunostained by an antibody for tyrosine hydroxylase. By using intracellular recording techniques on the acutely isolated SMA, membrane properties of the smooth muscle cells and the neuromuscular transmission in this preparation were investigated. With minimum tension and normal extracellular K(+) concentration (5 mM), the majority of muscle cells showed a resting potential near -80 mV and an input resistance of about 8 MOmega. V/I plot showed an inward rectification in these cells. Barium (50-500 microM) caused strong depolarization and an increase in input resistance. Transmural electrical stimulation evoked stimulation intensity-dependent depolarizations (2-31 mV) following a short latency ( approximately 20 ms). The evoked potential by a low intensity stimulus was completely blocked by 1 microM tetrodotoxin. The potential and a depolarization induced by norepinephrine (10 microM) was usually partially (40-90%) blocked by alpha-receptor antagonists prazosin and/or idazoxan with concentrations up to 1 microM. Action potentials were observed when the depolarization was more than -40 mV. It is concluded that SMA smooth muscle cells, similar to those in other brain small arteries, highly express inward rectifying potassium channels; the cells receive catecholaminergic innervation, and stimulation of the nerves elicited an excitatory junction potential that is partially mediated by adrenergic receptors.

Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of suprachiasmatic nucleus neurons.

Neurons in the suprachiasmatic nucleus (SCN) constitute the principal circadian pacemaker of mammals. In situ hybridization studies revealed expression of orphanin-FQ/nociceptin (OFQ/N) receptor (NOR) mRNA in the SCN, whereas no expression of mRNA for preproOFQ/N (ppOFQ/N) was detected. The presence of OFQ/N peptide in the SCN was demonstrated by radioimmunoassay. SCN neurons (88%) responded dose-dependently to OFQ/N with an outward current (EC50 = 22.3 nM) that was reduced in amplitude by membrane hyperpolarization and reversed polarity near the theoretical potassium equilibrium potential. [Phe1psi(Ch2-NH)Gly2]OFQ/N(1-13)NH2 (3 microM), a putative NOR antagonist, activated a small outward current and significantly reduced the amplitude of the OFQ/N-stimulated current. OFQ/N reduced the NMDA receptor-mediated increase in intracellular Ca2+. When injected unilaterally into the SCN of Syrian hamsters housed in constant darkness, OFQ/N (1-50 pmol) failed to alter the timing of the hamsters' wheel-running activity. However, injection of OFQ/N (0.1-50 pmol) before a brief exposure to light during the midsubjective night significantly attenuated the light-induced phase advances of the activity rhythm. These data are consistent with the interpretation that OFQ/N acting at specific receptors modulates the activity of SCN neurons and, thereby, the response of the circadian clock to light.