Biomedical subjects

Yong Xu

Publications and source records attributed to Yong Xu.

At least 55 records · Page 3Linked to original sources

PubMed2005

Collagen alpha1(I) gene (COL1A1) is repressed by RFX family.

Collagen type I is composed of three polypeptide chains transcribed from two separate genes (COL1A1 and COL1A2) with different promoters requiring coordinate regulation. Our recent publications, centering on COL1A2 regulation, demonstrate that methylation in the first exon of COL1A2 at a regulatory factor for X box (RFX) site (at -1 to +20) occurs in human cancer cells and correlates with increased RFX1 binding and decreased collagen transcription (Sengupta, P. K., Erhlich, M., and Smith, B. D. (1999) J. Biol. Chem. 274, 36649-36655; Sengupta, S., Smith, E. M., Kim, K., Murnane, M. J., and Smith, B. D. (2003) Cancer Res. 63, 1789-1797). In normal cells, RFX5 complex along with major histocompatibility class II transactivator (CIITA) is induced by interferon-gamma to occupy this site and repress collagen transcription (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2004) J. Biol. Chem. 279, 41319-41332). In this paper, we demonstrate that COL1A1 has an RFX consensus binding site surrounding the transcription start site (-11 to +10) that contains three methylation sites rather than one in the COL1A2 gene RFX binding site. RFX1 interacts weakly with the unmethylated COL1A1 site, and binds with higher affinity to the methylated site. RFX1 represses the unmethylated COL1A1 less efficiently than COL1A2. COL1A1 promoter activity is sensitive to DNA methylation and the COL1A1 gene is methylated in human cancer cells with coordinately decreased collagen expression. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (aza-dC) increases collagen gene expression with time in human cancer cells. On the other hand, RFX5 interacts with both collagen type I genes with a similar binding affinity and represses both promoters equally in transient transfections. Two dominant negative forms of RFX5 activate both collagen genes coordinately. Finally, CIITA RNA interference experiments indicate that CIITA induction is required for interferon gamma-mediated repression of both collagen type I genes.

Animals↗

PubMed2005

Spatial deconvolution technique to improve the accuracy of reconstructed three-dimensional diffuse optical tomographic images.

A straightforward spatial deconvolution operation is presented that seeks to invert the information-blurring property of first-order perturbation algorithms for diffuse optical tomography (DOT) image reconstruction. The method that was developed to generate these deconvolving operators, or filters, was conceptually based on the frequency-encoding process used in magnetic resonance imaging. The computation of an image-correcting filter involves the solution of a large system of linear equations, in which known true distributions and the corresponding recovered distributions are compared. Conversely, application of a filter involves only a simple matrix multiplication. Simulation results show that application of this deconvolution operation to three-dimensional DOT images reconstructed by the solution of a first-order perturbation equation (Born approximation) can yield marked enhancement of image quality. In the examples considered, use of image-correcting filters produces obvious improvements in image quality, in terms of both location and mirco(a) of the inclusions. The displacements between the true and recovered locations of an inclusion's centroid location are as small as 1 mm, in an 8-cm-diameter medium with 1.5-cm-diameter inclusions, and the peak value of the recovered micro(a) for the inclusions deviates from the true value by as little as 5%.

Algorithms↗

PubMed2005

Adrenomedullin stimulates nitric oxide release from SK-N-SH human neuroblastoma cells by modulating intracellular calcium mobilization.

We used SK-N-SH human neuroblastoma cells to test the hypothesis that adrenomedullin (ADM), a multifunctional neuropeptide, stimulates nitric oxide (NO) release by modulating intracellular free calcium concentration ([Ca2+]i) in neuron-like cells. We used a nitrite assay to demonstrate that ADM (10 pM to 100 nM) stimulated NO release from the cells, with a maximal response observed with 1 nM at 30 min. This response was blocked by 1 nM ADM(22-52), an ADM receptor antagonist or 2 microM vinyl-L-NIO, a neuronal NO synthase inhibitor. In addition, 5 microM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, an intracellular calcium chelator, eliminated the ADM-induced NO release. Similar results were observed when the cells were incubated in calcium-free medium or when L-type calcium channels were inhibited with 5 microM nifedipine or 10 microM nitrendipine. Depletion of calcium stores in the endoplasmic reticulum (ER) with 1 microM cyclopiazonic acid or 150 nM thapsigargin, or inhibition of ryanodine-sensitive receptors in the ER with 10 microM ryanodine attenuated the ADM-induced NO release. NO responses to ADM were mimicked by 1 mM dibutyryl cAMP, a cAMP analog, and were abrogated by 5 microM H-89, a protein kinase A inhibitor. Furthermore, Fluo-4 fluorescence-activated cell sorter analysis showed that ADM (1 nM) significantly increased [Ca2+]i at 30 min. This response was blocked by nifedipine (5 microM) or H-89 (5 microM) and was reduced by ryanodine (10 microM). These results suggest that ADM stimulates calcium influx through L-type calcium channels and ryanodine-sensitive calcium release from the ER, probably via cAMP-protein kinase A-dependent mechanisms. These elevations in [Ca2+)]i cause activation of neuronal NO synthase and NO release.

Adrenomedullin↗

PubMed2005

Preparation and evaluation of poly(L-lactide-co-glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography.

A kind of absorbable PLGA microbubble-based contrast agent (PLGA microspheres with porous or hollow inner structure) was fabricated by an improved double emulsion-solvent evaporation method. The contrast efficiency was evaluated and proved both in vitro and in vivo. By adjusting the polymer concentration and volume of the inner aqueous phase during the fabrication of microbubbles, the inner structure of the microbubbles could be controlled. Both air-filled and perfluoropropane-filled microbubbles can opacify the left ventricle. However, when compared with air-filled microbubbles, perfluoropropane-filled microbubbles can produce significantly longer enhancement in left ventricle in the dog model due to the lower diffusivity and lower solubility of perfluoropropane in blood. A suspension of perfluoropropane-filled PLGA microbubbles (1.8 microm average microbubbles size, 2 x 10(8) microbubbles/mL concentration) has successfully and safely achieved myocardial opacification in closed-chest dogs. A perfusion defect was observed in both of the two dogs with acute myocardial infarction with Power Contrast Imaging (PCI) triggered technology. In the examination of contrast in both ventricular and myocardial opacification, the high mechanical index (MI) was found to have superior contrast sensitivity over the low MI for PLGA-based contrast agents.

Acoustics↗

PubMed2005

Determination of atomic hydrogen in non-thermal hydrogen plasmas by means of molecular beam threshold ionization mass spectrometry.

Atomic hydrogen plays important roles in chemical vapor deposition of functional materials, plasma etching and new approaches to chemical synthesis of hydrogen-containing compounds. The present work reports experimental determinations of atomic hydrogen near the grounded electrode in medium-pressure dielectric barrier discharge hydrogen plasmas by means of molecular beam threshold ionization mass spectrometry (MB-TIMS). At certain discharge conditions (a.c. frequency of 24 kHz, 28 kV of peak-to-peak voltage), the measured hydrogen dissociation fraction is decreased from approximately 0.83% to approximately 0.14% as the hydrogen pressure increases from 2.0 to 14.0 Torr. A simulation method for extraction of the approximate electron beam energy distribution function in the mass spectrometer ionizer and a semi-quantitative approach to calibrate the mass discrimination effect caused by the supersonic beam formation and the mass spectrometer measurement are reported.

Journal Article↗

PubMed2005

Interactions of ultraspiracle with ecdysone receptor in the transduction of ecdysone- and juvenile hormone-signaling.

Analyses of integration of two-hormone signaling through the vertebrate nuclear hormone receptors, for which the retinoid X receptor is one partner, have generated a number of mechanistic models, including those described as 'subordination' models wherein ligand-activation of one partner is subordinate to the liganded state of the other partner. However, mechanisms by which two-hormone signaling is integrated through invertebrate nuclear hormone-binding receptors has not been heretofore experimentally elucidated. This report investigates the integration of signaling of invertebrate juvenile hormone (JH) and 20-OH ecdysone (20OHE) at the level of identified nuclear receptors (ultraspiracle and ecdysone receptor), which transcriptionally activate a defined model core promoter (JH esterase gene), through specified hormone response elements (DR1 and IR1). Application of JH III, or 20OHE, to cultured Sf9 cells transfected with a DR1JHECoreLuciferase (or IR1JHECoreLuciferase) reporter promoter each induced expression of the reporter. Cotreatment of transfected cells with both hormones yielded a greater than additive effect on transcription, for especially the IR1JHECoreLuciferase reporter. Overexpression in Sf9 cells of recombinant Drosophila melanogaster ultraspiracle (dUSP) fostered formation of dUSP oligomer (potentially homodimer), as measured by coimmunoprecipitation assay and electrophoretic mobility assay (EMSA) on a DR1 probe, and also increased the level of transcription in response to JH III, but did not increase the transcriptional response to either 20OHE treatment alone or to the two hormones together. Inapposite, overexpression of recombinant D. melanogaster ecdysone receptor (dEcR) in the transfected cells generated dUSP/dEcR heterodimer [as measured by EMSA (supershift) on a DR1 probe] and increased the transcriptional response to 20OHE-alone treatment, but did not increase the transcriptional response to the JH III-alone treatment. Our studies provide evidence that in this model system, JH III-activation of the reporter promoter is through USP oligomer (homodimer) that does not contain EcR, while the 20OHE-activation is through the USP/EcR heterodimer. These results also show that the integration of JH III and 20OHE signaling is through the USP/EcR heterodimer, but that when the EcR partner is unliganded, the USP partner in this system is unable to transduce the JH III-activation.

Animals↗

PubMed2005

Prevalence and illness beliefs of sleep paralysis among Chinese psychiatric patients in China and the United States.

To investigate the prevalence and illness beliefs of sleep paralysis (SP) among Chinese patients in a psychiatric out-patient clinic, consecutive Chinese/Chinese-American patients who attended psychiatric out-patient clinics in Boston and Shanghai were asked about their lifetime prevalence, personal experience and perceptions regarding the causes, precipitating factors, consequences, and help-seeking of SP. During the 4-month study period, 42 non-psychotic psychiatric out-patients from the Boston site and 150 patients from the Shanghai site were interviewed. The prevalence of SP was found to be 26.2% in Boston and 23.3% in Shanghai. Patients with post-traumatic stress disorder (PTSD) or panic disorder reported a higher prevalence of SP than did patients without these disorders. Patients attributed SP to fatigue, stress, and other psychosocial factors. Although the experience has traditionally been labeled 'ghost oppression' among the Chinese, only two patients, one from each site, endorsed supernatural causes of their SP. Sleep paralysis is common among Chinese psychiatric out-patients. The endorsement of supernatural explanations for SP is rare among contemporary Chinese patients.

China↗

PubMed2005

Childhood physical and sexual abuse in China.

In order to determine the prevalence and characteristics of childhood physical and sexual abuse in China, the authors conducted a survey in Shanghai. The Dissociative Disorders Interview Schedule was administered to 423 inpatients and 304 outpatients at Shanghai Mental Health Center, and to a non-clinical sample of 618 workers at a clothing factory. The results were compared to a previous sample of 502 respondents in the general population in Winnipeg, Canada. The identities of the perpetrators of physical and sexual abuse, and the types of sexual abuse reported were similar in the two countries; however, the rates of reported abuse were lower in China. Childhood sexual abuse appears to be far less common in the general population in Canada than in China.

Adult↗

PubMed2005

Synergistic effects of combining biocontrol agents with silicon against postharvest diseases of jujube fruit.

The synergistic effects of biocontrol yeasts Cryptococcus laurentii and Rhodotorula glutinis combined with silicon (Si) against Alternaria alternata and Penicillium expansum molds were investigated in jujube fruit (Chinese date, Zizyphus jujuba) stored at 20 and 0 degrees C, respectively. Combinations of C. laurentii and R. glutinis at 5 x 10(7) cells/ml with 2% Si was most effective in controlling the diseases caused by A. alternata and P. expansum on jujube fruit stored at 20 degrees C. When fruits were stored at 0 degrees C, combining C. laurentii and R. glutinis with Si was as effective against P. expansum as was Si or the yeasts applied alone and was more effective in controlling A. alternata. Si may have a fungistatic effect by directly inhibiting pathogen growth, but it did not greatly influence the growth of the antagonists.

Alternaria↗

PubMed2005

[Spectral analysis of dissolved organic matter derived from rice straw after chemical treatment].

Fourier transform infrared spectroscopy (FTIR), ultraviolet spectroscopy (UV), and nuclear magnetic resonance spectroscopy (NMR) were used to study the chemical composition of Dissolved Organic Matter (DOM) derived from rice straw in the hydrolysis process with a dilute complex acid solution. The results obtained are as follows. FTIR spectra could indicate the changes of DOM during the hydrolysis process of rice straw. With the progress of rice straw hydrolysis, methyl, methylene, aromatic compounds and carbohydrates decreased, most of aliphatic compounds were oxidized to CO2 and H2O, and others were turned into carbonates. Most of the organic silicon was hydrolyzed into inorganic silicon. The proteins, amino acids and other nitrogen were hydrolyzed to NH4+. All the recalcitrant fractions of rice straw, such as hemi-cellulose, cellulose and silicon sharply decreased during the process of chemical treatment. The results obtained in this paper proposed that the changes of DOM of rice straw in the hydrolysis could be an indication in the changes of chemical composition of rice straw during the hydrolyzation, and FTIR, UV and NMR were good methods to study the changes in the structure of organic compounds.

Acids↗

PubMed2005

[Effect of basic fibroblast growth factor on wound healing of bilioenteric anastomosis].

OBJECTIVE: To observe the effects of basic fibroblast growth factor (bFGF) on wound healing of bilioenteric anastomosis as to prevent postoperative biliary strictures. METHODS: A model of choledochoduodenostomy in 31 dogs were constructed at first, then bFGF was administered on the local anastomosis (bFGF group) for 1 week after the operation as compared with sodium chloride solution (control group). Both groups were observed with light microscope (HE, Masson staining) and electron microscope 3 days, 1 and 3 weeks and 3 and 6 months after the operation (n=3). Hydroxyproline was measured at the same time. RESULTS: bFGF group healed more quickly compared with control group. Good function of cells were detected by electron microscope. Better mucosa epithelia, fibroblast, and capillary vessel proliferation were detected by histological observation in bFGF group. In bFGF group, collagen fibers were arranged orderly. Three weeks after operation, collagen fibers in control group were orderless and in whirlpool. Hydroxyproline of bFGF group was lower than that of control group (P<0.05). CONCLUSION: bFGF administered in local anastomosis is an effective method to prevent postoperative anastomotic stenosis.

Animals↗

PubMed2005

Insulin resistance and carotid atherosclerosis in 221 patients with potential hyperglycemia.

OBJECTIVE: To investigate the relationship between insulin resistance and carotid atherosclerosis in patients with potential hyperglycemia. METHODS: A total of 221 patients were recruited among those with potential hyperglycemia. All participants underwent physical examination, medical history interview, and 75 g oral glucose tolerance test. Venous blood was sampled for measurement of insulin and cholesterol levels. The intima-media thickness (IMT) in bilateral common carotid arteries was observed by B-mode ultrasound. Insulin resistance index was calculated by homeostasis model assessment (HOMA-IR). Subjects were stratified in quintiles according to HOMA-IR values. Risk factors and atherosclerotic parameters were analyzed. RESULTS: With HOMA-IR value increase, incidence of impaired glucose tolerance, diabetes mellitus, hypertension, and coronary artery disease increased, the levels of triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting plasma glucose, 2 hour plasma glucose, and fasting insulin increased as well, while the level of high density lipoprotein cholesterol (HDL-C) decreased. Meanwhile, all atherosclerotic parameters increased. Multivariate regression analysis showed that TG, total cholesterol, HDL-C, LDL-C levels, and ln(HOMA-IR) were related to IMT, hence were risk factors for IMT increase. CONCLUSION: Insulin resistance is implicated in atherogenesis.

Aged↗

PubMed2004

Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor.

In the present study, we have used an approach combining protein structure modeling, molecular dynamics (MD) simulation, automated docking, and 3D QSAR analyses to investigate the detailed interactions of CCR5 with their antagonists. Homology modeling and MD simulation were used to build the 3D model of CCR5 receptor based on the high-resolution X-ray structure of bovine rhodopsin. A series of 64 CCR5 antagonists, 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes, were docked into the putative binding site of the 3D model of CCR5 using the docking method, and the probable interaction model between CCR5 and the antagonists were obtained. The predicted binding affinities of the antagonists to CCR5 correlate well with the antagonist activities, and the interaction model could be used to explain many mutagenesis results. All these indicate that the 3D model of antagonist-CCR5 interaction is reliable. Based on the binding conformations and their alignment inside the binding pocket of CCR5, three-dimensional structure-activity relationship (3D QSAR) analyses were performed on these antagonists using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Both CoMFA and CoMSIA provide statistically valid models with good correlation and predictive power. The q(2)(r(cross)(2)) values are 0.568 and 0.587 for CoMFA and CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were not included in the training set. Mapping these models back to the topology of the active site of CCR5 leads to a better understanding of antagonist-CCR5 interaction. These results suggest that the 3D model of CCR5 can be used in structure-based drug design and the 3D QSAR models provide clear guidelines and accurate activity predictions for novel antagonist design.

Binding Sites↗

PubMed2004

Alkyl lysophosphatidic acid and fluoromethylene phosphonate analogs as metabolically-stabilized agonists for LPA receptors.

We describe an efficient method for the synthesis of alkyl lysophosphatidic acid (LPA) analogs as well as alkyl LPA mono- and difluoromethylene phosphonate analogs. Each alkyl LPA analog was evaluated for subtype-specific LPA receptor agonist activity using a cell migration assay for LPA(1) activation in cancer cells and an intracellular calcium mobilization assay for LPA(2) and LPA(3) activation. Alkyl LPAs induced pronounced cell migration activity with equivalent or higher potency than sn-1-oleoyl LPA, while the alkyl LPA fluoromethylene phosphonates proved to be less potent agonists in this assay. However, each alkyl LPA analog activated Ca(2+) release by activation of LPA(2) and LPA(3) receptors. Interestingly, the absolute configuration of the sn-2 hydroxyl group of the alkyl LPA analogs was not recognized by any of the three LPA receptors. The use of alkyl LPA analogs further expands the scope of structure-activity studies, which will better define LPA-LPA receptor interactions.

Animals↗

PubMed2004

Lysophosphatidic acid production and action: validated targets in cancer?

The completion of the human genome project, the evolution of transcriptional profiling and the emergence of proteomics have focused attention on these areas in the pathophysiology and therapy of cancer. The role of lysophospholipids as potential mediators in cancer pathophysiology, screening and management has taken a major leap forward with the recent cloning of several enzymes involved in the metabolism of lysophospholipids. Lysophospholipids, although small molecules, contain a high "informational" content. Differences include the nature of the phosphate head group, the regiochemistry of the fatty acyl chain on the glyceryl backbone, the presence of ether versus ester linkages to the backbone, and the length and saturation of the fatty acyl or alkyl chain. This informational content is sufficient to result in a marked structure function activity relationship at their cognate receptors. Thus the emerging discipline of "functional lipidomics" is likely to prove as important as genomics and proteomics in terms of early diagnosis, prognosis, and therapy. Lysophospholipid levels are elevated in vivo in a number of pathophysiological states including ascitic fluid from ovarian cancer patients indicating a role in the pathophysiology of this devastating disease. Although controversial, levels of specific lysophospholipids may be altered in the blood of cancer patients providing a potential mechanism for early diagnosis. Several of the enzymes involved in the metabolism of lysophospholipids are aberrant in ovarian and other cancers. Further, the enzymes are active in the interstitial space, rendering them readily accessible to the effects of inhibitors including antibodies, proteins, and small molecules. In support of a role for lysophospholipids in the pathophysiology of cancer, expression of receptors for lysophospholipids is also aberrant in cancer cells from multiple different lineages. All of the cell surface receptors for lysophospholipids belong to the G protein coupled receptor family. As over 40% of all drugs in current use target this family of receptors, lysophospholipid receptors are highly "druggable." Indeed, a number of highly specific agonists and antagonists of lysophospholipid receptors have been identified. A number are in preclinical evaluation as therapeutics. We look forward to the next several years when the role of lysophospholipids in physiology and the pathophysiology and management of cancer and other diseases are fully elucidated.

Animals↗

PubMed2004

Major histocompatibility class II transactivator (CIITA) mediates repression of collagen (COL1A2) transcription by interferon gamma (IFN-gamma).

Interferon gamma (IFN-gamma) plays an important role during inflammation by repressing collagen and activating major histocompatibility class II (MHC-II) expression. Activation of MHC-II by IFN-gamma requires regulatory factor for X-box 5 (RFX5) complex as well as class II transactivator (CIITA). We have shown that the RFX family binds to the COL1A2 transcription start site, and the RFX5 complex represses COL1A2 gene expression during IFN-gamma response. In this report, we demonstrate that CIITA is a key mediator of COL1A2 repression by IFN-gamma. IFN-gamma up-regulates the expression of CIITA in a time-dependent manner in lung fibroblasts and promotes CIITA protein occupancy on COL1A2 transcription start site in vivo as judged by chromatin immunoprecipitation (ChIP) assays. There are coordinate decreases in the occupancy of RNA polymerase II on the collagen transcription start site with increasing CIITA occupancy during IFN-gamma treatment. In addition, we are able to specifically knockdown the IFN-gamma-stimulated expression of CIITA utilizing short hairpin interference RNA (shRNA) against CIITA. This leads to the alleviation of COL1A2 repression and MHC-II activation by IFN-gamma. RFX5 recruits CIITA to the collagen site as evidenced by DNA affinity chromatography. The presence of RFX5 complex proteins enhances the collagen repression by CIITA reaching levels occurring during IFN-gamma treatment. Co-expression of CIITA with deletion mutations and collagen promoter constructs demonstrates that CIITA represses collagen promoter mainly through its N-terminal region including the acidic domain and the proline/serine/threonine domain. Our data suggest that CIITA is a crucial member of a repressor complex responsible for mediating COL1A2 transcription repression by IFN-gamma.

Animals↗

PubMed2004

Decrease in arterial pressure induced by adrenomedullin in the hypothalamic paraventricular nucleus is mediated by nitric oxide and GABA.

We tested the hypothesis that the decrease in arterial pressure induced by adrenomedullin (ADM) in the hypothalamic paraventricular nucleus (PVN) is mediated by nitric oxide (NO) and/or GABA. Unilateral microinjections of ADM into the PVN of anesthetized rats caused a significant decrease in mean arterial pressure (MAP). The ADM-induced decrease in MAP was significantly attenuated by pretreatment with N(psi)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor), 7-nitroindazole sodium salt (7-NiNa, a selective neuronal NOS inhibitor), N5-(1-Iminoethyl)-L-ornithine (L-NIO, a selective endothelial NOS inhibitor) or bicuculline methiodide, but pretreatment with S-methylisothiourea (SMIT, a selective inducible NOS inhibitor) had no effect on this ADM-induced effect. In addition, coronal sections of rat brains were processed for combined NADPH-diaphorase (a marker of neuronal NOS-containing neurons) histochemistry and in situ hybridization for the receptor-activity-modifying protein 2 (a specific ADM receptor component). Double-labeled neurons were found in both parvocellular and magnocellular subdivisions of the PVN, confirming that NO-producing neurons in the PVN are capable of mediating ADM's effects. Thus, our data provide evidence that the ADM-induced decrease in MAP in the PVN is mediated by NO from neuronal and endothelial NOS, and by GABA.

Adrenomedullin↗

PubMed2004

Adrenomedullin in the rostral ventrolateral medulla increases arterial pressure and heart rate: roles of glutamate and nitric oxide.

This study was done to investigate the effects of microinjections of adrenomedullin (ADM), a vasoactive neuropeptide, in the rostral ventrolateral medulla (RVLM) on mean arterial pressure (MAP) and heart rate (HR) in urethane-anesthetized rats, and to assess the potential roles of glutamate and nitric oxide (NO) in these effects. Unilateral injections of ADM (0.01 or 0.1 pmol) into the RVLM significantly increased MAP and HR in a dose-dependent manner, whereas ADM at 0.001 pmol was ineffective. Microinjections of ADM (0.01 pmol) outside the RVLM had no effects on MAP or HR. Coinjections of a putative ADM receptor antagonist, ADM(22-52) (0.01 pmol), abolished the increases in MAP and HR evoked by ADM (0.01 pmol). The vasopressor effects of ADM (0.01 pmol) in the RVLM were abolished by coinjections of either dizocilpine hydrogen maleate (a selective NMDA glutamate receptor antagonist, 500 pmol) or 6-cyano-7-nitroquinoxaline-2,3-dione (a selective non-NMDA glutamate receptor antagonist, 50 pmol). The ADM-induced vasopressor effects were also abolished by coadministration of either 7-nitroindazole sodium salt (a selective neuronal NO synthase inhibitor, 0.05 pmol) or methylene blue (a soluble guanylyl cyclase inhibitor, 100 pmol). These results suggest that ADM in the RVLM stimulates increases in MAP and HR through ADM receptor-mediated mechanisms. These effects are mediated by glutamate via both NMDA and non-NMDA receptors. NO, derived from neuronal NO synthase, also contributes to the ADM-induced vasopressor effects via a soluble guanylyl cyclase-associated signaling pathway.

6-Cyano-7-nitroquinoxaline-2,3-dione↗