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991.
Aslan SC Randall DC Donohue KD Knapp CF Patwardhan AR McDowell SM Taylor RF Evans JM 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,292(3):R1146-R1157
We investigated autonomic control of cardiovascular function in able-bodied (AB), paraplegic (PARA), and tetraplegic (TETRA) subjects in response to head-up tilt following spinal cord injury. We evaluated spectral power of blood pressure (BP), baroreflex sensitivity (BRS), baroreflex effectiveness index (BEI), occurrence of systolic blood pressure (SBP) ramps, baroreflex sequences, and cross-correlation of SBP with heart rate (HR) in low (0.04-0.15 Hz)- and high (0.15-0.4 Hz)-frequency regions. During tilt, AB and PARA effectively regulated BP and HR, but TETRA did not. The numbers of SBP ramps and percentages of heartbeats involved in SBP ramps and baroreflex sequences increased in AB, were unchanged in PARA, and declined in TETRA. BRS was lowest in PARA and declined with tilt in all groups. BEI was greatest in AB and declined with tilt in all groups. Low-frequency power of BP and the peak of the SBP/HR cross-correlation magnitude were greatest in AB, increased during tilt in AB, remained unchanged in PARA, and declined in TETRA. The peak cross-correlation magnitude in HF decreased with tilt in all groups. Our data indicate that spinal cord injury results in decreased stimulation of arterial baroreceptors and less engagement of feedback control as demonstrated by lower 1) spectral power of BP, 2) number (and percentages) of SBP ramps and barosequences, 3) cross-correlation magnitude of SBP/HR, 4) BEI, and 5) changes in delay between SBP/HR. Diminished vasomotion and impaired baroreflex regulation may be major contributors to decreased orthostatic tolerance following injury. 相似文献
992.
Kregel KC Zhang HJ 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,292(1):R18-R36
Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The "oxidative stress theory" holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benefits associated with the development of anti-aging interventions and therapies. 相似文献
993.
Zimmerman SL Frisbie J Goldstein DL West J Rivera K Krane CM 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,292(1):R544-R555
Cope's gray tree frog Hyla chrysoscelis accumulates glycerol during cold acclimation. We hypothesized that, during this process, gray tree frogs adjust renal filtration and/or reabsorption rates to retain accumulated glycerol. During cold acclimation, plasma concentrations of glycerol rose >200-fold, to 51 mmol/l. Although fractional water reabsorption decreased, glomerular filtration rate (GFR) and, consequently, urine flow were <5% of warm levels, and fractional glycerol reabsorption increased. In contrast, dehydrated frogs increased fractional water reabsorption, decreased GFR, and did not accumulate glycerol. We hypothesized that expression of proteins from the aquaporin (AQP)/glyceroporin (GLP) family was associated with changing patterns of water and glycerol movement. We cloned the cDNA for three such proteins, quantified mRNA expression in nine tissues using real-time quantitative PCR, and functionally characterized them using a Xenopus oocyte expression system. HC-1, an AQP1-like water channel conferring low glycerol permeability, is expressed ubiquitously in warm- and cold-acclimated tissues. HC-2, a water channel most similar to AQP2, is primarily expressed in organs of osmoregulation. HC-3, which is most similar to AQP3, is functionally characterized as a GLP, with low permeability to water but high permeability to glycerol. Aspects of expression levels and functional characteristics varied between cold and warm conditions for each of the three AQPs, suggesting a complex pattern of involvement in osmoregulation related to thermal acclimation. 相似文献
994.
Thorp DB Haist JV Leppard J Milne KJ Karmazyn M Noble EG 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(1):R363-R371
Acute exercise increases myocardial tolerance to ischemia-reperfusion (I-R) injury in male but not in female rat hearts, possibly due to a decreased heat shock protein 70 (Hsp70) response in the female hearts. This study examined whether repetitive exercise training would increase Hsp70 and myocardial tolerance to I-R injury in female rat hearts. Adaptations in myocardial manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) were also assessed. Ten-week old male (M) and female (F) Sprague-Dawley rats (n = 40 total) exercise-trained for 14 wk; the last 8 wk consisted of running 1 h at 30 m/min (2% incline), 5 days/wk. Following training, left ventricle mechanical function (LVMF) was monitored for 30 min of reperfusion following 30 min of global ischemia (Langendorff procedure). Myocardial Hsp70 content was not different in M and F control groups, while increases were observed in both trained groups (M greater than F; P < 0.05). Although MnSOD content did not differ between groups, endothelial nitric oxide synthase (eNOS) levels were decreased in F, with no change in M, following training (P < 0.05). Hearts from control F demonstrated a greater recuperation of all indices of LVMF following I-R compared with control M hearts (P < 0.05). Hearts of trained M exhibited improved recovery of LVMF (left ventricular diastolic pressure, left ventricular end-diastolic pressure, +dP/dt, -dP/dt) during reperfusion compared with control M hearts (P < 0.05). In contrast, hearts of trained F did not show any change in recovery from I-R. Hence, exercise training is more beneficial to M than F in improving myocardial function following I-R injury. 相似文献
995.
Perni RB Chandorkar G Cottrell KM Gates CA Lin C Lin K Luong YP Maxwell JP Murcko MA Pitlik J Rao G Schairer WC Van Drie J Wei Y 《Bioorganic & medicinal chemistry letters》2007,17(12):3406-3411
Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors. 相似文献
996.
Lovell PJ Blaney FE Goodacre CJ Scott CM Smith PW Starr KR Thewlis KM Vong AK Ward SE Watson JM 《Bioorganic & medicinal chemistry letters》2007,17(4):1033-1036
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat. 相似文献
997.
Parker MF Bronson JJ Barten DM Corsa JA Du W Felsenstein KM Guss VL Izzarelli D Loo A McElhone KE Marcin LR Padmanabha R Pak R Polson CT Toyn JH Varma S Wang J Wong V Zheng M Roberts SB 《Bioorganic & medicinal chemistry letters》2007,17(21):5790-5795
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported. 相似文献
998.
UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants 总被引:4,自引:0,他引:4
Jospin M Watanabe S Joshi D Young S Hamming K Thacker C Snutch TP Jorgensen EM Schuske K 《Current biology : CB》2007,17(18):1595-1600
Synaptojanin is a lipid phosphatase required to degrade phosphatidylinositol 4,5 bisphosphate (PIP(2)) at cell membranes during synaptic vesicle recycling. Synaptojanin mutants in C. elegans are severely uncoordinated and are depleted of synaptic vesicles, possibly because of accumulation of PIP(2). To identify proteins that act downstream of PIP(2) during endocytosis, we screened for suppressors of synaptojanin mutants in the nematode C. elegans. A class of uncoordinated mutants called "fainters" partially suppress the locomotory, vesicle depletion, and electrophysiological defects in synaptojanin mutants. These suppressor loci include the genes for the NCA ion channels, which are homologs of the vertebrate cation leak channel NALCN, and a novel gene called unc-80. We demonstrate that unc-80 encodes a novel, but highly conserved, neuronal protein required for the proper localization of the NCA-1 and NCA-2 ion channel subunits. These data suggest that activation of the NCA ion channel in synaptojanin mutants leads to defects in recycling of synaptic vesicles. 相似文献
999.
Parker MF Barten DM Bergstrom CP Bronson JJ Corsa JA Deshpande MS Felsenstein KM Guss VL Hansel SB Johnson G Keavy DJ Lau WY Mock J Prasad CV Polson CT Sloan CP Smith DW Wallace OB Wang HH Williams A Zheng M 《Bioorganic & medicinal chemistry letters》2007,17(16):4432-4436
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity. 相似文献
1000.
Larsen SD Poel TJ Filipski KJ Kohrt JT Pfefferkorn JA Sorenson RJ Tait BD Askew V Dillon L Hanselman JC Lu GH Robertson A Sekerke C Kowala MC Auerbach BJ 《Bioorganic & medicinal chemistry letters》2007,17(20):5567-5572
An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. 相似文献