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The agouti-related protein (AGRP) is an endogenous antagonist of the brain melanocortin receptors (MC3R and MC4R) and is believed to be involved in feeding behavior and energy homeostasis. Previous results identified that the human AGRP decapeptide Yc[CRFFNAFC]Y binds to the MC3R and MC4R and acts as an antagonist at the MC4R but not at the MC3R. We have synthesized the amidated version of this decapeptide as well as performed elongation studies at both the N-and C-terminus of the monocyclic hAGRP(109-118) peptide. This study was designed to identify monocyclic peptide fragments of the hAGRP(86-132) to determine the minimal active monocyclic sequence necessary for antagonism at the MC3R. For binding studies, radiolabeled 125I-NDP-MSH versus 125I-hAGRP(86-132) were utilized to determine if there were differences in the ability of the AGRP fragments prepared herein to competitively displace the 125I-NDP-MSH versus AGRP(86-132) radiolabel. The binding IC(50) values of radiolabeled hAGRP(86-132) versus NDP-MSH were identical within experimental error, supporting the hypothesis that AGRP and NDP-MSH interact with overlapping binding epitopes at the MC3R and MC4R. The most notable results include identification of the TAYc[CRFFNAFC]YAR-NH(2) (pA(2)=6.1, K(i)=790nM, mMC3R) and the Yc[CRFFNAFC]YARKL-NH(2) (pA(2)=6.2, K(i)=630nM, mMC3R) peptides as the minimal monocyclic AGRP-based fragments possessing antagonist pharmacology at the MC3R. Interestingly, extension of the AGRP(109-118) decapeptide at both the N- and C-terminus by two amino acids conferred detectable mMC3R antagonism, while retaining high nanomolar MC4R antagonist and micromolar MC1R agonist pharmacological properties. These data support the hypothesis that elongation of the hAGRP(109-118) decapeptide results in antagonism at the MC3R while retaining MC1R agonist activity and MC4R antagonist activity. 相似文献
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Christopher Uhlig Pedro L Silva Débora Ornellas Raquel S Santos Paulo J Miranda Peter M Spieth Thomas Kiss Michael Kasper B?rbel Wiedemann Thea Koch Marcelo M Morales Paolo Pelosi Marcelo Gama de Abreu Patricia RM Rocco 《Respiratory research》2014,15(1):56
Introduction
We investigated the effects of intravenous and intratracheal administration of salbutamol on lung morphology and function, expression of ion channels, aquaporin, and markers of inflammation, apoptosis, and alveolar epithelial/endothelial cell damage in experimental pulmonary (p) and extrapulmonary (exp) mild acute respiratory distress syndrome (ARDS).Methods
In this prospective randomized controlled experimental study, 56 male Wistar rats were randomly assigned to mild ARDS induced by either intratracheal (n = 28, ARDSp) or intraperitoneal (n = 28, ARDSexp) administration of E. coli lipopolysaccharide. Four animals with no lung injury served as controls (NI). After 24 hours, animals were anesthetized, mechanically ventilated in pressure-controlled mode with low tidal volume (6 mL/kg), and randomly assigned to receive salbutamol (SALB) or saline 0.9% (CTRL), intravenously (i.v., 10 μg/kg/h) or intratracheally (bolus, 25 μg). Salbutamol doses were targeted at an increase of ≈ 20% in heart rate. Hemodynamics, lung mechanics, and arterial blood gases were measured before and after (at 30 and 60 min) salbutamol administration. At the end of the experiment, lungs were extracted for analysis of lung histology and molecular biology analysis. Values are expressed as mean ± standard deviation, and fold changes relative to NI, CTRL vs. SALB.Results
The gene expression of ion channels and aquaporin was increased in mild ARDSp, but not ARDSexp. In ARDSp, intravenous salbutamol resulted in higher gene expression of alveolar epithelial sodium channel (0.20 ± 0.07 vs. 0.68 ± 0.24, p < 0.001), aquaporin-1 (0.44 ± 0.09 vs. 0.96 ± 0.12, p < 0.001) aquaporin-3 (0.31 ± 0.12 vs. 0.93 ± 0.20, p < 0.001), and Na-K-ATPase-α (0.39 ± 0.08 vs. 0.92 ± 0.12, p < 0.001), whereas intratracheal salbutamol increased the gene expression of aquaporin-1 (0.46 ± 0.11 vs. 0.92 ± 0.06, p < 0.001) and Na-K-ATPase-α (0.32 ± 0.07 vs. 0.58 ± 0.15, p < 0.001). In ARDSexp, the gene expression of ion channels and aquaporin was not influenced by salbutamol. Morphological and functional variables and edema formation were not affected by salbutamol in any of the ARDS groups, regardless of the route of administration.Conclusion
Salbutamol administration increased the expression of alveolar epithelial ion channels and aquaporin in mild ARDSp, but not ARDSexp, with no effects on lung morphology and function or edema formation. These results may contribute to explain the negative effects of β2-agonists on clinical outcome in ARDS. 相似文献63.
64.
Responses of acutely isolated neurons from the rostral nucleus of the
solitary tract (rNST) to GABA receptor agonists and antagonists were
investigated using whole-cell recording in current clamp mode. The isolated
neurons retain their morphology and can be divided into multipolar,
elongate and ovoid cell types. Most rNST neurons (97%), including all three
cell types, respond to GABA with membrane hyperpolarization and a reduction
in input resistance. The GABA(A) receptor agonist muscimol reduces neuronal
input resistance in a concentration-dependent manner, whereas the GABA(B)
receptor agonist baclofen had no effect on any of the neurons tested. The
GABA and muscimol reversal potentials were both found to be -75 mV Both the
GABA competitive antagonist picrotoxin and the GABA(A) receptor antagonist
bicuculline block the effect of GABA in a concentration-dependent manner.
These results suggest that GABA activates all neurons in the rNST and that
inhibitory synaptic activity is important in brainstem processing of
gustatory and somatosensory information.
相似文献
65.
Replacement of receptor cells in the hamster vomeronasal epithelium after nerve transection 总被引:1,自引:1,他引:0
Chemoreceptor cells in the vomeronasal and olfactory epithelium are
replaced following experimentally induced degeneration. This study analyzes
quantitatively the time course and degree of vomeronasal receptor cell
replacement. Unilateral transection of the vomeronasal nerves in adult
hamster was used to induce a retrograde degeneration of receptor cells in
the vomeronasal organ. Histological measurement of both number of receptor
cells and epithelial thickness were made for recovery times from 0 to 60
days. After nerve transection, there was a gradual degeneration of receptor
cells, the number decreasing to 50% of control by day 2 and 16% by day 6.
During days 7-15 maximum receptor cell replacement was observed. Cell
number increased rapidly and reached a peak on day 15. At recovery times of
40-60 days, cell number returned to the control level. Epithelial
thickness, however, decreased to 60-70% during the degeneration period
(days 4-6) and did not return to control levels. After 40-60 days
epithelial thickness remained at 70% of control. These results demonstrate
that vomeronasal receptor cells are replaced following degeneration, but
epithelial thickness does not return to control levels. These findings
suggest that the number of replacement cells is not limited by the reduced
thickness of the epithelium, and that recovery mechanisms may function to
restore an optimum number of receptor cells.
相似文献
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