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Metabolic Inhibitor (metabolic + inhibitor)

Distribution by Scientific Domains

Medical Sciences	50%
Life Sciences	50%

Selected Abstracts

1-Methyl-4-phenylpridinium (MPP+)-induced functional run-down of GABAA receptor-mediated currents in acutely dissociated dopaminergic neurons

JOURNAL OF NEUROCHEMISTRY, Issue 1 2002
Jie Wu
Abstract We have evaluated GABAA receptor function during treatment of 1-methyl-4-phenylpridinium (MPP+) using patch-clamp perforated whole-cell recording techniques in acutely dissociated dopaminergic (DAergic) neurons from rat substantia nigra compacta (SNc). ,-Aminobutyric acid (GABA), glutamate or glycine induced inward currents (IGABA, IGlu, IGly) at a holding potential (VH) of ,45 mV. The IGABA was reversibly blocked by the GABAA receptor antagonist, bicuculline, suggesting that IGABA is mediated through the activation of GABAA receptors. During extracellular perfusion of MPP+ (1,10 ,m), IGABA, but neither IGlu nor IGly, declined (termed run-down) with repetitive agonist applications, indicating that the MPP+ -induced IGABA run-down occurred earlier than IGly or IGlu under our experimental conditions. The MPP+ -induced IGABA run-down can be prevented by a DA transporter inhibitor, mazindol, and can be mimicked by a metabolic inhibitor, rotenone. Using conventional whole-cell recording with different concentrations of ATP in the pipette solution, IGABA run-down can be induced by decreasing intracellular ATP concentrations, or prevented by supplying intracellular ATP, indicating that IGABA run-down is dependent on intracellular ATP concentrations. A GABAA receptor positive modulator, pentobarbital (PB), potentiated the declined IGABA and eliminated IGABA run-down. Corresponding to these patch-clamp data, tyrosine hydroxylase (TH) immunohistochemical staining showed that TH-positive cell loss was protected by PB during MPP+ perfusion. It is concluded that extracellular perfusion of MPP+ induces a functional run-down of GABAA receptors, which may cause an imbalance of excitation and inhibition of DAergic neurons. [source]

Mercury hinders recovery of shoot hydraulic conductivity during grapevine rehydration: evidence from a whole-plant approach

NEW PHYTOLOGIST, Issue 3 2006
Claudio Lovisolo
Summary ,,This experiment aimed to test whether recovery of shoot hydraulic conductivity after drought depends on cellular metabolism in addition to xylem hydraulics. ,,We rehydrated droughted grapevines (Vitis vinifera) after treating intact plants through the root with 0.5 mm mercuric chloride (a metabolic inhibitor) at the end of the stress period, before rehydration. The contribution of mercury-inhibited water transport in both shoot and root, and the extent of shoot vessel embolization, were assessed. ,,Drought stress decreased plant water potential and induced embolization of the shoot vessels. The rehydration in Hg-untreated plants re-established both shoot water potential and specific shoot hydraulic conductivity (Kss) at levels comparable with watered controls, and induced recovery of most of the embolisms formed in the shoot during the drought. In contrast, in plants treated with HgCl2, recovery of Kss and root hydraulic conductance were impaired. In rehydrated, Hg-treated plants, the effects of Hg on Kss were reversed when either the shoot or the root was treated with 60 mm,-mercaptoethanol as a mercuric scavenger. ,,This work suggests that plant cellular metabolism, sensitive to mercuric chloride, affects the recovery of shoot hydraulic conductivity during grapevine rehydration by interfering with embolism removal, and that it involves either the root or the shoot level. [source]

Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2006
R. Bains
Background:, The mitochondrial membrane potential (,,m) controls the generation of adenosine triphosphate (ATP) and reactive oxygen species, and sequesteration of intracellular Ca2+[Ca2+]i. Clinical concentrations of sevoflurane affect the ,,m in neural mitochondria, but the mechanisms remain elusive. The aim of the present study was to compare the effect of isoflurane and sevoflurane on ,,m in rat pre-synaptic terminals (synaptosomes), and to investigate whether these agents affect ,,m by inhibiting the respiratory chain. Methods:, Synaptosomes were loaded with the fluorescent probes JC-1 (,,m) and Fura-2 ([Ca2+]i) and exposed to isoflurane or sevoflurane. The effect of the anaesthetics on the electron transport chain was investigated by blocking complex I and complex V. Results:, Isoflurane 1 and 2 minimum alveolar concentration (MAC) decreased the normalized JC-1 ratio from 0.92 ± 0.03 in control to 0.86 ± 0.02 and 0.81 ± 0.01, respectively, reflecting a depolarization of the mitochondrial membrane (n = 9). Isoflurane 2 MAC increased [Ca2+]i. In Ca2+ -depleted medium, isoflurane still decreased ,,m while [Ca2+]i remained unaltered. The effect of isoflurane was more pronounced than for sevoflurane. Blocking complex V of the respiratory chain enhanced the isoflurane- and sevoflurane-induced mitochondrial depolarization, whereas blocking complex I and V decreased ,,m to the same extent in control, isoflurane and sevoflurane experiments. Conclusions:, Isoflurane and sevoflurane may act as metabolic inhibitors by depolarizing pre-synaptic mitochondria through inhibition of the electron transport chain, although isoflurane seems to inhibit mitochondrial function more significantly than sevoflurane. Both agents inhibit the respiratory chain sufficiently to cause ATP synthase reversal. [source]

The In Vivo Response of Novel Buprenorphine Metabolites, M1 and M3, to Antiretroviral Inducers and Inhibitors of Buprenorphine Metabolism

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2009
David E. Moody
The identification of two, M1 and M3, in urine suggests that they may be quantitatively significant metabolites. To further understand the in vivo regulation of this mode of metabolism, we evaluated 24-hr urine from subjects (10 per treatment group) on buprenorphine alone or with the antiretroviral agents: efavirenz, delavirdine, nelfinavir, ritonavir, and lopinavir/ritonavir. Quantitative analysis for buprenorphine and traditional metabolites and semi-quantitative analysis of M1 and M3 in urine were performed by liquid chromatography-electrospray ionization-tandem mass spectrometry. The renal clearance of buprenorphine and traditional metabolites were similar for all treatments except for lopinavir/ritonavir, suggesting that urine amounts of M1 and M3 would adequately reflect systemic changes (except lopinavir/ritonavir). Efavirenz decreased M1 and increased M3 consistent with its ability to induce cytochrome P450 (CYP) 3A. Delavirdine increased M1 and decreased M3 consistent with its ability to inhibit CYP3A. Both nelfinavir and ritonavir decreased both M1 and M3, consistent with their ability to inhibit CYP3A and 2C8. These results provide further information on the in vivo response of novel secondary metabolites of buprenorphine to metabolic inhibitors and inducers. [source]