Changes induced by malathion, methylparathion and parathion on membrane lipid physicochemical properties correlate with their toxicity

Perturbations induced by malathion, methylparathion and parathion on the physicochemical properties of dipalmitoylphosphatidylcholine (DPPC) were studied by fluorescence anisotropy of DPH and DPH-PA and by differential scanning calorimetry (DSC). Methylparathion and parathion (50 [mu]M) increased the fluorescence anisotropy evaluated by DPH-PA and DPH, either in gel or in the fluid phase of DPPC bilayers, but mainly in the fluid phase. Parathion is more effective than methylparathion. On the other hand, malathion had almost no effect. All the three xenobiotics displaced the phase transition midpoint to lower temperature values and broadened the phase transition profile of DPPC, the effectiveness following the sequence: parathion>methylparathion>>malathion. A shifting and broadening of the phase transition was also observed by DSC. Furthermore, at methylparathion/lipid molar ratio of 1/2 and at parathion/lipid molar ratio of 1/7, the DSC thermograms displayed a shoulder in the main peak, in the low temperature side, suggesting coexistence of phases. For higher ratios, the phase transition profile becomes sharp as the control transition, but the midpoint is shifted to the previous shoulder position. Conversely to methylparathion and parathion, malathion did not promote phase separation. The overall data from fluorescence anisotropy and calorimetry indicate that the degree of effect of the insecticides on the physicochemical membrane properties correlates with toxicity to mammals. Therefore, the in vivo effects of organophosphorus compounds may be in part related with their ability to perturb the phospholipid bilayer structure, whose integrity is essential for normal cell function.http://www.sciencedirect.com/science/article/B6T1T-42NY32W-K/1/9c5c8320a8dff42bbf122281b5056b8

Lipid composition and dynamics of cell membranes of Bacillus stearothermophilus adapted to amiodarone

Bacillus stearothermophilus, a useful model to evaluate membrane interactions of lipophilic drugs, adapts to the presence of amiodarone in the growth medium. Drug concentrations in the range of 1-2 [mu]M depress growth and 3 [mu]M completely suppresses growth. Adaptation to the presence of amiodarone is reflected in lipid composition changes either in the phospholipid classes or in the acyl chain moieties. Significant changes are observed at 2 [mu]M and expressed by a decrease of phosphatidylethanolamine (relative decrease of 23.3%) and phosphatidylglycerol (17.9%) and by the increase of phosphoglycolipid (162%). The changes in phospholipid acyl chains are expressed by a decrease of straight-chain saturated fatty acids (relative decrease of 12.2%) and anteiso-acids (22%) with a parallel increase of the iso-acids (9.8%). Consequently, the ratio straight-chain/branched iso-chain fatty acids decreases from 0.38 (control cultures) to 0.30 (cultures adapted to 2 [mu]M amiodarone). The physical consequences of the lipid composition changes induced by the drug were studied by fluorescence polarization of diphenylhexatriene and diphenylhexatriene-propionic acid, and by differential scanning calorimetry. The thermotropic profiles of polar lipid dispersions of amiodarone-adapted cells are more similar to control cultures (without amiodarone) than those resulting from a direct interaction of the drug with lipids, i.e., when amiodarone was added directly to liposome suspensions. It is suggested that lipid composition changes promoted by amiodarone occur as adaptations to drug tolerance, providing the membrane with physico-chemical properties compatible with membrane function, counteracting the effects of the drug.http://www.sciencedirect.com/science/article/B6VNN-419BF60-K/1/8f2d4fae7f9c131d26230cf4123da94

Utility of Pacemaker With Sleep Apnea Monitor to Predict Left Ventricular Overload and Acute Decompensated Heart Failure

Pacemakers with sleep apnea monitor (SAM) provide an easy tool to assess obstructive sleep apnea over long periods of time. The link between respiratory disturbances at night and the incidence of acute decompensated heart failure (ADHF) is not well established. We aimed at (1) determining the ability of SAM pacemakers to evaluate the extent of left ventricular overload and (2) assess the impact of respiratory disturbances at night on the occurrence of ADHF over 1-year of follow-up. We conducted a single-center prospective study. Consecutive patients with SAM pacemakers were comprehensively assessed. SAM automatically computes a respiratory disturbance index (RDI, apneas/hypopneas per hour - AH/h) in the previous night and the percentage of nights with RDI >20 AH/h in the previous 6 months. Thirty-seven patients were included (79.3 ± 11.2 years, 46% males). A high RDI in the previous night and a higher %nights with increased RDI were associated with increased NT-proBNP values (p = 0.008 and p = 0.013, respectively) and were the sole predictors of increased noninvasive pulmonary capillary wedge pressures (PCWP) in the morning of assessment (p = 0.031 and p = 0.044, respectively). Receiver operating characteristic curve analysis revealed an area under the curve of 0.804 (95% confidence interval 0.656 to 0.953, p = 0.002) for %nights with RDI >20 AH/h in the prediction of high PCWP. Patients with >12.5% of nights with RDI >20AH/h tended to have more ADHF during follow-up (log-rank p = 0.067). In conclusion, a high burden of apneas/hypopneas at night is associated with elevated NT-proBNP and PCWP values and an increased risk of ADHF over 1 year. These patients might benefit from early tailored clinical management

Ethylazinphos Interaction with Membrane Lipid Organization Induces Increase of Proton Permeability and Impairment of Mitochondrial Bioenergetic Functions

Ethylazinphos increases the passive proton permeability of lipid bilayers reconstituted with dipalmitoylphosphatidylcholine (DPPC) and mitochondrial lipids. A sharp increase of proton permeability is detected at insecticide/lipid molar ratios identical to those inducing phase separation in the plane of DPPC bilayers, as revealed by differential scanning calorimetry (DSC). Ethylazinphos progressively depresses the transmembrane potential ([Delta][Psi]) of mitochondria supported by piruvate/malate, succinate, or ascorbate/TMPD. Additionally, a decreased depolarization induced by ADP depends on ethylazinphos concentration, reflecting a phosphorylation depression. This loss of phosphorylation is a consequence of a decreased [Delta][Psi]. A decreased respiratory control ratio is also observed, since ethylazinphos stimulates state 4 respiration and inhibits ADP-stimulated respiration (state 3). Ethylazinphos concentrations up to 100 nmol/mg mitochondrial protein increase the rate of state 4 together with a decrease in [Delta][Psi], without significant perturbation of state 3 and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled respiration. For increased insecticide concentrations, the state 3 and FCCP-uncoupled respiration are inhibited to approximately the same extent. The perturbations are more pronounced when the energization is supported by pyruvate/malate and less effective when succinate is used as substrate. The present data, in association with previous DSC studies, indicate that ethylazinphos, at concentrations up to 100 nmol/mg mitochondrial protein, interacts with the lipid bilayer of mitochondrial membrane, changing the lipid organization and increasing the proton permeability of the inner membrane. The increased proton permeability explains the decreased oxidative phosphorylation coupling. Resulting disturbed ATP synthesis may significantly underlie the mechanisms of ethylazinphos toxicity, since most of cell energy in eukaryotes is provided by mitochondria.http://www.sciencedirect.com/science/article/B6WXH-45BBYFP-25/1/8df8835c5305825c596440b25248b30

Ethylazinphos Interaction with Membrane Lipid Organization Induces Increase of Proton Permeability and Impairment of Mitochondrial Bioenergetic Functions

Ethylazinphos increases the passive proton permeability of lipid bilayers reconstituted with dipalmitoylphosphatidylcholine (DPPC) and mitochondrial lipids. A sharp increase of proton permeability is detected at insecticide/lipid molar ratios identical to those inducing phase separation in the plane of DPPC bilayers, as revealed by differential scanning calorimetry (DSC). Ethylazinphos progressively depresses the transmembrane potential ([Delta][Psi]) of mitochondria supported by piruvate/malate, succinate, or ascorbate/TMPD. Additionally, a decreased depolarization induced by ADP depends on ethylazinphos concentration, reflecting a phosphorylation depression. This loss of phosphorylation is a consequence of a decreased [Delta][Psi]. A decreased respiratory control ratio is also observed, since ethylazinphos stimulates state 4 respiration and inhibits ADP-stimulated respiration (state 3). Ethylazinphos concentrations up to 100 nmol/mg mitochondrial protein increase the rate of state 4 together with a decrease in [Delta][Psi], without significant perturbation of state 3 and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled respiration. For increased insecticide concentrations, the state 3 and FCCP-uncoupled respiration are inhibited to approximately the same extent. The perturbations are more pronounced when the energization is supported by pyruvate/malate and less effective when succinate is used as substrate. The present data, in association with previous DSC studies, indicate that ethylazinphos, at concentrations up to 100 nmol/mg mitochondrial protein, interacts with the lipid bilayer of mitochondrial membrane, changing the lipid organization and increasing the proton permeability of the inner membrane. The increased proton permeability explains the decreased oxidative phosphorylation coupling. Resulting disturbed ATP synthesis may significantly underlie the mechanisms of ethylazinphos toxicity, since most of cell energy in eukaryotes is provided by mitochondria.http://www.sciencedirect.com/science/article/B6WXH-45BBYFP-25/1/8df8835c5305825c596440b25248b30