Absence of Stereospecific Effects of Bupivacaine Isomers on Heart Mitochondrial Bioenergetics

2000 ◽  
Vol 93 (2) ◽  
pp. 456-462 ◽  
Author(s):  
François Sztark ◽  
Karine Nouette-Gaulain ◽  
Monique Malgat ◽  
Philippe Dabadie ◽  
Jean-Pierre Mazat
Keyword(s):  
Oxidative Phosphorylation ◽  
Adenosine Triphosphate ◽  
Respiratory Chain ◽  
Local Anesthetics ◽  
Complex I ◽  
Metabolic Effects ◽  
Lipid Solubility ◽  
Mitochondrial Bioenergetics ◽  
Myocardial Depression ◽  
Mitochondrial Energy Metabolism

Background Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could, in part, explain some toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The purpose of this study was to compare the optically pure isomers of bupivacaine on heart mitochondrial bioenergetics. Methods Both bupivacaine enantiomers were tested on rat heart isolated mitochondria. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the four complexes of the respiratory chain were measured. Results No significant differences were found between R(+)- and S(-)-bupivacaine on mitochondrial oxidative phosphorylation with a similar dose-dependent decrease in adenosine triphosphate synthesis. Complex I (nicotinamide adenine dinucleotide ubiquinone reductase) was the enzymatic complex of the respiratory chain most sensitive to the bupivacaine isomers. Half-inhibitory concentrations for R(+)- and S(-)-bupivacaine were not statistically different (3.3 +/- 0.4 mm and 2.8 +/- 0.6 mm, respectively). Conclusions No stereospecific effects of bupivacaine enantiomers were shown in the inhibition of complex I activity and uncoupling of oxidative phosphorylation. This can be correlated with the lack of stereospecific effects of bupivacaine on myocardial depression. The lipid solubility of local anesthetics appears to be the principal physicochemical factor affecting the potency of these tertiary amines on mitochondrial bioenergetics.

Comparison of the Effects of Bupivacaine and Ropivacaine on Heart Cell Mitochondrial Bioenergetics 

1998 ◽  
Vol 88 (5) ◽  
pp. 1340-1349 ◽  
Author(s):  
Francois Sztark ◽  
Monique Malgat ◽  
Philippe Dabadie ◽  
Jean-Pierre Mazat
Keyword(s):  
Oxygen Consumption ◽  
Energy Metabolism ◽  
Adenosine Triphosphate ◽  
Respiratory Chain ◽  
Local Anesthetics ◽  
Metabolic Effects ◽  
Lipid Solubility ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Energy Metabolism ◽  
Isolated Mitochondria

Background High lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could in part explain some of the toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The aim of this study was to compare the bioenergetic effects of the local anesthetics bupivacaine and ropivacaine. Methods The effects of both local anesthetics on mitochondrial energy metabolism were studied in rat heart isolated mitochondria and in saponin-skinned left ventricle fibers. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the complexes of the respiratory chain were measured. Results Bupivacaine and ropivacaine acted, in isolated mitochondria, as uncouplers between oxygen consumption and phosphorylation of adenosine diphosphate. Further, an inhibitory effect of mitochondrial respiration was evidenced with both anesthetics during maximal respiration and was assigned to a direct inhibition of complex I of the respiratory chain. Mitochondrial adenosine triphosphate synthesis was decreased by both mechanisms. However, both in isolated mitochondria and in permeabilized heart fibers, ropivacaine was less potent than bupivacaine. Adenosine triphosphate synthesis was completely suppressed at 3 mM (approximately 0.1%) bupivacaine, whereas 3 mM ropivacaine induced only about a 40% inhibition. Conclusions Ropivacaine disturbs mitochondrial energy metabolism less than bupivacaine does. The lower lipid solubility of ropivacaine may be responsible for the lesser dose-dependent effects of this drug on mitochondrial bioenergetics.

Mitochondrial Complex I Function Affects Halothane Sensitivity in Caenorhabditis elegans 

2004 ◽  
Vol 101 (2) ◽  
pp. 365-372 ◽  
Author(s):  
Ernst-Bernhard Kayser ◽  
Phil G. Morgan ◽  
Margaret M. Sedensky
Keyword(s):  
Caenorhabditis Elegans ◽  
Oxidative Phosphorylation ◽  
Oxidative Damage ◽  
Adenosine Triphosphate ◽  
Complex I ◽  
Volatile Anesthetics ◽  
Mitochondrial Proteins ◽  
Wild Type ◽  
Complex Ii ◽  
C Elegans

Background : The gene gas-1 encodes a subunit of complex I of the mitochondrial electron transport chain in Caenorhabditis elegans. A mutation in gas-1 profoundly increases sensitivity of C. elegans to volatile anesthetics. It is unclear which aspects of mitochondrial function account for the hypersensitivity of the mutant. Methods : Oxidative phosphorylation was determined by measuring mitochondrial oxygen consumption using electron donors specific for either complex I or complex II. Adenosine triphosphate concentrations were determined by measuring luciferase activity. Oxidative damage to mitochondrial proteins was identified using specific antibodies. Results : Halothane inhibited oxidative phosphorylation in isolated wild-type mitochondria within a concentration range that immobilizes intact worms. At equal halothane concentrations, complex I activity but not complex II activity was lower in mitochondria from mutant (gas-1) animals than from wild-type (N2) animals. The halothane concentrations needed to immobilize 50% of N2 or gas-1 animals, respectively, did not reduce oxidative phosphorylation to identical rates in the two strains. In air, adenosine triphosphate concentrations were similar for N2 and gas-1 but were decreased in the presence of halothane only in gas-1 animals. Oxygen tension changed the sensitivity of both strains to halothane. When nematodes were raised in room air, oxidative damage to mitochondrial proteins was increased in the mutant animal compared with the wild type. Conclusions : Rates of oxidative phosphorylation and changes in adenosine triphosphate concentrations by themselves do not control anesthetic-induced immobility of wild-type C. elegans. However, they may contribute to the increased sensitivity to volatile anesthetics of the gas-1 mutant. Oxidative damage to proteins may be an important contributor to sensitivity to volatile anesthetics in C. elegans.

A new insight into the molecular hydrogen effect on coenzyme Q and mitochondrial function of rats

2020 ◽  
Vol 98 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Anna Gvozdjáková ◽  
Jarmila Kucharská ◽  
Branislav Kura ◽  
Ol’ga Vančová ◽  
Zuzana Rausová ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Phosphorylation ◽  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Complex I ◽  
Molecular Hydrogen ◽  
Coenzyme Q ◽  
Complex Ii ◽  
Atp Production ◽  
Q Cycle

Mitochondria are the major source of cellular energy metabolism. In the cardiac cells, mitochondria produce by way of the oxidative phosphorylation more than 90% of the energy supply in the form of ATP, which is utilized in many ATP-dependent processes, like cycling of the contractile proteins or maintaining ion gradients. Reactive oxygen species (ROS) are by-products of cellular metabolism and their levels are controlled by intracellular antioxidant systems. Imbalance between ROS and the antioxidant defense leads to oxidative stress and oxidative changes to cellular biomolecules. Molecular hydrogen (H2) has been proved as beneficial in the prevention and therapy of various diseases including cardiovascular disorders. It selectively scavenges hydroxyl radical and peroxynitrite, reduces oxidative stress, and has anti-inflammatory and anti-apoptotic effects. The effect of H2 on the myocardial mitochondrial function and coenzyme Q levels is not well known. In this paper, we demonstrated that consumption of H2-rich water (HRW) resulted in stimulated rat cardiac mitochondrial electron respiratory chain function and increased levels of ATP production by Complex I and Complex II substrates. Similarly, coenzyme Q9 levels in the rat plasma, myocardial tissue, and mitochondria were increased and malondialdehyde level in plasma was reduced after HRW administration. Based on obtained data, we hypothesize a new metabolic pathway of the H2 effect in mitochondria on the Q-cycle and in mitochondrial respiratory chain function. The Q-cycle contains three coenzyme Q forms: coenzyme Q in oxidized form (ubiquinone), radical form (semiquinone), or reduced form (ubiquinol). H2 may be a donor of both electron and proton in the Q-cycle and thus we can suppose stimulation of coenzyme Q production. When ubiquinone is reduced to ubiquinol, lipid peroxidation is reduced. Increased CoQ9 concentration can stimulate electron transport from Complex I and Complex II to Complex III and increase ATP production via mitochondrial oxidative phosphorylation. Our results indicate that H2 may function to prevent/treat disease states with disrupted myocardial mitochondrial function.

Molecular Mechanisms of the Inhibitory Effects of Bupivacaine, Levobupivacaine, and Ropivacaine on Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channels in the Cardiovascular System

2004 ◽  
Vol 101 (2) ◽  
pp. 390-398 ◽  
Author(s):  
Takashi Kawano ◽  
Shuzo Oshita ◽  
Akira Takahashi ◽  
Yasuo Tsutsumi ◽  
Yoshinobu Tomiyama ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
Adenosine Triphosphate ◽  
Local Anesthetics ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Katp Channels ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
Sulfonylurea Receptor ◽  
Inhibitory Effects

Background Sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted KATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits. Methods The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted KATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs. Results Bupivacaine inhibited the activities of cardiac KATP channels (IC50 = 52 microm) stereoselectively (levobupivacaine, IC50 = 168 microm; ropivacaine, IC50 = 249 microm). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2 delta C36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac KATP channels with approximately eightfold higher potency than vascular KATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit. Conclusions Inhibitory effects of local anesthetics on KATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac KATP channels more potently than vascular KATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.

scholarly journals Relative Contribution of Different Mitochondrial Oxidative Phosphorylation Components to the Retinal Pigment Epithelium Barrier Function: Implications for RPE-Related Retinal Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8130
Author(s):  
Michael H. Guerra ◽  
Thangal Yumnamcha ◽  
Lalit P. Singh ◽  
Ahmed S. Ibrahim
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Barrier Function ◽  
Complex I ◽  
Retinal Pigment Epithelial ◽  
Retinal Pigment ◽  
Retinal Diseases ◽  
Dependent Manner ◽  
Pigment Epithelial ◽  
Dose Dependent

Disruption of retinal pigment epithelial (RPE) barrier integrity is involved in the pathology of several blinding retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy (DR), but the underlying causes and pathophysiology are not completely well-defined. Mitochondria dysfunction has often been considered as a potential candidate implicated in such a process. In this study, we aimed to dissect the role of different mitochondrial components; specifically, those of oxidative phosphorylation (OxPhos), in maintaining the barrier functionality of RPE. Electric cell-substrate impedance sensing (ECIS) technology was used to collect multi-frequency electrical impedance data to assess in real-time the barrier formation of the RPE cells. For this purpose, the human retinal pigment epithelial cell line—ARPE-19—was used and treated with varying concentrations of specific mitochondrial inhibitors that target different steps in OxPhos: Rotenone for complex I (the largest protein complex in the electron transport chain (ETC)); oligomycin for ATP synthase; and carbonyl cyanide-p-trifluoromethoxyphenyl hydrazone (FCCP) for uncoupling ATP synthesis from the accompanying ETC. Furthermore, data were modeled using the ECIS-Zθ software to investigate in depth the effects of these inhibitors on three separate barrier parameters: cell–cell interactions (Rb), cell–matrix interactions (α), and the cell membrane capacitance (Cm). The viability of ARPE-19 cells was determined by lactate dehydrogenase (LDH) Cytotoxicity Assay. The ECIS program’s modeling demonstrated that FCCP and thus OxPhos uncoupling disrupt the barrier function in the ARPE-19 cells across all three components of the total resistance (Rb, α, and Cm) in a dose-dependent manner. On the other hand, oligomycin and thus ATP synthase inhibition mostly affects the ARPE-19 cells' attachment to their substrate evident by a significant decrease in α resistance in a dose-dependent manner, both at the end and throughout the duration of the experiment. On the contrary, rotenone and complex I inhibition mostly affect the ARPE-19 paracellular resistance Rb in a dose-dependent manner compared to basolateral resistance α or Cm. Our results clearly demonstrate differential roles for different mitochondrial components in maintaining RPE cell functionality in which uncoupling of OxPhos is a major contributing factor to the disruption barrier function. Such differences can be used in investigating gene expression as well as for screening of selective agents that improve the OxPhos coupling efficiency to be used in the therapeutic approach for treating RPE-related retinal diseases.

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