Linked Life Data

11790774

Source:http://linkedlifedata.com/resource/pubmed/id/11790774

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2002-4-1
pubmed:abstractText
We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mm or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca(2+), release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca(2+) dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
12221-7
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:11790774-Anesthetics, Local, pubmed-meshheading:11790774-Animals, pubmed-meshheading:11790774-Bupivacaine, pubmed-meshheading:11790774-Calcium, pubmed-meshheading:11790774-Cell Membrane, pubmed-meshheading:11790774-Cyclosporine, pubmed-meshheading:11790774-Cytochrome c Group, pubmed-meshheading:11790774-Dose-Response Relationship, Drug, pubmed-meshheading:11790774-Esophagus, pubmed-meshheading:11790774-Hydrogen-Ion Concentration, pubmed-meshheading:11790774-Microscopy, Fluorescence, pubmed-meshheading:11790774-Mitochondria, pubmed-meshheading:11790774-Muscle, Skeletal, pubmed-meshheading:11790774-Muscle Fibers, Skeletal, pubmed-meshheading:11790774-Oxygen, pubmed-meshheading:11790774-Oxygen Consumption, pubmed-meshheading:11790774-Rats, pubmed-meshheading:11790774-Rats, Wistar, pubmed-meshheading:11790774-Time Factors
pubmed:year
2002
pubmed:articleTitle
Bupivacaine myotoxicity is mediated by mitochondria.
pubmed:affiliation
Department of Biomedical Sciences, University of Padova and the Consiglio Nazionale delle Ricerche Units for the Study of Muscle Pathophysiology and Biomembranes, Viale Giuseppe Colombo 3, I-35121 Padova, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't