Local anesthetics structure-dependently interact with anionic phospholipid membranes to modify the fluidity
Hironori Tsuchiya1, Takahiro Ueno, Maki Mizogami
1Department of Dental Basic Education, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan. hiro@dent.asahi-u.ac.jp
Chemico-Biological Interactions
|October 27, 2009
Summary
Bupivacaine
Area of Science:
- Pharmacology
- Biochemistry
- Membrane Biophysics
Background:
- Bupivacaine exhibits higher cardiotoxicity than other local anesthetics, but the underlying mechanisms are not fully understood.
- Cardiotoxic compounds can alter cell membrane properties by interacting with lipid bilayers.
- Investigating local anesthetic interactions with lipid membranes may elucidate structure-selective cardiotoxicity.
Purpose of the Study:
- To comparatively study the interaction of amide local anesthetics with lipid membranous systems.
- To determine the relationship between local anesthetic interaction with membranes and their cardiotoxicity.
Main Methods:
- Amide local anesthetics were reacted with unilamellar vesicles of varying lipid compositions.
- Membrane fluidity modification was measured using fluorescence polarization.
- Interactions were studied in biomimetic membranes mimicking cardiomyocyte mitochondrial membranes.
Main Results:
- Local anesthetics increased membrane fluidity; this effect was enhanced by anionic phospholipids, particularly cardiolipin.
- Bupivacaine showed the strongest interaction with cardiolipin-containing membranes, correlating with its known cardiotoxicity.
- Bupivacaine significantly fluidized cardiolipin-containing membranes at cardiotoxicologically relevant concentrations.
Conclusions:
- Bupivacaine's cardiotoxicity may stem from its interaction with cardiolipin in mitochondrial membranes.
- Electrostatic and hydrophobic interactions with cardiolipin and phospholipid acyl chains are proposed mechanisms.
- This structure-dependent membrane interaction provides a mechanistic insight into local anesthetic-selective cardiotoxicity.
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