Amiodarone effects on membrane organization evaluated by fluorescence polarization

Area of Science:

• Membrane biophysics
• Pharmacology
• Cardiovascular research

Background:

• Amiodarone is a widely used antiarrhythmic drug.
• Its effects on cell membrane physical properties are not fully understood.
• Membrane physical state influences drug efficacy and potential side effects.

Purpose of the Study:

• To investigate the impact of amiodarone on the physical state of synthetic and native cell membranes.
• To determine how cholesterol concentration modulates amiodarone's effects on membrane fluidity and order.
• To explore potential links between amiodarone-induced membrane changes and cardiac dysfunction.

Main Methods:

• Utilized fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene (DPH) and its derivative (DPH-PA) to probe membrane core and outer regions.
• Investigated effects on synthetic lipid bilayers (DMPC, DPPC) and native membranes (mitochondria, brain microsomes).
• Varied amiodarone concentrations and cholesterol content in lipid models.

Main Results:

• Amiodarone broadened phase transitions and lowered transition midpoints in DMPC gel phase bilayers.
• In fluid phases, amiodarone generally increased lipid order, an effect dependent on cholesterol concentration.
• High cholesterol levels (>20 mol%) reversed amiodarone's ordering effect, inducing disorder in synthetic and native membranes.

Conclusions:

• Amiodarone significantly alters membrane physical properties, influencing lipid order in a cholesterol-dependent manner.
• Observed ordering effects in mitochondria may lead to bioenergetic disturbances.
• These membrane alterations could contribute to the electromechanical dysfunction observed in the myocardium.