[Membrane biophysical interaction of amlodipine and antioxidant properties].
OBJECTIVE
To assess the potential benefits of the antioxidant activity of certain pharmacological agents that may be beneficial in the treatment of cardiovascular disease, including coronary heart disease and heart failure, by reducing irreversible cell injury due to oxyradical damage.


METHODS
The antioxidant activities of representative calcium antagonists were examined and correlated with the molecular membrane interactions of the compounds, as measured by radioligand binding assays and high resolution differential scanning calorimetry.


RESULTS
The results of these experiments show a direct relationship between the antioxidant activities of the calcium antagonists and their affinity for the membrane lipid bilayer, as well as their ability to modulate membrane thermodynamic properties (amlodipine > verapamil >> diltiazem). The charged 1,4-dihydropyridine calcium antagonist amlodipine had the highest affinity for the membrane bilayer (Kp10(4)) and produced the largest changes in membrane thermodynamic properties, including a reduction in the thermal phase transition temperature (-11%), enthalpy (-14%) and cooperative unit size (-59%), relative to control phosphatidylcholine liposomes.


CONCLUSIONS
These findings indicate that lipophilic calcium antagonists inhibit lipid peroxidation in cellular membranes as a result of modulating physicochemical properties of the membrane lipid bilayer, independently of calcium channel inhibition. The antioxidant activity of highly lipophilic calcium antagonists, such as amlodipine, may contribute to new cytoprotective mechanisms of action in cardiovascular disease.
Mason
R P
RP
Département de Médecine et de Biochimie, MCP Hahnemann University School of Medicine, Pittsburg, Pennsylvania, USA. Mason@pgh.auhs.edu
Trumbore
M W
MW
Mason
P E
PE
D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D015227:Lipid Peroxidation; D008297:Male; D008861:Microsomes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013816:Thermodynamics
D000975:Antioxidants; D002121:Calcium Channel Blockers; D017311:Amlodipine