Favorable amphiphilicity of nimodipine facilitates its interactions with brain membranes.
Nimodipine is a 1,4-dihydropyridine (DHP) calcium channel blocker which is used in the treatment of neurological deficits associated with subarachnoid hemorrhage. Small angle x-ray diffraction, differential scanning calorimetry, and equilibrium and kinetic binding techniques were used to study the interaction of nimodipine with bovine brain phosphatidylcholine (BBPC) membranes of varying cholesterol content. At concentrations (5 x 10(-10) M) near its Kd, the membrane partition coefficient of nimodipine was inversely related to the cholesterol to phospholipid (C:P) mole ratio in both model and native (rat synaptoneurosome) membranes. The nonspecific dissociation rate of nimodipine from BBPC was significantly slower at low C:P mole ratio (0.1:1) than at high C:P mole ratio (0.6:1). Calorimetric analysis showed that nimodipine decreased both the main phase transition temperature and cooperative unit size of melt for dimyristoyl phosphatidylcholine, dependent on membrane cholesterol content. Small angle x-ray diffraction analysis showed that nimodipine occupies a position in BBPC approx +/- 15 A from the center of the hydrocarbon core, near the hydrocarbon core/water interface. These data indicate that nimodipine is an amphiphilic molecule which rapidly washes out of and transports across membrane bilayers, facilitating its interactions with membranes and possibly its transport across the blood-brain barrier.
Department of Biochemistry, University of Connecticut Health Center, Farmington 06030.
L G
LG
Herbette
P E
PE
Mason
K R
KR
Sweeney
M W
MW
Trumbore
R P
RP
Mason
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002152:Calorimetry, Differential Scanning; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008563:Membrane Lipids / Q000737:chemistry*; D008961:Models, Structural; D009553:Nimodipine / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D008563:Membrane Lipids; D009553:Nimodipine